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Lei ZJ, Ma YJ, Fan QQ, Wu ZX, Zheng YY, Sun G, Xi ZW, Shen C, Shen YM. Visible-Light-Mediated Three-Component Alkene 1,2-Alkylpyridylation Reaction Using Alkylboronic Acids as Radical Precursors for the Synthesis of 4-Alkylpyridines. J Org Chem 2025; 90:3563-3569. [PMID: 40029075 DOI: 10.1021/acs.joc.4c02600] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/05/2025]
Abstract
We report the photocatalyzed three-component alkene 1,2-alkylpyridylation reaction between alkylboronic acids, 4-cyanopyridine, and an olefin to achieve the pyridination and alkylation of the olefin and the synthesis of structurally diversified 4-alkylpyridines. The readily available and easily manipulated alkylboronic acids were used as alkyl radical precursors. The reactions take place under mild conditions with a broad substrate scope and are easy to scale up to gram level, and they are therefore of potential practical value for the synthesis and structural modification of biologically active alkylpyridine derivatives.
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Affiliation(s)
- Zi-Jun Lei
- School of Chemistry and Chemical Engineering, Zhejiang Sci-Tech University, Hangzhou, Zhejiang 310018, PR China
| | - Yi-Jian Ma
- School of Chemistry and Chemical Engineering, Zhejiang Sci-Tech University, Hangzhou, Zhejiang 310018, PR China
| | - Qian-Qian Fan
- School of Chemistry and Chemical Engineering, Zhejiang Sci-Tech University, Hangzhou, Zhejiang 310018, PR China
| | - Zhi-Xiong Wu
- School of Chemistry and Chemical Engineering, Zhejiang Sci-Tech University, Hangzhou, Zhejiang 310018, PR China
| | - Yi-Yang Zheng
- School of Chemistry and Chemical Engineering, Zhejiang Sci-Tech University, Hangzhou, Zhejiang 310018, PR China
| | - Guoming Sun
- Zhejiang Sci-Tech University Shengzhou Innovation Research Institute, Shengzhou 312400, PR China
| | - Zi-Wei Xi
- School of Chemistry and Chemical Engineering, Zhejiang Sci-Tech University, Hangzhou, Zhejiang 310018, PR China
- Zhejiang Sci-Tech University Shengzhou Innovation Research Institute, Shengzhou 312400, PR China
| | - Chengshuo Shen
- School of Chemistry and Chemical Engineering, Zhejiang Sci-Tech University, Hangzhou, Zhejiang 310018, PR China
- Zhejiang Sci-Tech University Shengzhou Innovation Research Institute, Shengzhou 312400, PR China
| | - Yong-Miao Shen
- School of Chemistry and Chemical Engineering, Zhejiang Sci-Tech University, Hangzhou, Zhejiang 310018, PR China
- Zhejiang Sci-Tech University Shengzhou Innovation Research Institute, Shengzhou 312400, PR China
- Key Laboratory of Excited-State Materials of Zhejiang Province, Zhejiang University, Hangzhou 310027, PR China
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Li J, Wang D, Duan Q, Su N, Li X, Qiu H. The efficacy of anti-angiogenic drugs in gastric-type endocervical adenocarcinoma: A retrospective study. J Obstet Gynaecol Res 2025; 51:e16247. [PMID: 39988602 DOI: 10.1111/jog.16247] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2024] [Accepted: 02/09/2025] [Indexed: 02/25/2025]
Abstract
OBJECTIVES Gastric-type endocervical adenocarcinoma (GEA) is a rare malignant tumor that is not associated with high-risk HPV infection, known for its high invasiveness and resistance to current treatments. This study assessed the effectiveness of anti-angiogenic regimens in real-world GEA patients. METHODS Patients with GEA were enrolled between February 2012 and March 2023, and their clinicopathological characteristics were collected from their medical records. The patients were categorized into groups based on whether they received anti-angiogenic treatments or not. Survival analysis was conducted using the Kaplan-Meier method. RESULTS A total of 43 GEA patients were enrolled in this study, with 23 cases who received anti-angiogenic drugs (nine received them as the primary treatment, 12 as first-line therapy after recurrence/metastasis, and two as second-line therapy) as the observation group. The other 20 patients who received similar treatments without the anti-angiogenic regimens serve as the control group. Compared to the control group, the addition of anti-angiogenic drugs as the primary treatment mildly extended progression-free survival (PFS) while not being statistically significant (16 months vs 11 months, p = 0.744). The negative results were also observed in 12 patients who started anti-angiogenic therapy as first-line therapy after recurrence/metastasis (8.5 months vs 9 months, p = 0.518). As for the overall survival (OS), no benefits were detected in either patients who started the anti-angiogenic therapy as primary or subsequent treatments (p = 0.499 and 0.450, respectively). CONCLUSION We firstly evaluated the efficacy of anti-angiogenic drugs in treating patients with GEA. Although with a small sample size, our preliminary results clearly proposed that the anti-angiogenic therapy failed in suppressing tumors and should not be a preferred choice for GEA. As a much rarer tumor without standard treatments, we herein warned of a pitfall for gynecologic oncologists when facing this malignancy.
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Affiliation(s)
- Jing Li
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China
| | - Dian Wang
- Department of Gynecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China
| | - Qing Duan
- Department of Gynecologic Oncology, Anyang Tumor Hospital, Anyang, Henan Province, China
| | - Ning Su
- Department of Gynecologic Oncology, The Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou, Henan Province, China
| | - Xiufang Li
- Department of Gynecologic Oncology, Anyang Tumor Hospital, Anyang, Henan Province, China
| | - Haifeng Qiu
- Department of Gynecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China
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Rahman I, Liang B, Sajid A, Ambudkar SV, Huang H. Photodynamic priming modulates cellular ATP levels to overcome P-glycoprotein-mediated drug efflux in chemoresistant triple-negative breast cancer. Photochem Photobiol 2025; 101:188-205. [PMID: 38824410 PMCID: PMC11737009 DOI: 10.1111/php.13970] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2024] [Revised: 05/13/2024] [Accepted: 05/14/2024] [Indexed: 06/03/2024]
Abstract
P-glycoprotein (P-gp, ABCB1) is a well-researched ATP-binding cassette (ABC) drug efflux transporter linked to the development of cancer multidrug resistance (MDR). Despite extensive studies, approved therapies to safely inhibit P-gp in clinical settings are lacking, necessitating innovative strategies beyond conventional inhibitors or antibodies to reverse MDR. Photodynamic therapy is a globally approved cancer treatment that uses targeted, harmless red light to activate non-toxic photosensitizers, confining its cytotoxic photochemical effects to disease sites while sparing healthy tissues. This study demonstrates that photodynamic priming (PDP), a sub-cytotoxic photodynamic therapy process, can inhibit P-gp function by modulating cellular respiration and ATP levels in light accessible regions. Using chemoresistant (VBL-MDA-MB-231) and chemosensitive (MDA-MB-231) triple-negative breast cancer cell lines, we showed that PDP decreases mitochondrial membrane potential by 54.4% ± 30.4 and reduces mitochondrial ATP production rates by 94.9% ± 3.46. Flow cytometry studies showed PDP can effectively improve the retention of P-gp substrates (calcein) by up to 228.4% ± 156.3 in chemoresistant VBL-MDA-MB-231 cells, but not in chemosensitive MDA-MB-231 cells. Further analysis revealed that PDP did not alter the cell surface expression level of P-gp in VBL-MDA-MB-231 cells. These findings indicate that PDP can reduce cellular ATP below the levels that is required for the function of P-gp and improve intracellular substrate retention. We propose that PDP in combination with chemotherapy drugs, might improve the efficacy of chemotherapy and overcome cancer MDR.
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Affiliation(s)
- Idrisa Rahman
- Fischell Department of BioengineeringUniversity of MarylandCollege ParkMarylandUSA
- Laboratory of Cell Biology, Center for Cancer ResearchNational Cancer Institute, National Institutes of HealthBethesdaMarylandUSA
| | - Barry Liang
- Fischell Department of BioengineeringUniversity of MarylandCollege ParkMarylandUSA
- Laboratory of Cell Biology, Center for Cancer ResearchNational Cancer Institute, National Institutes of HealthBethesdaMarylandUSA
| | - Andaleeb Sajid
- Laboratory of Cell Biology, Center for Cancer ResearchNational Cancer Institute, National Institutes of HealthBethesdaMarylandUSA
| | - Suresh V. Ambudkar
- Laboratory of Cell Biology, Center for Cancer ResearchNational Cancer Institute, National Institutes of HealthBethesdaMarylandUSA
| | - Huang‐Chiao Huang
- Fischell Department of BioengineeringUniversity of MarylandCollege ParkMarylandUSA
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Zuo L, Ling J, Hu N, Chen R. Establishment and validation of a population pharmacokinetic model for apatinib in patients with tumors. BMC Cancer 2024; 24:1346. [PMID: 39487410 PMCID: PMC11529441 DOI: 10.1186/s12885-024-13118-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2024] [Accepted: 10/28/2024] [Indexed: 11/04/2024] Open
Abstract
OBJECTIVE This study aimed to develop a population pharmacokinetic (PPK) model for oral apatinib in Chinese oncology patients and investigate the factors influencing the pharmacokinetics of apatinib. METHODS We gathered 199 blood concentration monitoring data points from 91 inpatient oncology participants receiving oral apatinib at the Third Affiliated Hospital of Soochow University. Covariates, such as age, gender, body weight, and indices of liver and renal function, were examined to assess their influence on the pharmacokinetic parameters of apatinib. The PPK model was developed using the nonlinear mixed-effects modeling procedure (NONMEM), and model validation was conducted using the bootstrap method and normalized prediction distribution error (NPDE) method. RESULTS The structural model adopted a one-compartment structure with first-order elimination. Notably, aspartate aminotransferase (AST) and the co-administered drug type emerged as primary covariates affecting apatinib clearance (CL/F). The finalized model was expressed as CL/F (L/h) = 56.7 × (AST/26.6)-0.298 × θ, when apatinib was combined with monoclonal antibodies, θ was 1; when combined with paclitaxel, θ was 0.58; when combined with other drugs (e.g., platinum, capecitabine, or the combination of tegafur, gimeracil, and oteracil potassium), θ was 1.60; When used as monotherapy, θ was 1.38. V/F = 674 L, and the absorption rate constant (Ka) was fixed at 0.08 h-1. Bootstrap results affirmed the model's reliability and stability, while NPDE outcomes attested to the model's fit. CONCLUSION Our study successfully established a PPK model for apatinib in oncology patients, revealing that liver function status and co-administered drug types significantly impacted apatinib CL/F. This finding underscored the potential necessity for dose adjustments to optimize efficacy, particularly in patients undergoing different chemotherapy regimens involving apatinib.
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Affiliation(s)
- Li'an Zuo
- Department of Pharmacy, The First People's Hospital of Changzhou, The Third Affiliated Hospital of Soochow University, Changzhou, Jiang Su, 213003, China
| | - Jing Ling
- Department of Pharmacy, The First People's Hospital of Changzhou, The Third Affiliated Hospital of Soochow University, Changzhou, Jiang Su, 213003, China
| | - Nan Hu
- Department of Pharmacy, The First People's Hospital of Changzhou, The Third Affiliated Hospital of Soochow University, Changzhou, Jiang Su, 213003, China
| | - Rong Chen
- Department of Pharmacy, The First People's Hospital of Changzhou, The Third Affiliated Hospital of Soochow University, Changzhou, Jiang Su, 213003, China.
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Li XQ, Yang J, Liu B, Han SM. Disitamab vedotin combined with apatinib in gastric cancer: A case report and review of literature. World J Clin Oncol 2024; 15:1351-1358. [DOI: 10.5306/wjco.v15.i10.1351] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2024] [Revised: 08/18/2024] [Accepted: 08/29/2024] [Indexed: 09/29/2024] Open
Abstract
BACKGROUND In patients with human epidermal growth factor receptor 2 (HER2)-overexpressing gastric cancer (GC), the combination of HER2 targeting and a standard first-line chemotherapy regimen has been demonstrated to significantly improve their prognosis. However, in a proportion of patients, cancer progresses within a short period of time, and there is currently no standard treatment after disease progression.
CASE SUMMARY This study presents a case of a 51-year-old male with advanced GC who underwent radical resection (Billroth type II subtotal gastrectomy and gastrojejunostomy) and resection of liver metastases. Immunohistochemical staining revealed a HER2 score of 2+, a dMMR status, and a Ki67 proliferation index of 30% to 40%. The gene test results indicated the presence of ERBB2 amplification and a PD-L1 expression level of less than 5%. Since December 2021, the patient has experienced disease progression during both first-line (two cycles of KN026 combined with KN046) and second-line (five cycles of nivolumab combined with trastuzumab and SOX chemotherapy) treatment regimens. The patient's prognosis following the first and second lines of treatment was unfavorable, with progression occurring in a relatively short time. For third-line therapy, disitamab vedotin (RC48) plus apatinib was used. At the time of this report, the patient had achieved a progression-free survival (PFS) of 25.8 months, which exceeded the median survival time for patients with advanced GC.
CONCLUSION Despite the unfavorable prognosis associated with advanced GC, the implementation of personalized treatment approaches may still prove beneficial for select patients. In patients with HER2-positive GC with extensive metastatic involvement, the use of the HER2-targeted combination with apatinib has demonstrated the potential to prolong both PFS and overall survival.
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Affiliation(s)
- Xiao-Qian Li
- Department of Medical Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan 510000, Shandong Province, China
| | - Jing Yang
- Department of Medical Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan 510000, Shandong Province, China
| | - Bo Liu
- Department of Medical Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan 510000, Shandong Province, China
| | - Shu-Mei Han
- Department of Medical Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan 510000, Shandong Province, China
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Ming Y, Gong Y, Fu X, Ouyang X, Peng Y, Pu W. Small-molecule-based targeted therapy in liver cancer. Mol Ther 2024; 32:3260-3287. [PMID: 39113358 PMCID: PMC11489561 DOI: 10.1016/j.ymthe.2024.08.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2023] [Revised: 03/13/2024] [Accepted: 08/02/2024] [Indexed: 08/23/2024] Open
Abstract
Liver cancer is one of the most prevalent malignant tumors worldwide. According to the Barcelona Clinic Liver Cancer staging criteria, clinical guidelines provide tutorials to clinical management of liver cancer at their individual stages. However, most patients diagnosed with liver cancer are at advanced stage; therefore, many researchers conduct investigations on targeted therapy, aiming to improve the overall survival of these patients. To date, small-molecule-based targeted therapies are highly recommended (first line: sorafenib and lenvatinib; second line: regorafenib and cabozantinib) by current the clinical guidelines of the American Society of Clinical Oncology, European Society for Medical Oncology, and National Comprehensive Cancer Network. Herein, we summarize the small-molecule-based targeted therapies in liver cancer, including the approved and preclinical therapies as well as the therapies under clinical trials, and introduce their history of discovery, clinical trials, indications, and molecular mechanisms. For drug resistance, the revealed mechanisms of action and the combination therapies are also discussed. In fact, the known small-molecule-based therapies still have limited clinical benefits to liver cancer patients. Therefore, we analyze the current status and give our ideas for the urgent issues and future directions in this field, suggesting clues for novel techniques in liver cancer treatment.
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Affiliation(s)
- Yue Ming
- Laboratory of Molecular Oncology, Frontiers Science Center for Disease-related Molecular Network, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610064, China
| | - Yanqiu Gong
- National Clinical Research Center for Geriatrics and Department of General Practice, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Xuewen Fu
- Jinhua Huanke Environmental Technology Co., Ltd., Jinhua 321000, China
| | - Xinyu Ouyang
- Laboratory of Molecular Oncology, Frontiers Science Center for Disease-related Molecular Network, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610064, China; West China School of Medicine, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Yong Peng
- Laboratory of Molecular Oncology, Frontiers Science Center for Disease-related Molecular Network, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610064, China; Frontier Medical Center, Tianfu Jincheng Laboratory, Chengdu 610212, China.
| | - Wenchen Pu
- Laboratory of Molecular Oncology, Frontiers Science Center for Disease-related Molecular Network, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610064, China; West China School of Medicine, West China Hospital, Sichuan University, Chengdu 610041, China.
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Ji N, Li H, Zhang Y, Li Y, Wang P, Chen X, Liu YN, Wang JQ, Yang Y, Chen ZS, Li Y, Wang R, Kong D. Lansoprazole (LPZ) reverses multidrug resistance (MDR) in cancer through impeding ATP-binding cassette (ABC) transporter-mediated chemotherapeutic drug efflux and lysosomal sequestration. Drug Resist Updat 2024; 76:101100. [PMID: 38885537 DOI: 10.1016/j.drup.2024.101100] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2024] [Revised: 05/21/2024] [Accepted: 05/30/2024] [Indexed: 06/20/2024]
Abstract
AIMS Lansoprazole is one of the many proton pump inhibitors (PPIs) that acts more strongly with ABCB1 and ABCG2. The present study is to investigate the potential of lansoprazole on reversal of ABCB1/G2-mediated MDR in cancer, in vitro and in vivo. METHODS Reversal studies and combination evaluation were conducted to determine the synergistic anti-MDR effects on lansoprazole. Lysosomal staining was used to determination of lansoprazole on ABCB1-mediated lysosomal sequestration. Substrate accumulation and efflux assays, ATPase activity, and molecular docking were conducted to evaluate lansoprazole on ABCB1/G2 functions. Western blot and immunofluorescence were used to detect lansoprazole on ABCB1/G2 expression and subcellular localization. MDR nude mice models were established to evaluate the effects of lansoprazole on MDR in vivo. RESULTS Lansoprazole attenuated ABCB1/G2-mediated MDR and exhibited synergistic effects with substrate drugs in MDR cells. In vivo experiments demonstrated that lansoprazole attenuated ABCB1/G2-mediated MDR and exhibited synergistic effects that augmented the sensitivity of substrate anticancer drugs in ABCB1/G2-mediated settings without obvious toxicity. Lansoprazole impeded lysosomal sequestration mediated by ABCB1, leading to a substantial increase in intracellular accumulation of substrate drugs. The effects of lansoprazole were not attributable to downregulation or alterations in subcellular localization of ABCB1/G2. Lansoprazole promoted the ATPase activity of ABCB1/G2 and competitively bound to the substrate-binding region of ABCB1/G2. CONCLUSIONS These findings present novel therapeutic avenues whereby the combination of lansoprazole and chemotherapeutic agents mitigates MDR mediated by ABCB1/G2 overexpression.
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MESH Headings
- Animals
- Humans
- Mice
- Antineoplastic Agents/pharmacology
- ATP Binding Cassette Transporter, Subfamily B/metabolism
- ATP Binding Cassette Transporter, Subfamily B/genetics
- ATP Binding Cassette Transporter, Subfamily G, Member 2/metabolism
- ATP Binding Cassette Transporter, Subfamily G, Member 2/genetics
- Cell Line, Tumor
- Drug Resistance, Multiple/drug effects
- Drug Resistance, Neoplasm/drug effects
- Lansoprazole/pharmacology
- Lysosomes/metabolism
- Lysosomes/drug effects
- Mice, Nude
- Molecular Docking Simulation
- Neoplasm Proteins
- Neoplasms/drug therapy
- Neoplasms/metabolism
- Neoplasms/pathology
- Proton Pump Inhibitors/pharmacology
- Xenograft Model Antitumor Assays
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Affiliation(s)
- Ning Ji
- Tianjin Key Laboratory of Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, National Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Tianjin 300060, China; Tianjin Medical University, Tianjin 300070, China
| | - Hui Li
- Tianjin Key Laboratory of Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, National Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Tianjin 300060, China; Tianjin Medical University, Tianjin 300070, China; Key Laboratory of Immune Microenvironment and Diseases (Ministry of Education), Tianjin Medical University, Tianjin 300070, China
| | - Yixuan Zhang
- Tianjin Key Laboratory of Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, National Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Tianjin 300060, China; Tianjin Medical University, Tianjin 300070, China; Key Laboratory of Immune Microenvironment and Diseases (Ministry of Education), Tianjin Medical University, Tianjin 300070, China
| | - Yuelin Li
- Tianjin Key Laboratory of Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, National Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Tianjin 300060, China; Tianjin Medical University, Tianjin 300070, China; Key Laboratory of Immune Microenvironment and Diseases (Ministry of Education), Tianjin Medical University, Tianjin 300070, China
| | - Peiyu Wang
- Tianjin Key Laboratory of Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, National Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Tianjin 300060, China; Tianjin Medical University, Tianjin 300070, China; Key Laboratory of Immune Microenvironment and Diseases (Ministry of Education), Tianjin Medical University, Tianjin 300070, China
| | - Xin Chen
- Tianjin Key Laboratory of Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, National Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Tianjin 300060, China; Tianjin Medical University, Tianjin 300070, China; Key Laboratory of Immune Microenvironment and Diseases (Ministry of Education), Tianjin Medical University, Tianjin 300070, China
| | - Yi-Nan Liu
- Tianjin Key Laboratory of Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, National Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Tianjin 300060, China; Tianjin Medical University, Tianjin 300070, China; Key Laboratory of Immune Microenvironment and Diseases (Ministry of Education), Tianjin Medical University, Tianjin 300070, China
| | - Jing-Quan Wang
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USA
| | - Yuqi Yang
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USA
| | - Zhe-Sheng Chen
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USA
| | - Yueguo Li
- Tianjin Key Laboratory of Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, National Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Tianjin 300060, China; Tianjin Medical University, Tianjin 300070, China.
| | - Ran Wang
- Tianjin Key Laboratory of Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, National Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Tianjin 300060, China; Tianjin Medical University, Tianjin 300070, China; Key Laboratory of Immune Microenvironment and Diseases (Ministry of Education), Tianjin Medical University, Tianjin 300070, China.
| | - Dexin Kong
- Tianjin Key Laboratory of Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, National Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Tianjin 300060, China; Tianjin Medical University, Tianjin 300070, China; Key Laboratory of Immune Microenvironment and Diseases (Ministry of Education), Tianjin Medical University, Tianjin 300070, China.
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Cai Q, Hu K, Dong S, Li X, Hu S, Deng W, Ou W. Tumor cavitation in patients with non-small-cell lung cancer receiving anti-angiogenic therapy with apatinib. Transl Lung Cancer Res 2024; 13:1708-1717. [PMID: 39118887 PMCID: PMC11304154 DOI: 10.21037/tlcr-24-465] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2024] [Accepted: 07/04/2024] [Indexed: 08/10/2024]
Abstract
Background Cavities have been reported in approximately 20% of lung cancer after anti-angiogenesis treatments. However, the effect of which on treatment outcomes remains unclear. This study sought to investigate the incidence and radiographic patterns of tumor cavitation in patients with non-small cell lung cancer (NSCLC) treated with apatinib, and its associations with patients' clinical characteristics and outcomes. Methods A total of 300 patients with NSCLC treated with apatinib were retrospectively identified. Baseline and follow-up chest computed tomography scans were reviewed to identify tumor cavitation, and the subsequent filling-in of the cavitation. A multivariate logistic regression analysis was conducted to identify the factors associated with tumor cavitation. Survival curves were constructed using the Kaplan-Meier method and compared using the log-rank test. Results Of the 300 patients, 51 (17.0%) developed lung cavitation after initiating apatinib therapy. The results of the multivariate analysis showed that apatinib combination therapy (vs. apatinib monotherapy, odds ratio: 0.593, 95% confidence interval: 0.412-0.854, P=0.005) was significantly associated with tumor cavitation. Patients with tumor cavitation had significantly longer progression-free survival (PFS) than those without cavitation (8.2 vs. 5.2 months, P<0.01). Of the patients, 18 had cavity filling after progression, while 13 had persistent cavities after progression. The corresponding median PFS times were 11.9 and 3.2 months in patients with filled and persistent cavities after disease progression, respectively (P<0.001). Conclusions Tumor cavitation occurred in 17% of the NSCLC patients treated with apatinib and was associated with better PFS. Patients who had cavities filled after progression had a better prognosis than those with persistent cavities.
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Affiliation(s)
- Qian Cai
- Thoracic Inner Department I, Hubei Cancer Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Kui Hu
- Department of Radiology, Hubei Cancer Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shuang Dong
- Thoracic Inner Department I, Hubei Cancer Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiaoyu Li
- Thoracic Inner Department I, Hubei Cancer Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Sheng Hu
- Thoracic Inner Department I, Hubei Cancer Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Wenyou Deng
- Department of Radiology, Hubei Cancer Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Wulin Ou
- Thoracic Inner Department I, Hubei Cancer Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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An Z, He L, Chen T, Liang B, Wu Q. The efficacy and safety of EGFR-TKI in recurrent/metastatic nasopharyngeal carcinoma patients: A systematic review and meta-analysis. Laryngoscope Investig Otolaryngol 2024; 9:e1279. [PMID: 38803463 PMCID: PMC11129551 DOI: 10.1002/lio2.1279] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2024] [Accepted: 05/09/2024] [Indexed: 05/29/2024] Open
Abstract
Objectives EGFR-tyrosine kinase inhibitor (TKI) is used to treat recurrent and metastatic nasopharyngeal carcinoma (rmNPC). This meta-analysis aims to study the efficacy and safety of EGFR-TKI in treating patients with rmNPC. Methods We conducted a systematic search of PubMed, Embase, and Web of Science up to November 2023, and included literature that met the criteria. We extracted objective response rate (ORR), disease control rate (DCR), median progression-free survival (mPFS), median overall survival (mOS), and adverse reaction-related events and performed meta-analysis using Stata 14.0. Results A total of nine articles were included. The summary results showed that the ORR for patients treated with EGFR-TKI for rmNPC was 38% (95% CI = 27%-49%), the DCR was 71% (95% CI = 61%-80%), the mPFS was 6.29 months (95% CI = 5.22-7.35), and the mOS was 15.94 months (95% CI = 14.68-17.20). The most common grade 3-4 adverse reaction events in these patients were mucositis, nasopharyngeal necrosis, and oral ulceration. We found an incidence rate of 49% (95% CI = 38%-61%) for grade 3-4 adverse events (AEs). The anti-PD1 combined with TKI treatment method is more effective than the EGFR-TKI alone for treating rmNPC. Conclusion The study shows that EGFR-TKI has good efficacy in treating rmNPC but does not translate into survival benefits and owns a high incidence of grade 3-4 AEs. More RCT trials are needed in the future to verify the efficacy of anti-PD1 combined with TKI treatment method.
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Affiliation(s)
- Zeqi An
- Department of Otorhinolaryngology Head and Neck SurgeryShenzhen University General HospitalShenzhenChina
| | - Libin He
- Department of Otorhinolaryngology Head and Neck SurgeryShenzhen University General HospitalShenzhenChina
| | - Tuo Chen
- Department of Otorhinolaryngology Head and Neck SurgeryShenzhen University General HospitalShenzhenChina
| | - Bosen Liang
- Department of Otorhinolaryngology Head and Neck SurgeryShenzhen University General HospitalShenzhenChina
| | - Qiang Wu
- Department of Otorhinolaryngology Head and Neck SurgeryShenzhen University General HospitalShenzhenChina
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Zhao S, Su L, Huang F, Zhuo C, Ye Z, Li H, Yin Y, Gao P, Zhu Y, Lin R. Phase I trial of apatinib and paclitaxel+oxaliplatin+5-FU/levoleucovorin for treatment-naïve advanced gastric cancer. Cancer Sci 2024; 115:1611-1621. [PMID: 38354746 PMCID: PMC11093206 DOI: 10.1111/cas.16110] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2023] [Revised: 01/23/2024] [Accepted: 01/31/2024] [Indexed: 02/16/2024] Open
Abstract
Chinese guidelines recommend POF (paclitaxel, oxaliplatin, and 5-FU/levoleucovorin) as first-line treatment for advanced gastric cancer (AGC). Apatinib can augment the antitumor effect of paclitaxel, oxaliplatin, or fluorouracil in preclinical studies of AGC. A phase I clinical trial was conducted to evaluate the anticancer activity and maximum tolerated dose (MTD) of apatinib plus POF in treatment-naïve patients with AGC and to establish a recommended phase II dose. Participants received escalating doses of daily oral apatinib (250, 375, 500, 625, 750, and 850 mg) plus POF every 2 weeks using a conventional "3 + 3" study design. Among 21 treated patients, one experienced a dose-limiting toxicity (grade 3 skin ulceration at 850 mg). No MTD was reached. Apatinib 750 mg plus POF was recommended for phase II study. The most common grade 3-4 adverse events (AEs) were neutropenia (33.3%), mucositis (14.3%), and hand-foot syndrome (14.3%). Median progression-free and overall survival were 10.4 months (95% CI: 6.3, 14.6) and 18.4 months (95% CI: 9.8, 28.2), respectively. Apatinib up to 850 mg coadministered with POF was well tolerated with manageable AEs. The safety and anticancer activity of this regimen warrants its further investigation as first-line treatment for AGC in a larger study.
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Affiliation(s)
- Shen Zhao
- Department of Gastrointestinal Medical OncologyClinical Oncology School of Fujian Medical University, Fujian Cancer Hospital (Fujian Branch of Fudan University Shanghai Cancer Center)FuzhouChina
- Fujian Key Laboratory of Translational Cancer MedicineFuzhouChina
| | - LiYu Su
- Department of Gastrointestinal Medical OncologyClinical Oncology School of Fujian Medical University, Fujian Cancer Hospital (Fujian Branch of Fudan University Shanghai Cancer Center)FuzhouChina
| | - Feng Huang
- Department of Gastrointestinal SurgeryClinical Oncology School of Fujian Medical University, Fujian Cancer Hospital (Fujian Branch of Fudan University Shanghai Cancer Center)FuzhouChina
| | - Changhua Zhuo
- Department of Gastrointestinal SurgeryClinical Oncology School of Fujian Medical University, Fujian Cancer Hospital (Fujian Branch of Fudan University Shanghai Cancer Center)FuzhouChina
| | - Zaisheng Ye
- Department of Gastrointestinal SurgeryClinical Oncology School of Fujian Medical University, Fujian Cancer Hospital (Fujian Branch of Fudan University Shanghai Cancer Center)FuzhouChina
| | - Hui Li
- Department of Gastrointestinal Medical OncologyClinical Oncology School of Fujian Medical University, Fujian Cancer Hospital (Fujian Branch of Fudan University Shanghai Cancer Center)FuzhouChina
| | - Yi Yin
- Department of Gastrointestinal Medical OncologyClinical Oncology School of Fujian Medical University, Fujian Cancer Hospital (Fujian Branch of Fudan University Shanghai Cancer Center)FuzhouChina
- Fujian Key Laboratory of Translational Cancer MedicineFuzhouChina
| | - Pengqiang Gao
- Department of Thoracic SurgeryFujian Medical University Union HospitalFuzhouChina
| | - Yong Zhu
- Department of Thoracic SurgeryFujian Medical University Union HospitalFuzhouChina
| | - Rongbo Lin
- Department of Gastrointestinal Medical OncologyClinical Oncology School of Fujian Medical University, Fujian Cancer Hospital (Fujian Branch of Fudan University Shanghai Cancer Center)FuzhouChina
- Fujian Key Laboratory of Translational Cancer MedicineFuzhouChina
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11
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Yu Y, Li Y, Xu C, Zhang W. Efficacy and safety of apatinib for elderly patients with previously treated extensive-stage colorectal cancer patients and the prognostic significance of common adverse reactions. Indian J Cancer 2024; 61:317-323. [PMID: 36861718 DOI: 10.4103/ijc.ijc_1368_20] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2021] [Accepted: 07/18/2021] [Indexed: 03/03/2023]
Abstract
BACKGROUND This study was designed to investigate the efficacy and safety of apatinib monotherapy in the treatment of elderly patients with advanced colorectal cancer (CRC) who have progressed on the standard regimens. METHODS The data of 106 elderly patients with advanced CRC who have progressed on standard treatment were analyzed. The primary endpoint of this study was progression-free survival (PFS), the secondary endpoints were objective response rate (ORR), disease control rate (DCR), and overall survival (OS). The safety outcomes were assessed by the proportion and severity of adverse events. RESULTS Efficacy was assessed using the best overall response of patients during treatment with apatinib, including 0 patients with complete response, 9 patients with partial response, 68 patients with stable disease, and 29 patients with progressive disease. ORR and DCR were 8.5 and 72.6%, respectively. The median PFS of 106 patients was 3.6 months, and the median OS was 10.1 months. The most frequent adverse reactions of elderly patients with advanced CRC receiving apatinib treatment were hypertension (59.4%) and hand-foot syndrome (HFS) (48.1%). The median PFS of patients with and without hypertension was 5.0 and 3.0 months, respectively ( P = 0.008). The median PFS of patients with and without HFS was 5.4 and 3.0 months, respectively ( P = 0.013). CONCLUSIONS The clinical benefit of apatinib monotherapy was observed in elderly patients with advanced CRC who have progressed on the standard regimens. The adverse reactions of hypertension and HFS were positively related to treatment efficacy.
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Affiliation(s)
- Yongjun Yu
- Tianjin Union Medical Center, Department of Anorectal, Tianjin, P. R. China
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12
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Huang W, Wang C, Shen Y, Chen Q, Huang Z, Liu J, Lin X, Wang L, Wu F, Chen X, Li N, Hong Y, Chen M, Li J, Huang C. A real-world study of the effectiveness and safety of apatinib-based regimens in metastatic triple-negative breast cancer. BMC Cancer 2024; 24:39. [PMID: 38182995 PMCID: PMC10768098 DOI: 10.1186/s12885-023-11790-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2023] [Accepted: 12/22/2023] [Indexed: 01/07/2024] Open
Abstract
PURPOSE This investigation sought to examine the efficacy and safety of low-dose apatinib used alongside chemotherapy in the clinical management of patients with metastatic triple-negative breast cancer (TNBC) within a real-world setting, whilst comparing the outcomes with those treated solely with chemotherapy. METHODS This case series study analyzed clinical data and treatment outcomes of 163 patients with metastatic TNBC who underwent rescue treatment at the Medical Oncology Department of Clinical Oncology, Fujian Cancer Hospital, School of Fujian Medical University, China, between October 2011 and January 2023. All the patients underwent rescue treatment with either chemotherapy alone or apatinib (250 mg/day) combined with chemotherapy. The study's primary outcome was progression-free survival (PFS), whereas the secondary outcomes included overall survival (OS), objective response rate (ORR), disease control rate (DCR), and safety profiles. RESULTS The study was designed to compare two groups [1]. Out of the 163 TNBC patients who participated in the study, 107 individuals (65.6%) received treatment based on chemotherapy, whereas 56 patients (34.4%) were given treatment based on a combination of low-dose apatinib (250 mg/day) and other treatments, including chemotherapy. After propensity score matching (PSM), the objective response rate (ORR) and disease control rate (DCR) of patients with advanced triple-negative breast cancer (TNBC) who received apatinib-based treatment were 50.0 and 90.0%, respectively, while they were 6.7 and 20.0%, respectively, for the chemotherapy-based group (P < 0.001). The group that received apatinib-based treatment showed superior results in both PFS and OS compared to the group that received chemotherapy. The median PFS and OS for the apatinib-based group were 7.8 and 20.3 months, respectively, while they were only 2.2 months and 9.0 months, respectively, for the chemotherapy-based group (P < 0.001) [2]. Patients who were administered combo therapies, including PD-1 inhibitors, were excluded. In total, 97 patients received chemotherapy alone, while 34 patients were treated with apatinib in combination with chemotherapy. After propensity score matching (PSM), the ORR and DCR for the total group who received combo therapies were 44.4 and 81.5%, respectively, while they were 11.1 and 22.2%, respectively, for the chemotherapy alone group (P < 0.001). The group receiving both apatinib and chemotherapy displayed notable advantages over the group solely receiving chemotherapy in regards to PFS and OS for the entirety of the population. The PFS was found to be 7.8 months in comparison to 2.1 months (P < 0.001) and the OS was 21.1 months in contrast to 9.0 months (P < 0.001). Apatinib combined with chemotherapy induced grade 3/4 hematological toxicities, including neutropenia (8.8%) and thrombocytopenia (2.9%). Additionally, non-hematological toxicities were commonly observed, such as Hand-foot syndrome (35.3%), proteinuria (26.5%), hypertension (61.8%), higher alanine aminotransferase levels (26.5%), and fatigue (35.3%). The most frequent non-hematological grade 3/4 toxicities were Hand-foot syndrome (2.9%) and hypertension (5.9%). The study did not report any fatal adverse effects. CONCLUSIONS The combination of low-dose apatinib with chemotherapy has proven to be more effective than chemotherapy alone in treating metastatic triple-negative breast cancer (TNBC). Additionally, the occurrence of grade 3/4 non-hematologic toxicities was significantly lower compared to the recommended dose of apatinib.
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Affiliation(s)
- Weiwei Huang
- Department of Medical Oncology, Fujian Medical University Union Hospital, No.29, Xinquan Road, Gulou District, Fuzhou, Fujian province, 350001, China
- Department of Medical Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, No.91, Fuma Road, Jin'an District, Fuzhou, Fujian province, 350014, China
- Fujian Key Laboratory of Translational Cancer Medicine, Fujian Cancer Hospotial, No.91, Fuma Road, Jin'an District, Fuzhou, Fujian province, 350014, China
| | - Chenxi Wang
- Fujian Key Laboratory of Innate Immune Biology, Biomedical Research Center of South China, Fujian Normal University Qishan Campus, College Town, Fuzhou, Fujian Province, 350117, PR China
| | - Yangkun Shen
- Fujian Key Laboratory of Innate Immune Biology, Biomedical Research Center of South China, Fujian Normal University Qishan Campus, College Town, Fuzhou, Fujian Province, 350117, PR China
| | - Qi Chen
- Fujian Key Laboratory of Innate Immune Biology, Biomedical Research Center of South China, Fujian Normal University Qishan Campus, College Town, Fuzhou, Fujian Province, 350117, PR China
| | - Zhijian Huang
- Department of Breast Surgical Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, No. 91, Fuma Road, Jin'an District, Fuzhou, Fujian province, 350014, China
| | - Jian Liu
- Department of Medical Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, No.91, Fuma Road, Jin'an District, Fuzhou, Fujian province, 350014, China
| | - Xiaoyan Lin
- Department of Medical Oncology, Fujian Medical University Union Hospital, No.29, Xinquan Road, Gulou District, Fuzhou, Fujian province, 350001, China.
- Fujian Key Laboratory of Translational Cancer Medicine, Fujian Cancer Hospotial, No.91, Fuma Road, Jin'an District, Fuzhou, Fujian province, 350014, China.
| | - Lili Wang
- Department of Medical Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, No.91, Fuma Road, Jin'an District, Fuzhou, Fujian province, 350014, China
| | - Fan Wu
- Department of Medical Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, No.91, Fuma Road, Jin'an District, Fuzhou, Fujian province, 350014, China
| | - Xinhua Chen
- Department of Medical Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, No.91, Fuma Road, Jin'an District, Fuzhou, Fujian province, 350014, China
| | - Nani Li
- Department of Medical Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, No.91, Fuma Road, Jin'an District, Fuzhou, Fujian province, 350014, China
| | - Yi Hong
- Department of Medical Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, No.91, Fuma Road, Jin'an District, Fuzhou, Fujian province, 350014, China
| | - Mulan Chen
- Department of Medical Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, No.91, Fuma Road, Jin'an District, Fuzhou, Fujian province, 350014, China
| | - Jieyu Li
- Laboratory of Immuno-Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, No.91, Fuma Road, Jin'an District, Fuzhou, Fujian province, 350014, China
| | - Chuanzhong Huang
- Laboratory of Immuno-Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, No.91, Fuma Road, Jin'an District, Fuzhou, Fujian province, 350014, China
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Bergonzini C, Gregori A, Hagens TMS, van der Noord VE, van de Water B, Zweemer AJM, Coban B, Capula M, Mantini G, Botto A, Finamore F, Garajova I, McDonnell LA, Schmidt T, Giovannetti E, Danen EHJ. ABCB1 overexpression through locus amplification represents an actionable target to combat paclitaxel resistance in pancreatic cancer cells. J Exp Clin Cancer Res 2024; 43:4. [PMID: 38163893 PMCID: PMC10759666 DOI: 10.1186/s13046-023-02879-8] [Citation(s) in RCA: 13] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2023] [Accepted: 10/30/2023] [Indexed: 01/03/2024] Open
Abstract
BACKGROUND Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest types of cancer and the chemotherapies such as gemcitabine/nab-paclitaxel are confronted with intrinsic or acquired resistance. The aim of this study was to investigate mechanisms underlying paclitaxel resistance in PDAC and explore strategies to overcome it. METHODS Three paclitaxel (PR) and gemcitabine resistant (GR) PDAC models were established. Transcriptomics and proteomics were used to identify conserved mechanisms of drug resistance. Genetic and pharmacological approaches were used to overcome paclitaxel resistance. RESULTS Upregulation of ABCB1 through locus amplification was identified as a conserved feature unique to PR cells. ABCB1 was not affected in any of the GR models and no cross resistance was observed. The ABCB1 inhibitor verapamil or siRNA-mediated ABCB1 depletion sensitized PR cells to paclitaxel and prevented efflux of ABCB1 substrates in all models. ABCB1 expression was associated with a trend towards shorter survival in patients who had received gemcitabine/nab-paclitaxel treatment. A pharmacological screen identified known and novel kinase inhibitors that attenuate efflux of ABCB1 substrates and sensitize PR PDAC cells to paclitaxel. CONCLUSION Upregulation of ABCB1 through locus amplification represents a novel, conserved mechanism of PDAC paclitaxel resistance. Kinase inhibitors identified in this study can be further (pre) clinically explored as therapeutic strategies to overcome paclitaxel resistance in PDAC.
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Affiliation(s)
- Cecilia Bergonzini
- Leiden Academic Center for Drug Research, Leiden University, Leiden, The Netherlands
| | - Alessandro Gregori
- Physics of Life Processes, Leiden Institute of Physics, Leiden University, Leiden, The Netherlands
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, VU University, Amsterdam, The Netherlands
| | - Tessa M S Hagens
- Leiden Academic Center for Drug Research, Leiden University, Leiden, The Netherlands
| | - Vera E van der Noord
- Leiden Academic Center for Drug Research, Leiden University, Leiden, The Netherlands
| | - Bob van de Water
- Leiden Academic Center for Drug Research, Leiden University, Leiden, The Netherlands
| | - Annelien J M Zweemer
- Leiden Academic Center for Drug Research, Leiden University, Leiden, The Netherlands
| | - Bircan Coban
- Leiden Academic Center for Drug Research, Leiden University, Leiden, The Netherlands
| | - Mjriam Capula
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, VU University, Amsterdam, The Netherlands
- Cancer Pharmacology Lab, Fondazione Pisana Per La Scienza, San Giuliano, Pisa, Italy
| | - Giulia Mantini
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, VU University, Amsterdam, The Netherlands
| | - Asia Botto
- Proteomics and Metabolomics Lab, Fondazione Pisana Per La Scienza, San Giuliano, Pisa, Italy
- Department of Chemistry and Industrial Chemistry, University of Pisa, Pisa, Italy
| | - Francesco Finamore
- Proteomics and Metabolomics Lab, Fondazione Pisana Per La Scienza, San Giuliano, Pisa, Italy
| | - Ingrid Garajova
- Medical Oncology Unit, University Hospital of Parma, Parma, Italy
| | - Liam A McDonnell
- Proteomics and Metabolomics Lab, Fondazione Pisana Per La Scienza, San Giuliano, Pisa, Italy
| | - Thomas Schmidt
- Physics of Life Processes, Leiden Institute of Physics, Leiden University, Leiden, The Netherlands
| | - Elisa Giovannetti
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, VU University, Amsterdam, The Netherlands.
- Cancer Pharmacology Lab, Fondazione Pisana Per La Scienza, San Giuliano, Pisa, Italy.
| | - Erik H J Danen
- Leiden Academic Center for Drug Research, Leiden University, Leiden, The Netherlands.
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14
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Liu R, Zou T, Yu S, Li W, Wei S, Gong Y, Zhang Z, Zhang S, Yi D. Photoredox-Catalyzed Three-Component 1,2-Cyanoalkylpyridylation of Styrenes with Nonredox-Active Cyclic Oximes. J Org Chem 2023; 88:16410-16423. [PMID: 37943006 DOI: 10.1021/acs.joc.3c01936] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2023]
Abstract
Three-component alkene 1,2-difunctionalizations have emerged as a powerful strategy for rapid buildup of diverse and complex alkylpyridines, but the distal functionalized alkyl radicals for the alkene 1,2-alkylpyridylations were still rare. Herein, we report an example of regioselective three-component 1,2-cyanoalkylpyridylation of feedstock styrenes with accessible nonredox-active cyclic oximes through visible-light photoredox catalysis, providing a series of structurally diverse β-cyanoalkylated alkylpyridines. This protocol proceeds through a radical relay pathway including the generation of iminyl radicals enabled by phosphoranyl radical-mediated β-scission, radical transposition through C-C bond cleavage, highly selective radical addition, and precise radical-radical cross-coupling sequence, thus facilitating the regioselective formation of two distinct C-C single bonds in a single-pot operation. This synthetic strategy features mild conditions, broad compatibility of functional groups and substrate scope, diverse product derivatization, and late-stage modification.
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Affiliation(s)
- Rui Liu
- Green Pharmaceutical Technology Key Laboratory of Luzhou City, Central Nervous System Drug Key Laboratory of Sichuan Province, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China
| | - Ting Zou
- Pharmacy Intravenous Admixture Service, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou 646000, Sichuan, China
| | - Sha Yu
- Green Pharmaceutical Technology Key Laboratory of Luzhou City, Central Nervous System Drug Key Laboratory of Sichuan Province, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China
| | - Weicai Li
- Green Pharmaceutical Technology Key Laboratory of Luzhou City, Central Nervous System Drug Key Laboratory of Sichuan Province, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China
| | - Siping Wei
- Green Pharmaceutical Technology Key Laboratory of Luzhou City, Central Nervous System Drug Key Laboratory of Sichuan Province, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China
| | - Yimou Gong
- Green Pharmaceutical Technology Key Laboratory of Luzhou City, Central Nervous System Drug Key Laboratory of Sichuan Province, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China
| | - Zhijie Zhang
- Green Pharmaceutical Technology Key Laboratory of Luzhou City, Central Nervous System Drug Key Laboratory of Sichuan Province, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China
| | - Shiqi Zhang
- Natural Products Research Center, Chengdu Institution of Biology, Chinese Academy of Science, Chengdu, Sichuan 610041, China
| | - Dong Yi
- Green Pharmaceutical Technology Key Laboratory of Luzhou City, Central Nervous System Drug Key Laboratory of Sichuan Province, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China
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15
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Wu CP, Hsiao SH, Wu YS. Perspectives on drug repurposing to overcome cancer multidrug resistance mediated by ABCB1 and ABCG2. Drug Resist Updat 2023; 71:101011. [PMID: 37865067 DOI: 10.1016/j.drup.2023.101011] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2023] [Revised: 10/07/2023] [Accepted: 10/08/2023] [Indexed: 10/23/2023]
Abstract
The overexpression of the human ATP-binding cassette (ABC) transporters in cancer cells is a common mechanism involved in developing multidrug resistance (MDR). Unfortunately, there are currently no approved drugs specifically designed to treat multidrug-resistant cancers, making MDR a significant obstacle to successful chemotherapy. Despite over two decades of research, developing transporter-specific inhibitors for clinical use has proven to be a challenging endeavor. As an alternative approach, drug repurposing has gained traction as a more practical method to discover clinically effective modulators of drug transporters. This involves exploring new indications for already-approved drugs, bypassing the lengthy process of developing novel synthetic inhibitors. In this context, we will discuss the mechanisms of ABC drug transporters ABCB1 and ABCG2, their roles in cancer MDR, and the inhibitors that have been evaluated for their potential to reverse MDR mediated by these drug transporters. Our focus will be on providing an up-to-date report on approved drugs tested for their inhibitory activities against these drug efflux pumps. Lastly, we will explore the challenges and prospects of repurposing already approved medications for clinical use to overcome chemoresistance in patients with high tumor expression of ABCB1 and/or ABCG2.
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Affiliation(s)
- Chung-Pu Wu
- Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan; Department of Physiology and Pharmacology, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan; Molecular Medicine Research Center, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan; Department of Obstetrics and Gynecology, Taipei Chang Gung Memorial Hospital, Taipei 10507, Taiwan.
| | - Sung-Han Hsiao
- Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan
| | - Yu-Shan Wu
- Department of Chemistry, Tunghai University, Taichung 40704, Taiwan.
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Pan H, Zhou X, Shen L, Li Y, Dong W, Wang S, Zhang Y, Pan W, Xie C, Cai X. Efficacy of apatinib+radiotherapy vs radiotherapy alone in patients with advanced multiline therapy failure for non small cell lung cancer with brain metastasis. Br J Radiol 2023; 96:20220550. [PMID: 37162165 PMCID: PMC10461264 DOI: 10.1259/bjr.20220550] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2022] [Revised: 04/25/2023] [Accepted: 04/30/2023] [Indexed: 05/11/2023] Open
Abstract
OBJECTIVE Lung cancer is the leading cause of cancer-associated mortality worldwide. Central nervous system (CNS) metastasis is a prevalent and serious complication. The most common treatment for brain metastasis (BM) is still radiation therapy (RT). An increasing number of drugs have been shown to have intracranial activity or to sensitize tumours to radiotherapy. METHODS Consecutive advanced multiline therapy failure in patients with non-small-cell lung cancer (NSCLC) with BM at the authors' hospital were retrospectively reviewed. Eligible patients were divided into two groups: Apatinib+RT group and RT group. Intracranial progression-free survival (PFS) and overall survival (OS) were analysed using the Kaplan-Meier method. RESULTS The median intracranial PFS for the RT group and Apatinib+RT group was 5.83 months and 11.81 months (p = 0.034). The median OS for the RT group and Apatinib+RT group was 9.02 months and 13.62 months (p = 0.311). The Apatinib+RT group had a better intracranial PFS, but there were no significant differences between the two arms in OS. The Apatinib+RT group had significantly reduced symptoms caused by BM. CONCLUSION RT combined with apatinib could help to control intracranial metastases. The Apatinib+RT group had significantly reduced symptoms caused by BM and improved quality of life for patients, the safety of the two treatments was similar. ADVANCES IN KNOWLEDGE Here, we propose that RT combined with apatinib can significantly relieve brain symptoms and tolerate side-effects without affecting OS in patients with BM following failure of multiline therapy for NSCLC. Of course, this paper is a retrospective origin study, and more powerful evidence is needed to demonstrate.
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Affiliation(s)
- Huanle Pan
- Department of Radiation and Medical Oncology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Xiaobo Zhou
- Department of Radiation and Medical Oncology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Lanxiao Shen
- Department of Radiation and Medical Oncology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Yida Li
- Department of Radiation and Medical Oncology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Wenjun Dong
- Department of Radiation and Medical Oncology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Saijun Wang
- Department of Radiation and Medical Oncology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Yuyue Zhang
- Department of Radiation and Medical Oncology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Wenkai Pan
- Department of Radiation and Medical Oncology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Congying Xie
- Department of Radiation and Medical Oncology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Xiaona Cai
- Department of Ultrasonography, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
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Roskoski R. Small molecule protein kinase inhibitors approved by regulatory agencies outside of the United States. Pharmacol Res 2023; 194:106847. [PMID: 37454916 DOI: 10.1016/j.phrs.2023.106847] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/03/2023] [Accepted: 07/03/2023] [Indexed: 07/18/2023]
Abstract
Owing to genetic alterations and overexpression, the dysregulation of protein kinases plays a significant role in the pathogenesis of many autoimmune and neoplastic disorders and protein kinase antagonists have become an important drug target. Although the efficacy of imatinib in the treatment of chronic myelogenous leukemia in the United States in 2001 was the main driver of protein kinase inhibitor drug discovery, this was preceded by the approval of fasudil (a ROCK antagonist) in Japan in 1995 for the treatment of cerebral vasospasm. There are 21 small molecule protein kinase inhibitors that are approved in China, Japan, Europe, and South Korea that are not approved in the United Sates and 75 FDA-approved inhibitors in the United States. Of the 21 agents, eleven target receptor protein-tyrosine kinases, eight inhibit nonreceptor protein-tyrosine kinases, and two block protein-serine/threonine kinases. All 21 drugs are orally bioavailable or topically effective. Of the non-FDA approved drugs, sixteen are prescribed for the treatment of neoplastic diseases, three are directed toward inflammatory disorders, one is used for glaucoma, and fasudil is used in the management of vasospasm. The leading targets of kinase inhibitors approved by both international regulatory agencies and by the FDA are members of the EGFR family, the VEGFR family, and the JAK family. One-third of the 21 internationally approved drugs are not compliant with Lipinski's rule of five for orally bioavailable drugs. The rule of five relies on four parameters including molecular weight, number of hydrogen bond donors and acceptors, and the Log of the partition coefficient.
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Affiliation(s)
- Robert Roskoski
- Blue Ridge Institute for Medical Research, 221 Haywood Knolls Drive, Hendersonville, NC 28791-8717, United States.
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Zhang R, Chen Y, Liu X, Gui X, Zhu A, Jiang H, Shao B, Liang X, Yan Y, Zhang J, Song G, Li H. Efficacy of apatinib 250 mg combined with chemotherapy in patients with pretreated advanced breast cancer in a real-world setting. Front Oncol 2023; 13:1076469. [PMID: 37397355 PMCID: PMC10314217 DOI: 10.3389/fonc.2023.1076469] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2022] [Accepted: 06/02/2023] [Indexed: 07/04/2023] Open
Abstract
Objectives This study evaluated the efficacy and safety of apatinib (an oral small-molecule tyrosine kinase inhibitor targeting VEGFR-2) 250 mg combined with chemotherapy in patients with pretreated metastatic breast cancer in a real-world setting. Patients and methods A database of patients with advanced breast cancer who received apatinib between December 2016 and December 2019 in our institution was reviewed, and patients who received apatinib combined with chemotherapy were included. Progression-free survival (PFS), overall survival (OS), the objective response rate (ORR), the disease control rate (DCR), and treatment-related toxicity were analyzed. Results In total, 52 evaluated patients with metastatic breast cancer previously exposed to anthracyclines or taxanes who received apatinib 250 mg combined with chemotherapy were enrolled in this study. Median PFS and OS were 4.8 (95% confidence interval [CI] = 3.2-6.4) and 15.4 months (95% CI = 9.2-21.6), respectively. The ORR and DCR were 25% and 86.5%, respectively. Median PFS for the previous line of treatment was 2.1 months (95% CI = 0.65-3.6), which was significantly shorter than that for the apatinib-chemotherapy combination (p < 0.001). No significant difference was identified in the ORR and PFS among the subgroups(subtypes, target lesion, combined regimens and treatment lines). The common toxicities related to apatinib were hypertension, hand-foot syndrome, proteinuria, and fatigue events. Conclusion Apatinib 250 mg combined with chemotherapy provided favorable efficacy in patients with pretreated metastatic breast cancer regardless of molecular types and treatment lines. The toxicities of the regimen were well tolerated and manageable. This regimen could be a potential treatment option in patients with refractory pretreated metastatic breast cancers.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | - Huiping Li
- *Correspondence: Guohong Song, ; Huiping Li,
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19
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Long J, Chen B, Liu Z. Comparative efficacy and safety of molecular targeted agents combined with transarterial chemoembolization in the treatment of unresectable hepatocellular carcinoma: a network meta-analysis. Front Oncol 2023; 13:1179431. [PMID: 37265792 PMCID: PMC10230082 DOI: 10.3389/fonc.2023.1179431] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2023] [Accepted: 05/09/2023] [Indexed: 06/03/2023] Open
Abstract
Objective At present, several molecular targeted agents(MTAs) combined with transarterial chemoembolization (TACE) have been employed to treat unresectable hepatocellular carcinoma (HCC). In this meta-analysis, we compared the efficacy and safety of different MTAs combined with TACE to enable effective decision-making for the clinical treatment of unresectable HCC. Methods Pubmed, Web of Science, EMBASE, and Cochrane Library were retrieved to evaluate the efficacy and safety of different MTAs combined with TACE in cohort studies and randomized controlled trials. The hazard ratios and 95% confidence intervals (CIs) were calculated to investigate the impact of various therapies on overall survival (OS) and progression-free survival. However, the objective response rate (ORR), disease control rate (DCR), adverse events (AEs), and ≥grade-3 adverse events (≥G3-AEs) were calculated using odd ratios and 95% CIs. The node-splitting approach was used to test the heterogeneity. The funnel plot was utilized to analyze the publication bias. Additionally, according to the ranking plots, we ranked various treatments. Results A total of 45 studies involving 10,774 patients with 8 treatment strategies were included in our network meta-analysis. Our network meta-analysis showed that apatinib+TACE provided the highest OS (62.2%), ORR (44.7%), and DCR (45.6%), while and lenvatinib+TACE offered the best PFS (78.9%). Besides, there was no statistically significant difference in AEs and ≥G3-AEs among treatment options. Conclusion Apatinib+TACE demonstrated the best OS, ORR, and DCR with no additional AEs and ≥G3-AEs. Therefore, for the treatment scheme of MTAs combined with TACE, apatinib+TACE may be the best option for patients with unresectable HCC. Systematic review registration https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42023388609.
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Affiliation(s)
- Jiaye Long
- Department of Interventional Radiology, Inner Mongolia Forestry General Hospital, The Second Clinical Medical School of Inner Mongolia University for The Nationalities, Yakeshi, Inner Mongolia, China
| | - Baoxiang Chen
- Department of Interventional Radiology, Inner Mongolia Forestry General Hospital, The Second Clinical Medical School of Inner Mongolia University for The Nationalities, Yakeshi, Inner Mongolia, China
| | - Zhaohui Liu
- Department of Urology, Inner Mongolia Forestry General Hospital, The Second Clinical Medical School of Inner Mongolia University for The Nationalities, Yakeshi, Inner Mongolia, China
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Jang S, Strickland B, Finis L, Kooijman JJ, Melis JJTM, Zaman GJR, Van Tornout J. Comparative biochemical kinase activity analysis identifies rivoceranib as a highly selective VEGFR2 inhibitor. Cancer Chemother Pharmacol 2023; 91:491-499. [PMID: 37148323 DOI: 10.1007/s00280-023-04534-7] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2023] [Accepted: 04/23/2023] [Indexed: 05/08/2023]
Abstract
Vascular endothelial growth factor receptor 2 (VEGFR2), a key regulator of tumor angiogenesis, is highly expressed across numerous tumor types and has been an attractive target for anti-cancer therapy. However, clinical application of available VEGFR2 inhibitors has been challenged by limited efficacy and a wide range of side effects, potentially due to inadequate selectivity for VEGFR2. Thus, development of potent VEGFR2 inhibitors with improved selectivity is needed. Rivoceranib is an orally administered tyrosine kinase inhibitor that potently and selectively targets VEGFR2. A comparative understanding of the potency and selectivity of rivoceranib and approved inhibitors of VEGFR2 is valuable to inform rationale for therapy selection in the clinic. Here, we performed biochemical analyses of the kinase activity of VEGFR2 and of a panel of 270 kinases to compare rivoceranib to 10 FDA-approved kinase inhibitors ("reference inhibitors") with known activity against VEGFR2. Rivoceranib demonstrated potency within the range of the reference inhibitors, with a VEGFR2 kinase inhibition IC50 value of 16 nM. However, analysis of residual kinase activity of the panel of 270 kinases showed that rivoceranib displayed greater selectivity for VEGFR2 compared with the reference inhibitors. Differences in selectivity among compounds within the observed range of potency of VEGFR2 kinase inhibition are clinically relevant, as toxicities associated with available VEGFR2 inhibitors are thought to be partly due to their effects against kinases other than VEGFR2. Together, this comparative biochemical analysis highlights the potential for rivoceranib to address clinical limitations associated with off-target effects of currently available VEGFR2 inhibitors.
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Lei Y, Lin L, Cheng S, Shao Q, Ding C, Zuo R, Chen W, Liao Q, Liu G. Acute inflammatory reaction during anti-angiogenesis therapy combined with immunotherapy as a possible indicator of the therapeutic effect: Three case reports and literature review. Front Oncol 2023; 13:1072480. [PMID: 37124541 PMCID: PMC10140593 DOI: 10.3389/fonc.2023.1072480] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Accepted: 03/27/2023] [Indexed: 05/02/2023] Open
Abstract
The posterior line treatment of unresectable advanced or metastatic gastrointestinal (GI) tumors has always been a challenging point. In particular, for patients with microsatellite stable (MSS)/mismatch repair proficient (pMMR) 0GI tumors, the difficulty of treatment is exacerbated due to their insensitivity to immune drugs. Accordingly, finding a new comprehensive therapy to improve the treatment effect is urgent. In this study, we report the treatment histories of three patients with MSS/pMMR GI tumors who achieved satisfactory effects by using a comprehensive treatment regimen of apatinib combined with camrelizumab and TAS-102 after the failure of first- or second-line regimens. The specific contents of the treatment plan were as follows: apatinib (500 mg/d) was administered orally for 10 days, followed by camrelizumab (200 mg, ivgtt, day 1, 14 days/cycle) and TAS-102 (20 mg, oral, days 1-21, 28 days/cycle). Apatinib (500 mg/d) was maintained during treatment. Subsequently, we discuss the possible mechanism of this combination and review the relevant literature, and introduce clinical trials on anti-angiogenesis therapy combined with immunotherapy.
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Affiliation(s)
- Yihui Lei
- The School of Clinical Medical, Fujian Medical University, Fuzhou, Fujian, China
| | - Li Lin
- Department of Gastrointestinal Surgery, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China
| | - Shuyu Cheng
- Institute of Gastrointestinal Oncology, Medical College of Xiamen University, Xiamen, Fujian, China
| | - Qiming Shao
- The School of Clinical Medical, Fujian Medical University, Fuzhou, Fujian, China
| | - Chenchun Ding
- Institute of Gastrointestinal Oncology, Medical College of Xiamen University, Xiamen, Fujian, China
| | - Renjie Zuo
- Institute of Gastrointestinal Oncology, Medical College of Xiamen University, Xiamen, Fujian, China
| | - Weiping Chen
- The School of Clinical Medical, Fujian Medical University, Fuzhou, Fujian, China
| | - Quan Liao
- Institute of Gastrointestinal Oncology, Medical College of Xiamen University, Xiamen, Fujian, China
| | - Guoyan Liu
- The School of Clinical Medical, Fujian Medical University, Fuzhou, Fujian, China
- Department of Gastrointestinal Surgery, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China
- Institute of Gastrointestinal Oncology, Medical College of Xiamen University, Xiamen, Fujian, China
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Qiu H, Su N, Yan S, Li J. Real-world Efficacy Data on Anti-Angiogenic Drugs in Recurrent Small Cell Cervical Carcinoma: A Retrospective Study. Technol Cancer Res Treat 2023; 22:15330338231160393. [PMID: 36883253 PMCID: PMC9996736 DOI: 10.1177/15330338231160393] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/09/2023] Open
Abstract
OBJECTIVE Small cell carcinoma of the cervix (SCCC) is rare but extremely aggressive and resistant to current therapies. We herein evaluate the efficacy of bevacizumab, apatinib, and anlotinib in recurrent/metastatic SCCC patients in a real-world setting. METHODS Recurrent/metastatic SCCC patients were recruited between January 2013 and July 2020. Baseline characteristics were extracted from medical records, and patients were divided into an anti-angiogenic group and non-anti-angiogenic group. The efficacy of treatments was determined using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria. Kaplan-Meier analysis was performed for survival analysis. RESULTS Sixteen patients received anti-angiogenic drugs after tumor recurrence/metastasis; of them, 10 cases received them as first-line treatment, 5 cases as second-line treatment, and 1 case as fourth-line treatment. Another 23 patients received traditional therapies, including surgery, chemotherapy, and radiotherapy. The use of anti-angiogenic drugs in first-line treatment significantly prolonged progression-free survival (PFS) compared to the controls, with a median PFS of 8 months (2-20 months) and 3 months (1-10 months), respectively (P = .025). This trend was also notable in patients who started anti-angiogenic treatment after the second-line recurrence/metastasis. However, there was no benefits for overall survival (OS) in either the 10 first-line cases or all 16 cases (P = .499 and .31, respectively). Both bevacizumab and small molecule drugs (apatinib and anlotinib) presented similar efficacy in SCCC patients. CONCLUSIONS At present, this is the largest cohort study that provides real-world data, showing that anti-angiogenic regimens could significantly prolong PFS in recurrent/metastatic SCCC. Aside from bevacizumab, the novel oral small molecule drugs provide more choices with similar efficacy. These findings warrant further validation in well-designed future studies.
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Affiliation(s)
- Haifeng Qiu
- Department of Gynecology, 191599The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Ning Su
- Department of Gynecologic Oncology, The Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou, China
| | - Shuping Yan
- Department of Pathology, 191599The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Jing Li
- Department of Oncology, 191599The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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Zhou L, Zhang W, Xiang Y, Qian Z, Zhou J, Ni L, Feng Y, Gao B. The apatinib and pemetrexed combination has antitumor and antiangiogenic effects against NSCLC. Open Life Sci 2023; 18:20220533. [PMID: 36910471 PMCID: PMC9993329 DOI: 10.1515/biol-2022-0533] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2022] [Revised: 05/17/2022] [Accepted: 11/02/2022] [Indexed: 03/09/2023] Open
Abstract
Chemotherapy for advanced non-small-cell lung cancer (NSCLC) remains the first treatment choice. Angiogenesis inhibitors are effective for lung cancer treatment. This study explored whether chemotherapy combined with angiogenesis inhibitors could achieve better efficacy in NSCLC. The zebrafish A549 xenograft model was used to investigate the combined effect of apatinib and chemotherapeutic agents in NSCLC. Apatinib combined with pemetrexed demonstrated the highest antitumor effect compared with apatinib combined with gemcitabine or paclitaxel in vitro. In the zebrafish A549 xenograft model, apatinib and pemetrexed, alone or in combination, showed significant inhibition of tumor growth. Co-treatment with apatinib and pemetrexed demonstrated the best antitumor effects, suggesting that the combination of apatinib and pemetrexed might be a promising alternative therapy for patients with lung cancer. Apatinib combined with pemetrexed had enhanced antitumor effects compared with either one alone in the zebrafish model of NSCLC.
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Affiliation(s)
- Ling Zhou
- Department of Respiratory Medicine, Rui Jin Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai 200025, China
| | - Wenchao Zhang
- Department of Allergy, Henan Provincial People's Hospital, Henan University, Zhengzhou 450000, China
| | - Yi Xiang
- Department of Respiratory Medicine, Rui Jin Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai 200025, China
| | - Zijun Qian
- Department of Respiratory Medicine, Rui Jin Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai 200025, China
| | - Jianping Zhou
- Department of Respiratory Medicine, Rui Jin Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai 200025, China
| | - Lei Ni
- Department of Respiratory Medicine, Rui Jin Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai 200025, China
| | - Yun Feng
- Department of Respiratory Medicine, Rui Jin Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai 200025, China
| | - Beili Gao
- Department of Respiratory Medicine, Rui Jin Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai 200025, China
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Federico P, Giunta EF, Tufo A, Tovoli F, Petrillo A, Daniele B. Resistance to Antiangiogenic Therapy in Hepatocellular Carcinoma: From Molecular Mechanisms to Clinical Impact. Cancers (Basel) 2022; 14:6245. [PMID: 36551730 PMCID: PMC9776845 DOI: 10.3390/cancers14246245] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2022] [Revised: 12/08/2022] [Accepted: 12/10/2022] [Indexed: 12/23/2022] Open
Abstract
Antiangiogenic drugs were the only mainstay of advanced hepatocellular carcinoma (HCC) treatment from 2007 to 2017. However, primary or secondary resistance hampered their efficacy. Primary resistance could be due to different molecular and/or genetic characteristics of HCC and their knowledge would clarify the optimal treatment approach in each patient. Several molecular mechanisms responsible for secondary resistance have been discovered over the last few years; they represent potential targets for new specific drugs. In this light, the advent of checkpoint inhibitors (ICIs) has been a new opportunity; however, their use has highlighted other issues: the vascular normalization compared to a vessel pruning to promote the delivery of an active cancer immunotherapy and the development of resistance to immunotherapy which leads to a better selection of patients as candidates for ICIs. Nevertheless, the combination of antiangiogenic therapy plus ICIs represents an intriguing approach with high potential to improve the survival of these patients. Waiting for results from ongoing clinical trials, this review depicts the current knowledge about the resistance to antiangiogenic drugs in HCC. It could also provide updated information to clinicians focusing on the most effective combinations or sequential approaches in this regard, based on molecular mechanisms.
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Affiliation(s)
- Piera Federico
- Medical Oncology Unit, Ospedale del Mare, 80147 Naples, Italy
| | - Emilio Francesco Giunta
- Department of Precision Medicine, School of Medicine, University of Study of Campania “L. Vanvitelli”, 80131 Naples, Italy
| | - Andrea Tufo
- Surgical Unit, Ospedale del Mare, 80147 Napoli, Italy
| | - Francesco Tovoli
- Department of Medical and Surgical Sciences, University of Bologna, 40126 Bologna, Italy
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy
| | | | - Bruno Daniele
- Medical Oncology Unit, Ospedale del Mare, 80147 Naples, Italy
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Zhao M, Ma H, Cheng P, Yang H, Zhao Y, Han Q. Apatinib combined with temozolomide treatment for pseudoprogression in glioblastoma: A case report. Medicine (Baltimore) 2022; 101:e32156. [PMID: 36626518 PMCID: PMC9750629 DOI: 10.1097/md.0000000000032156] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
RATIONALE Glioblastoma is the most common malignant tumor of the central nervous system, which originates from glial cells and corresponding precursors. Due to its strong invasion and rapid growth, the prognosis of patients after treatment is very poor and easy to relapse. PATIENT CONCERNS In August 2015, a 48 years old man with a relapse of glioblastoma. DIAGNOSES The patient was diagnosed by computed tomography, magnetic resonance imaging, and pathological biopsy in this case report. INTERVENTIONS The patient underwent 2 surgeries, radiotherapy, and multiple regular chemotherapy sessions over the next 6 years. Apatinib, an inhibitor of vascular endothelial growth factor receptor 2 was given to treat recurrent glioma. OUTCOMES It was found that radiotherapy combined with temozolomide administration often increased the size of the original lesion or produced a new glioblastoma lesion. The lesion development was similar to tumor progression, which was called pseudoprogression. And it significantly prolonged the survival of this patient. LESSONS Surgery, radiotherapy and chemotherapy with apatinib and temozolomide are effective to treat the patients with pseudoprogression in glioblastoma.
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Affiliation(s)
- Mingming Zhao
- First Ward of Cancer Center, People’s Hospital of Henan University, Zhengzhou, China
| | - Haodong Ma
- First Ward of Cancer Center, Henan Provincial People’s Hospital, Zhengzhou, China
| | - Peng Cheng
- First Ward of Cancer Center, Henan Provincial People’s Hospital, Zhengzhou, China
| | - Hongjie Yang
- First Ward of Cancer Center, Henan Provincial People’s Hospital, Zhengzhou, China
| | - Yang Zhao
- First Ward of Cancer Center, Henan Provincial People’s Hospital, Zhengzhou, China
| | - Qian Han
- First Ward of Cancer Center, Henan Provincial People’s Hospital, Zhengzhou, China
- * Correspondence: Qian Han, First Ward of Cancer Center, Henan Provincial People’s Hospital, 7 Weiwu Road, Jinshui District, Zhengzhou 450003, China (e-mail: )
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Wang J, Huang D, Yang W, Song Q, Jia Y, Chen P, Cheng Y. The efficacy and safety of Apatinib in the treatment of advanced non-small cell lung cancer: A retrospective trial. Front Oncol 2022; 12:1030798. [PMID: 36505785 PMCID: PMC9727187 DOI: 10.3389/fonc.2022.1030798] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Accepted: 11/08/2022] [Indexed: 11/24/2022] Open
Abstract
Background As a potent inhibitor of the vascular endothelial growth factor (VEGF) signaling pathway, Apatinib has been used in antitumor treatment for some time. The study aimed to research the therapeutic effects and toxicity of Apatinib in the treatment of advanced non-small cell lung cancer (NSCLC). Methods We retrospectively analyzed 128 NSCLC patients treated with Apatinib in Qilu Hospital of Shandong University. Response Evaluation Criteria in Solid Tumors (RECIST) criteria was adopted to evaluate the treatment effect, and Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 was conducted to determine the Adverse Events (AEs). Cox proportional hazard model and Kaplan-Meier function were applied to evaluate the progression-free survival (PFS) and overall survival (OS). Results Among 128 NSCLC patients, partial response (PR) were observed in 15 patients, stable disease (SD) in 66 patients and progressive disease (PD) in 47 patients. The objective response rate (ORR) and disease control rate (DCR) accounted for 11.7% and 63.3% respectively. The median PFS (mPFS) and median OS (mOS) were 4.4 months and 17.2 months. Common side effects of Apatinib were hypertension (n=48), proteinuria (n=35), and hand-foot syndrome (HFS) (n=30), all of the side effects were controllable. No significant difference was observed in efficacy and AEs between the higher dose group (Apatinib>500mg/d) and the lower dose group (Apatinib=500mg/d). Conclusions The study suggested that Apatinib with a lower dose (=500mg/d) has good efficacy and safety in the treatment of advanced NSCLC after first-line chemotherapy.
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Gong T, Huang Q, Tang F, Wang Y, Li Z, Luo Y, Min L, Zhou Y, Tu C. Activity and safety of apatinib monotherapy or apatinib combined with chemotherapy for patients with metastatic or unresectable osteosarcoma over the age of 40 years: A retrospective analysis. Front Oncol 2022; 12:1031787. [PMID: 36387068 PMCID: PMC9664205 DOI: 10.3389/fonc.2022.1031787] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Accepted: 10/17/2022] [Indexed: 12/01/2023] Open
Abstract
BACKGROUND Osteosarcoma commonly develops during childhood and adolescence. Only one-third of osteosarcoma patients have been clinically detected over the age of 40 years, and the survivorship of those patients is quite dismal. Apatinib, a novel multitarget angiogenesis inhibitor, has shown a short-term efficacy in advanced or metastatic osteosarcoma. However, the data for apatinib in the older patients with osteosarcoma are limited. We aim to evaluate the efficacy and safety of apatinib combined with chemotherapy versus apatinib monotherapy in the treatment of patients over 40 years old with metastatic or unresectable osteosarcoma. METHODS We retrospectively analyzed the patients with metastatic osteosarcoma who were treated with apatinib monotherapy or apatinib combined with chemotherapy between May 2015 and December 2018 in the Department of Orthopedics at West China Hospital. Apatinib was initially administered with a dose of 500 mg daily, and the dose was adjusted according to toxicity. The objective response rate (ORR), disease control rate (DCR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS) were investigated. The treatment-related adverse events and the safety of apatinib were also documented. RESULTS A total of 45 patients (28 men, 17 women) with metastatic or unresectable osteosarcoma were finally included, and 41 patients received at least one cycle of treatment and were evaluable for efficacy. Of 41 patients, 24 who were intolerant to intensive chemotherapy or have failed standard chemotherapy received apatinib monotherapy, and 17 patients were treated with apatinib plus chemotherapy. The median PFS and median OS were longer in the group treated with apatinib combined with chemotherapy than those of the apatinib monotherapy group (5.6 months vs. 2.6 months; 15.1 months vs. 9.7 months). Moreover, the median DOR was significantly prolonged in the group treated with apatinib combined with chemotherapy compared with that in the monotherapy group. CONCLUSION Apatinib demonstrated promising activity in patients over 40 years old with metastatic or unresectable osteosarcoma. The combination of apatinib and chemotherapy conferred a durable response compared with apatinib monotherapy, which might be an alternative therapeutic strategy for the management of osteosarcoma in older patients.
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Affiliation(s)
- Taojun Gong
- Department of Orthopedics, Orthopaedic Research Institute, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Qi Huang
- Operating Room, West China Hospital, Sichuan University/West China School of Nursing, Sichuan University, Chengdu, Sichuan, China
| | - Fan Tang
- Department of Orthopedics, Orthopaedic Research Institute, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Yitian Wang
- Department of Orthopedics, Orthopaedic Research Institute, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Zhuangzhuang Li
- Department of Orthopedics, Orthopaedic Research Institute, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Yi Luo
- Department of Orthopedics, Orthopaedic Research Institute, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Li Min
- Department of Orthopedics, Orthopaedic Research Institute, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Yong Zhou
- Department of Orthopedics, Orthopaedic Research Institute, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Chongqi Tu
- Department of Orthopedics, Orthopaedic Research Institute, West China Hospital, Sichuan University, Chengdu, Sichuan, China
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Jia W, Liu Z, Zhan L, Zhao Q, Qiu W, Kuang J. Editorial: Apatinib and Anlotinib in the Treatment of Radioactive Iodine Refractory and Highly Invasive Thyroid Carcinoma. J Clin Med 2022; 11:6380. [PMID: 36362609 PMCID: PMC9657471 DOI: 10.3390/jcm11216380] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2022] [Accepted: 10/25/2022] [Indexed: 08/30/2023] Open
Abstract
Thyroid cancer (TC) is the most prevalent endocrine malignancy, with a rising incidence in the past decade [...].
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Affiliation(s)
| | | | | | | | - Weihua Qiu
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Jie Kuang
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
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Khan AI, Mashat GD, Hazique M, Khan KI, Ramesh P, Kanagalingam S, Zargham Ul Haq F, Victory Srinivasan N, Khan S. Efficacy and Safety of Apatinib in the Treatment of Chemotherapy-Refractory Metastatic Colorectal Cancer: A Systematic Review. Cureus 2022; 14:e29920. [PMID: 36348923 PMCID: PMC9633256 DOI: 10.7759/cureus.29920] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Accepted: 10/04/2022] [Indexed: 01/24/2023] Open
Abstract
The purpose of this study was to systematically review the current evidence on apatinib and offer a better understanding of its safety and efficacy in metastatic colorectal cancer (mCRC) patients who have not responded to standard chemotherapies. This systematic review was conducted using research from the last 10 years (May 30, 2012, to May 30, 2022) and was obtained from the following databases: PubMed, PubMed Central (PMC), ScienceDirect, and Google Scholar. After removing duplicates, screening titles and abstracts, and applying eligibility criteria and quality appraisal, 11 articles were left for this systematic review (one meta-analysis, eight non-randomized studies, and two traditional reviews). Out of the 11 studies, six were on apatinib monotherapy, while three were on apatinib combination therapy. Apatinib has demonstrated efficacy in the monotherapy and combination therapy trials and has exhibited an acceptable safety profile as the adverse events were predominantly graded 1-2 and could be easily managed. Therefore, apatinib is an encouraging candidate for third-line therapy in chemotherapy-refractory mCRC patients. This conclusion should be confirmed and validated by studies with larger, randomized clinical trials to gain better insight and to directly compare the efficacy and safety of apatinib with all current third-line therapies together so that clinicians can easily assess which treatment modality is superior for chemotherapy-refractory mCRC patients.
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Affiliation(s)
- Aujala Irfan Khan
- Research, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Ghadi D Mashat
- Pediatrics, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Mohammad Hazique
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Kokab Irfan Khan
- Research, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Prasana Ramesh
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | | | - Fnu Zargham Ul Haq
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | | | - Safeera Khan
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
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Abstract
RATIONALE Outcomes remain poor in children with recurrent ependyomams (rEPNs), despite advances in surgery and radiotherapy. Systemic therapeutic options are limited, given the low response to chemotherapy and targeted drugs. There is an urgent need for efective pharmacotherapy. Apatinib is a multitarget tyrosine kinase inhibitor, which has been reported to exhibit broad antitumor profiles. However, its effects on rEPNs have not been reported thus far. PATIENT CONCERNS We present a 5-year-old recurrent ependyomam patient benefting from apatinib and temozolomide. The patient was diagnosed with ependyomam in January 2016 and treated with surgery and radiotherapy. After surgery, the patient walked with an mild unsteady gait. He was diagnosed with recurrence in November 2018 following which he was treated with reoperation, reirradiation and chemotherapy (etopside, cisplatin, and temozolomide [TMZ]). The patients increased gait instability in April 2019. DIAGNOSES Magnetic resonance imaging (MRI) showed progression of the disease. The lession at the left edge of the fourth ventricle and cerebellar peduncles was significantly increased. INTERVENTIONS The patient was administer TMZ (200 mg/m2/d, d1-5, 28 days as a cycle) + apatinib (250 mg, every other day). Twelve cycle of TMZ and apatinib were given. OUTCOMES The tumor significantly shrank during the patient received TMZ and apatinib. After 9 months of medication, MRI revealed a nearly complete response However, the tumor progressed on May 5, 2020. From the beginning of the application of TMZ and apatinib, the progression-free survival was 1 year and the survival time was 19 months. Grade 1 leukocytopenia was observed without other adverse effects. CONCLUSION Apatinib and temozolomide treatment with mild side effects may be a new option for children with recurrent ependyomams.
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Affiliation(s)
- Shuangshuang Zhao
- Department of Radiation Oncology, Hangzhou Cancer Hospital, Hangzhou, Zhejiang, P.R. China
| | - Zhipeng Shen
- Department of Neurosurgery, The Chilidren’s Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, PR China
| | - Juan Li
- Department of Radiation Oncology, Hangzhou Cancer Hospital, Hangzhou, Zhejiang, P.R. China
| | - Lei Shi
- Department of Radiation Oncology, Hangzhou Cancer Hospital, Hangzhou, Zhejiang, P.R. China
| | - Ni Zhang
- Department of Radiation Oncology, Hangzhou Cancer Hospital, Hangzhou, Zhejiang, P.R. China
- *Correspondence: Ni Zhang, Department of Radiation Oncology, Hangzhou Cancer Hospital, Hangzhou, Zhejiang, 310002, PR China (e-mail: )
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Chen C, Liu X, Deng L, Liao Y, Liu S, Hu P, Liang Q. Evaluation of the efficacy of transcatheter arterial embolization combined with apatinib on rabbit VX2 liver tumors by intravoxel incoherent motion diffusion-weighted MR imaging. Front Oncol 2022; 12:951587. [PMID: 36176396 PMCID: PMC9513231 DOI: 10.3389/fonc.2022.951587] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2022] [Accepted: 08/25/2022] [Indexed: 11/26/2022] Open
Abstract
Background and purpose It is crucial to evaluate the efficacy, recurrence, and metastasis of liver tumors after clinical treatment. This study aimed to investigate the value of Introvoxel Incoherent Motion (IVIM) imaging in the evaluation of rabbit VX2 liver tumors treated with Transcatheter Arterial Embolization (TAE) combined with apatinib. Methods Twenty rabbit VX2 liver tumor models were established and randomly divided into either the experimental group (n=15) or the control group (n=5). The experimental group was treated with TAE combined with oral apatinib after successful tumor inoculation, while no treatment was administered following inoculation in the control group. IVIM sequence scan was performed in the experimental group before treatment, at 7 and 14 days after treatment. All rabbits were sacrificed after the last scan of the experimental group. Marginal tissues from the tumors of both groups were excised for immunohistochemical analysis to observe and compare the expression of microvessel density (MVD). The alterations of IVIM-related parameters of tumor tissues in the experimental group, including Apparent Diffusion Coefficient (ADC), True Diffusion Coefficient (D), Pseudodiffusion Coefficient (D*), and Perfusion Fraction (f) were compared at different periods, and the correlation between these parameters and MVD was analyzed. Results After treatment, ADC and D values significantly increased, whereas D* and f values both decreased, with statistically significant differences.(P<0.05). The average tumor MVD of the experimental group after TAE combined with apatinib ((33.750 ± 6.743) bars/high power field (HPF)) was significantly lower than that in the control group ((64.200 ± 10.164) bars/HPF)). Moreover, D and f were positively correlated with tumor MVD in the experimental group (r=0.741 for D and r=0.668 for f, P<0.05). However, there was no significant correlation between ADC and D* values of the experimental group and tumor MVD (r=0.252 for ADC and r=0.198 for D*, P>0.05). Conclusion IVIM imaging can be employed to evaluate the efficacy of TAE combined with apatinib in rabbit VX2 liver tumors. Alterations in D and f values were closely related to the MVD of liver tumor tissues.
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Affiliation(s)
- Can Chen
- Department of Radiology, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Xiao Liu
- Department of Radiology, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Lingling Deng
- Department of Radiology, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Yunjie Liao
- Department of Radiology, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Sheng Liu
- Department of Radiology, The Third Xiangya Hospital, Central South University, Changsha, China
- Teaching and Research Section of Imaging and Nuclear Medicine, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Pengzhi Hu
- Department of Radiology, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Qi Liang
- Department of Radiology, The Third Xiangya Hospital, Central South University, Changsha, China
- *Correspondence: Qi Liang,
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Xu Y, Wang X, Sun C, Gao Z, He H, Qiu S, Guo Y, Ma X, Song J, Ma K. A phase II study of antiangiogenic therapy (Apatinib) plus chemotherapy as second-line treatment in advanced small cell lung cancer. Cancer Med 2022; 12:2979-2989. [PMID: 36082491 PMCID: PMC9939110 DOI: 10.1002/cam4.5217] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2022] [Revised: 08/03/2022] [Accepted: 08/23/2022] [Indexed: 11/12/2022] Open
Abstract
INTRODUCTION Currently, only a few options are available for the treatment of patients with small-cell lung cancer (SCLC) after the failure of first-line platinum-based chemotherapy. The present study aimed to evaluate the efficacy and safety of apatinib plus chemotherapy for second-line treatment of advanced SCLC. PATIENTS AND METHODS This prospective clinical trial recruited patients treated with apatinib plus second-line chemotherapy until disease progression or intolerable toxicity. Logrank test power analysis was used for calculating samples. The primary endpoint was progression-free survival (PFS), and the secondary endpoints were objective response rate (ORR), disease control rate (DCR), overall survival (OS), and safety. RESULTS A total of 29/31 enrolled patients were available for response evaluation until October 2019. The ORR and DCR were 27.59% (8/29) and 96.55% (28/29), respectively. The median PFS and OS were 7.36 months and 14.16 months, respectively, indicating better efficacy compared with the standard second-line chemotherapies. The most common adverse events (AEs) were neutropenia (41.94%, 13/31), followed by leucopenia (35.48%, 11/31) and thrombocytopenia (25.81%, 8/31). The grade 3-4 AEs occurred in 12 (38.71%) patients, of which neutropenia (19.35%, 6/31), leucopenia (9.68%, 3/31), and proteinuria (6.45%, 2/31) were most common. Patients receiving an initial dose of apatinib 250 mg had a better tolerance. CONCLUSION Antiangiogenic therapy plus chemotherapy had encouraging efficacy in advanced SCLC patients, which provides an insight into the current status of second-line therapy in SCLC.
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Affiliation(s)
- Yinghui Xu
- Cancer CenterThe First Hospital of Jilin UniversityChangchunChina
| | - Xu Wang
- Cancer CenterThe First Hospital of Jilin UniversityChangchunChina
| | - Chao Sun
- Cancer CenterThe First Hospital of Jilin UniversityChangchunChina
| | - Zhiru Gao
- Cancer CenterThe First Hospital of Jilin UniversityChangchunChina
| | - Hua He
- Cancer CenterThe First Hospital of Jilin UniversityChangchunChina
| | - Shi Qiu
- Cancer CenterThe First Hospital of Jilin UniversityChangchunChina
| | - Ye Guo
- Cancer CenterThe First Hospital of Jilin UniversityChangchunChina
| | - Xiaohui Ma
- Cancer CenterThe First Hospital of Jilin UniversityChangchunChina
| | - Junya Song
- Cancer CenterThe First Hospital of Jilin UniversityChangchunChina
| | - Kewei Ma
- Cancer CenterThe First Hospital of Jilin UniversityChangchunChina
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Synergistic Lethality Effects of Apatinib and Homoharringtonine in Acute Myeloid Leukemia. JOURNAL OF ONCOLOGY 2022; 2022:9005804. [PMID: 36081666 PMCID: PMC9448536 DOI: 10.1155/2022/9005804] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Accepted: 07/05/2022] [Indexed: 11/26/2022]
Abstract
Purpose The significance of vascular endothelial growth factor receptor (VEGFR)-2 in numerous solid tumors and acute myeloid leukemia (AML) has been demonstrated, but Apatinib remains largely unexplored. In this study, whether Apatinib combined with homoharringtonine (HHT) kills AML cell lines and its possible mechanisms have been explored. Methods AML cell lines were treated with Apatinib and HHT in different concentrations with control, Apatinib alone, HHT alone, and Apatinib combined with HHT. The changes of IC50 were measured by CCK8 assay, and apoptosis rate, cell cycle, and the mitochondrial membrane potential in each group were measured by flow cytometry. Finally, the possible cytotoxicity mechanism was analyzed by Western blotting. Results Our results noted that Apatinib combined with HHT remarkably inhibited cell proliferation, reduced the capacity of colony-forming, and induced apoptosis and cell cycle arrest in AML cells. Mechanistically, Apatinib and HHT play a role as a suppressor in the expression of VEGFR-2 and the downstream signaling cascades, such as the PI3K, MAPK, and STAT3 pathways. Conclusion Our preclinical data demonstrate that Apatinib combined with HHT exerts a better antileukemia effect than Apatinib alone by inhibiting the VEGFR-2 signaling pathway, suggesting the potential role of Apatinib and HHT in the treatment of AML. This study provides clinicians with innovative combination therapies and new therapeutic targets for the treatment of AML.
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Zeng T, Sun C, Liang Y, Yang F, Yan X, Bao S, Zhang Y, Huang X, Fu Z, Li W, Yin Y. A Real-World Multicentre Retrospective Study of Low-Dose Apatinib for Human Epidermal Growth Factor Receptor 2-Negative Metastatic Breast Cancer. Cancers (Basel) 2022; 14:cancers14174084. [PMID: 36077621 PMCID: PMC9454649 DOI: 10.3390/cancers14174084] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2022] [Revised: 08/13/2022] [Accepted: 08/20/2022] [Indexed: 11/16/2022] Open
Abstract
Treatment options for human epidermal growth factor receptor (HER2)-negative breast cancer patients are limited in comparison to the HER2-positive patients, particularly for metastatic breast cancer patients. Apatinib is a small-molecule tyrosine kinase inhibitor that targets the vascular endothelial growth factor receptor 2 (VEGFR-2). Here, we reported the apatinib-based therapy data in HER2-negative metastatic breast cancer. Apatinib was taken at a dose of 250 mg orally once per day and combined with standard chemotherapy regimens. The PFS and OS of 128 patients were 4.7 months and 15.3 months, respectively. The objective response rate (ORR) and the disease control rate (DCR) were 22.7% and 80.5%, respectively. Patients with breast cancer susceptibility gene (BRCA) mutations were found to have a longer PFS and OS. Moreover, combination immunotherapy or paclitaxel-platinum regimens shared an improved response to other regimens. Most of the adverse effects (hypertension, anaemia, and hand-foot syndrome) were grade 1 to 2. Metastatic breast cancer patients could benefit from apatinib therapy at a low dosage, and the adverse effects are mild in real-world clinical practice. Furthermore, BRCA may be a putative biomarker for apatinib in HER2-negative breast cancer. Immunotherapy or paclitaxel-platinum regimens may be recommended to combine with apatinib therapy.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | - Wei Li
- Correspondence: (W.L.); (Y.Y.); Tel.: +86-025-68307102 (W.L. & Y.Y.)
| | - Yongmei Yin
- Correspondence: (W.L.); (Y.Y.); Tel.: +86-025-68307102 (W.L. & Y.Y.)
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35
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Zhang HH, Du XJ, Deng ML, Zheng L, Yao DC, Wang ZQ, Yang QY, Wu SX. Apatinib for recurrent/progressive glioblastoma multiforme: A salvage option. Front Pharmacol 2022; 13:969565. [PMID: 36060005 PMCID: PMC9432461 DOI: 10.3389/fphar.2022.969565] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Accepted: 07/25/2022] [Indexed: 12/01/2022] Open
Abstract
Purpose: The recurrent/progressive glioblastoma multiforme (GBM) carries a dismal prognosis and the definitive treatment strategy has not yet been established. This study aimed to assess the efficacy and safety of apatinib in recurrent/progressive GBM patients. Materials and methods: The clinical data of 19 recurrent/progressive GBM patients who received apatinib treatment from November 2015 to December 2019 at Sun Yat-sen University Cancer Center were collected retrospectively in this study. Objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and treatment-related adverse events (AEs) were reviewed and assessed. Results: The overall ORR was 52.6%, and the DCR was 73.7%. Median PFS and OS were 5.1 and 10.4 months, respectively. The 6-month PFS and OS rates were 38.9% and 68.4%, respectively. The 12-month PFS and OS rates were 16.7% and 36.8%, respectively. The treatment-related toxicities were generally well-tolerated. The most common grade 3/4 AEs were hand-foot syndrome (36.8%) and hypertension (21.1%). Conclusion: Our study showed that apatinib therapy provided a better salvaging option for recurrent/progressive GBM patients and the toxicity was manageable.
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Affiliation(s)
- Hong-Hong Zhang
- Department of Radiation Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
- Department of Radiation Oncology, Xiang’an Hospital of Xiamen University, Cancer Research Center, School of Medicine, Xiamen University, Xiamen, China
| | - Xiao-Jing Du
- Department of Radiation Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Mei-Ling Deng
- Department of Radiation Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Lie Zheng
- Department of Medical Imaging, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Dun-Chen Yao
- Department of Radiation Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Zhi-Qiang Wang
- Department of Radiation Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Qun-Ying Yang
- Department of Neurosurgery, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Shao-Xiong Wu
- Department of Radiation Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
- *Correspondence: Shao-Xiong Wu,
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A curated binary pattern multitarget dataset of focused ATP-binding cassette transporter inhibitors. Sci Data 2022; 9:446. [PMID: 35882865 PMCID: PMC9325750 DOI: 10.1038/s41597-022-01506-z] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Accepted: 06/28/2022] [Indexed: 12/20/2022] Open
Abstract
Multitarget datasets that correlate bioactivity landscapes of small-molecules toward different related or unrelated pharmacological targets are crucial for novel drug design and discovery. ATP-binding cassette (ABC) transporters are critical membrane-bound transport proteins that impact drug and metabolite distribution in human disease as well as disease diagnosis and therapy. Molecular-structural patterns are of the highest importance for the drug discovery process as demonstrated by the novel drug discovery tool ‘computer-aided pattern analysis’ (‘C@PA’). Here, we report a multitarget dataset of 1,167 ABC transporter inhibitors analyzed for 604 molecular substructures in a statistical binary pattern distribution scheme. This binary pattern multitarget dataset (ABC_BPMDS) can be utilized for various areas. These areas include the intended design of (i) polypharmacological agents, (ii) highly potent and selective ABC transporter-targeting agents, but also (iii) agents that avoid clearance by the focused ABC transporters [e.g., at the blood-brain barrier (BBB)]. The information provided will not only facilitate novel drug prediction and discovery of ABC transporter-targeting agents, but also drug design in general in terms of pharmacokinetics and pharmacodynamics.
| Measurement(s) | Influx • Efflux • Tracer • Transport velocity | | Technology Type(s) | Fluorometry • Radioactivity • Plate reader • Flow cytometer • Tracer distribution | | Factor Type(s) | half-maximal inhibition concentration | | Sample Characteristic - Organism | Homo sapiens | | Sample Characteristic - Environment | cell culture | | Sample Characteristic - Location | Kingdom of Norway • Germany • Australia • Latvia |
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Li H, Huang H, Zhang T, Feng H, Wang S, Zhang Y, Ji X, Cheng X, Zhao R. Apatinib: A Novel Antiangiogenic Drug in Monotherapy or Combination Immunotherapy for Digestive System Malignancies. Front Immunol 2022; 13:937307. [PMID: 35844616 PMCID: PMC9276937 DOI: 10.3389/fimmu.2022.937307] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Accepted: 05/30/2022] [Indexed: 02/03/2023] Open
Abstract
Digestive system malignancies are one of the primary causes of cancer-related death. Meanwhile, angiogenesis has been proved to play an important role in the process of cancer neovascularization. Apatinib, a novel targeted antiangiogenic molecule, could generate highly selective competition in the vascular endothelial growth factor receptor-2, involved in tumor progression and metastasis. It has been implied as a promising cancer treatment agent that can prevent tumor cell proliferation meanwhile inhibit tumor angiogenesis. Furthermore, completed clinical trials demonstrated that apatinib could prolong the progression-free survival and overall survival in advanced gastric cancer and primary liver cancer. Recent studies revealed that apatinib had a synergistic effect with immunotherapy as a second-line and third-line treatment regimen for some other cancers. In this review, we summarize the pharmacological properties of apatinib and the latest clinical application in chemotherapy-refractory patients with advanced digestive system cancer. Based on the comparable survival results, the molecular mechanisms of apatinib are prospective to include the antiangiogenic, apoptosis-inducing, and autophagy-inducing properties in the corresponding signaling pathway. Treatment of apatinib monotherapy or combination immunotherapy remains the optimal option for patients with digestive system malignancies in the future.
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Affiliation(s)
- Haosheng Li
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Institute of Digestive surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Haiyan Huang
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Institute of Digestive surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Tao Zhang
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Institute of Digestive surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Haoran Feng
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Institute of Digestive surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Shaodong Wang
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Institute of Digestive surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yaqi Zhang
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Institute of Digestive surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiaopin Ji
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Institute of Digestive surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- *Correspondence: Xiaopin Ji, ; Xi Cheng, ; Ren Zhao,
| | - Xi Cheng
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Institute of Digestive surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- *Correspondence: Xiaopin Ji, ; Xi Cheng, ; Ren Zhao,
| | - Ren Zhao
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Institute of Digestive surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- *Correspondence: Xiaopin Ji, ; Xi Cheng, ; Ren Zhao,
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Lin H, Weng X, Wu X, Wu L. The efficacy and safety of apatinib in patients with recurrent or metastatic nasopharyngeal carcinoma: a systematic review and meta-analysis. Transl Cancer Res 2022; 11:1770-1780. [PMID: 35836539 PMCID: PMC9273677 DOI: 10.21037/tcr-22-1467] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2022] [Accepted: 06/17/2022] [Indexed: 01/02/2023]
Abstract
Background Apatinib is a small-molecule tyrosine kinase inhibitor targeting VEGFR-2, which was recently used in a phase II clinical trial for the treatment of recurrent or metastatic nasopharyngeal carcinoma (rmNPC). However, there is no consistent conclusion on its efficacy and safety on rmNPC. This study conducted a meta-analysis of clinical research on the efficacy and safety of apatinib in the treatment of rmNPC. Methods In April 2022, the PubMed, Web of Science, Scopus, Chinese National Knowledge Infrastructure (CNKI), CMB, and Wanfang databases were systematically searched, and relevant research literature were screened and analyzed. The clinical trial literatures using apatinib as the main single or combined treatment for rmNPC patients were selected and combined with objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and other efficacy and safety indicators. Results The meta-analysis included 12 studies, including 408 patients with rmNPC. The methodological index for nonrandomized studies scale was used to evaluate the bias of the included literatures and found that the bias was low. A total of 408 rmNPC patients were included in the included literature, with 11 studies being a phase II single-arm trial and one being a phase II non-randomized controlled trial. The ORR of patients with rmNPC treated with apatinib was 41.5% (95% CI: 34.8%, 48.2%), and the DCR was 80.2% (95% CI: 70.9%, 89.6%). The median PFS was 6.4 months (95% CI: 5.3, 7.4), and the median OS was 14.8 months (95% CI: 10.7, 18.9). The incidence of hypertension, hand-foot skin reaction, and proteinuria was 31% (95% CI: 19–43%), 29% (95% CI: 20–39%), and 13% (95% CI: 6–20%), respectively. Discussion The efficacy of apatinib in the treatment of rmNPC patients is similar to that of the previous second-line chemotherapy drugs, but since most studies are phase II single-arm studies, the advantages and disadvantages of the existing second-line chemotherapy regimens cannot be determined.
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Affiliation(s)
- Huixiong Lin
- Department of Internal Medicine-Oncology, Qionghai People's Hospital, Qionghai, China
| | - Xiangqian Weng
- Department of Radiotherapy, The First Affiliated Hospital of Hainan Medical University, Haikou, China
| | - Xiangji Wu
- Department of Otolaryngology Head and Neck Surgery, Qionghai People's Hospital, Qionghai, China
| | - Lizhong Wu
- Department of Otolaryngology Head and Neck Surgery, Qionghai People's Hospital, Qionghai, China
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Wu CP, Murakami M, Wu YS, Lin CL, Li YQ, Huang YH, Hung TH, Ambudkar SV. The multi-targeted tyrosine kinase inhibitor SKLB610 resensitizes ABCG2-overexpressing multidrug-resistant cancer cells to chemotherapeutic drugs. Biomed Pharmacother 2022; 149:112922. [PMID: 36068781 PMCID: PMC10506422 DOI: 10.1016/j.biopha.2022.112922] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2022] [Revised: 03/30/2022] [Accepted: 04/01/2022] [Indexed: 11/18/2022] Open
Abstract
The overexpression of ATP-binding cassette (ABC) transporter ABCB1 (P-glycoprotein) or ABCG2 (BCRP/MXR/ABCP) in cancer cells is frequently associated with the development of multidrug resistance (MDR) in cancer patients, which remains a major obstacle to effective cancer treatment. By utilizing energy derived from ATP hydrolysis, both transporters have been shown to reduce the chemosensitivity of cancer cells by actively effluxing cytotoxic anticancer drugs out of cancer cells. Knowing that there are presently no approved drugs or other therapeutics for the treatment of multidrug-resistant cancers, in recent years, studies have investigated the repurposing of tyrosine kinase inhibitors (TKIs) to act as agents against MDR mediated by ABCB1 and/or ABCG2. SKLB610 is a multi-targeted TKI with potent activity against vascular endothelial growth factor receptor 2 (VEGFR2), platelet-derived growth factor receptor (PDGFR), and fibroblast growth factor receptor 2 (FGFR2). In this study, we investigate the interaction of SKLB610 with ABCB1 and ABCG2. We discovered that neither ABCB1 nor ABCG2 confers resistance to SKLB610, but SKLB610 selectively sensitizes ABCG2-overexpressing multidrug-resistant cancer cells to cytotoxic anticancer agents in a concentration-dependent manner. Our data indicate that SKLB610 reverses ABCG2-mediated MDR by attenuating the drug-efflux function of ABCG2 without affecting its total cell expression. These findings are further supported by results of SKLB610-stimulated ABCG2 ATPase activity and in silico docking of SKLB610 in the drug-binding pocket of ABCG2. In summary, we reveal the potential of SKLB610 to overcome resistance to cytotoxic anticancer drugs, which offers an additional treatment option for patients with multidrug-resistant cancers and warrants further investigation.
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Affiliation(s)
- Chung-Pu Wu
- Graduate Institute of Biomedical Sciences, Chang Gung University, Taoyuan 33302, Taiwan; Department of Physiology and Pharmacology, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan; Department of Obstetrics and Gynecology, Taipei Chang Gung Memorial Hospital, Taipei 10507, Taiwan.
| | - Megumi Murakami
- Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, United States
| | - Yu-Shan Wu
- Department of Chemistry, Tunghai University, Taichung 40704, Taiwan
| | - Chun-Ling Lin
- Graduate Institute of Biomedical Sciences, Chang Gung University, Taoyuan 33302, Taiwan
| | - Yan-Qing Li
- Graduate Institute of Biomedical Sciences, Chang Gung University, Taoyuan 33302, Taiwan
| | - Yang-Hui Huang
- Graduate Institute of Biomedical Sciences, Chang Gung University, Taoyuan 33302, Taiwan; Department of Physiology and Pharmacology, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan
| | - Tai-Ho Hung
- Department of Obstetrics and Gynecology, Taipei Chang Gung Memorial Hospital, Taipei 10507, Taiwan; Department of Medicine, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan; Department of Obstetrics and Gynecology, Keelung Chang Gung Memorial Hospital, Keelung 20401, Taiwan
| | - Suresh V Ambudkar
- Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, United States
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40
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Zhang L, Ye B, Lin Y, Li YD, Wang JQ, Chen Z, Ping FF, Chen ZS. Ribociclib Inhibits P-gp-Mediated Multidrug Resistance in Human Epidermoid Carcinoma Cells. Front Pharmacol 2022; 13:867128. [PMID: 35450042 PMCID: PMC9016416 DOI: 10.3389/fphar.2022.867128] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Accepted: 03/08/2022] [Indexed: 11/13/2022] Open
Abstract
The efficacy of cancer chemotherapy can be attenuated or abrogated by multidrug resistance (MDR) in cancer cells. In this study, we determined the effect of the CDK4/6 inhibitor, ribociclib (or LEE011), on P-glycoprotein (P-gp)-mediated MDR in the human epidermoid carcinoma MDR cell line, KB-C2, which is widely used for studying P-gp-mediated MDR in cancers. The incubation of KB-C2 cells with ribociclib (3–9 µM) increased the efficacy of colchicine, a substrate for P-gp. The cell expression of P-gp was down-regulated at both translation and transcription levels. Furthermore, ribociclib produced a 3.5-fold increase in the basal activity of P-gp ATPase, and the concentration required to increase basal activity by 50% (EC50) was 0.04 μM. Docking studies indicated that ribociclib interacted with the drug-substrate binding site of P-gp. The short-term and long-term intracellular accumulation of doxorubicin greatly increased in the KB-C2 cells co-cultured with ribociclib, indicating ribociclib inhibited the drug efflux activity of P-gp. The results of our study indicate that LEE011 may be a potential agent for combined therapy of the cancers with P-gp mediated MDR.
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Affiliation(s)
- Lei Zhang
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, United States.,State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou, China.,University of Chinese Academy of Sciences, Beijing, China
| | - Biwei Ye
- State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou, China.,Fujian Agriculture and Forestry University, Fuzhou, China
| | - Yunfeng Lin
- State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou, China.,Fujian Agriculture and Forestry University, Fuzhou, China
| | - Yi-Dong Li
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, United States
| | - Jing-Quan Wang
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, United States
| | - Zhuo Chen
- State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou, China.,University of Chinese Academy of Sciences, Beijing, China
| | - Feng-Feng Ping
- Department of Reproductive Medicine, Wuxi People's Hospital Affiliated to Nanjing Medical University, Wuxi, China
| | - Zhe-Sheng Chen
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, United States
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41
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Preclinical studies of the triazolo[1,5-a]pyrimidine derivative WS-716 as a highly potent, specific and orally active P-glycoprotein (P-gp) inhibitor. Acta Pharm Sin B 2022; 12:3263-3280. [PMID: 35967279 PMCID: PMC9366537 DOI: 10.1016/j.apsb.2022.03.023] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2022] [Revised: 03/04/2022] [Accepted: 03/08/2022] [Indexed: 02/05/2023] Open
Abstract
Multidrug resistance (MDR) is the main cause of clinical treatment failure and poor prognosis in cancer. Targeting P-glycoprotein (P-gp) has been regarded as an effective strategy to overcome MDR. In this work, we reported our preclinical studies of the triazolo[1,5-a]pyrimidine-based compound WS-716 as a highly potent, specific, and orally active P-gp inhibitor. Through direct binding to P-gp, WS-716 inhibited efflux function of P-gp and specifically reversed P-gp-mediated MDR to paclitaxel (PTX) in multiple resistant cell lines, without changing its expression or subcellular localization. WS-716 and PTX synergistically inhibited formation of colony and 3D spheroid, induced apoptosis and cell cycle arrest at G2/M phase in resistant SW620/Ad300 cells. In addition, WS-716 displayed minimal effect on the drug-metabolizing enzyme cytochrome P4503A4 (CYP3A4). Importantly, WS-716 increased sensitivity of both pre-clinically and clinically derived MDR tumors to PTX in vivo with the T/C value of 29.7% in patient-derived xenograft (PDX) models. Relative to PTX treatment alone, combination of WS-716 and PTX caused no obvious adverse reactions. Taken together, our preclinical studies revealed therapeutic promise of WS-716 against MDR cancer, the promising data warrant its further development for cancer therapy.
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Fu H, Wu ZX, Lei ZN, Teng QX, Yang Y, Ashby CR, Lei Y, Lian Y, Chen ZS. The Resistance of Cancer Cells to Palbociclib, a Cyclin-Dependent Kinase 4/6 Inhibitor, is Mediated by the ABCB1 Transporter. Front Pharmacol 2022; 13:861642. [PMID: 35350768 PMCID: PMC8957877 DOI: 10.3389/fphar.2022.861642] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Accepted: 02/18/2022] [Indexed: 11/13/2022] Open
Abstract
Palbociclib was approved by the United States Food and Drug Administration for use, in combination with letrozole, as a first-line treatment for estrogen receptor-positive/human epidermal growth factor receptor 2-negative (ER+/HER2-) postmenopausal metastatic breast cancer. However, recent studies show that palbociclib may be an inhibitor of the ABCB1 transporter, although this remains to be elucidated. Therefore, we conducted experiments to determine the interaction of palbociclib with the ABCB1 transporter. Our in vitro results indicated that the efficacy of palbociclib was significantly decreased in the ABCB1-overexpressing cell lines. Furthermore, the resistance of ABCB1-overexpressing cells to palbociclib was reversed by 3 μM of the ABCB1 inhibitor, verapamil. Moreover, the incubation of ABCB1-overexpressing KB-C2 and SW620/Ad300 cells with up to 5 μM of palbociclib for 72 h, significantly upregulated the protein expression of ABCB1. The incubation with 3 µM of palbociclib for 2h significantly increased the intracellular accumulation of [3H]-paclitaxel, a substrate of ABCB1, in ABCB1 overexpressing KB-C2 cells but not in the corresponding non-resistant parental KB-3-1 cell line. However, the incubation of KB-C2 cells with 3 μM of palbociclib for 72 h decreased the intracellular accumulation of [3H]-paclitaxel due to an increase in the expression of the ABCB1 protein. Palbociclib produced a concentration-dependent increase in the basal ATPase activity of the ABCB1 transporter (EC50 = 4.73 μM). Molecular docking data indicated that palbociclib had a high binding affinity for the ABCB1 transporter at the substrate binding site, suggesting that palbociclib may compete with other ABCB1 substrates for the substrate binding site of the ABCB1. Overall, our results indicate that palbociclib is a substrate for the ABCB1 transporter and that its in vitro anticancer efficacy is significantly decreased in cancer cells overexpressing the ABCB1.
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Affiliation(s)
- Han Fu
- School of Public Health, Guangzhou Medical University, Guangzhou, China
| | - Zhuo-Xun Wu
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, United States
| | - Zi-Ning Lei
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, United States.,Guangdong Provincial Key Laboratory of Digestive Cancer Research, Precision Medicine Center, The Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen, China
| | - Qiu-Xu Teng
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, United States
| | - Yuqi Yang
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, United States
| | - Charles R Ashby
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, United States
| | - Yixiong Lei
- School of Public Health, Guangzhou Medical University, Guangzhou, China
| | - Yuyin Lian
- School of Public Health, Guangzhou Medical University, Guangzhou, China
| | - Zhe-Sheng Chen
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, United States
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43
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Malekan M, Ebrahimzadeh MA. Vascular Endothelial Growth Factor Receptors [VEGFR] as Target in Breast Cancer Treatment: Current Status in Preclinical and Clinical Studies and Future Directions. Curr Top Med Chem 2022; 22:891-920. [PMID: 35260067 DOI: 10.2174/1568026622666220308161710] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Revised: 01/11/2022] [Accepted: 01/20/2022] [Indexed: 12/09/2022]
Abstract
Breast cancer [BC] is one of the most common cancers among women, one of the leading causes of a considerable number of cancer-related death globally. Among all procedures leading to the formation of breast tumors, angiogenesis has an important role in cancer progression and outcomes. Therefore, various anti-angiogenic strategies have developed so far to enhance treatment's efficacy in different types of BC. Vascular endothelial growth factors [VEGFs] and their receptors are regarded as the most well-known regulators of neovascularization. VEGF binding to vascular endothelial growth factor receptors [VEGFRs] provides cell proliferation and vascular tissue formation by the subsequent tyrosine kinase pathway. VEGF/VEGFR axis displays an attractive target for anti-angiogenesis and anti-cancer drug design. This review aims to describe the existing literature regarding VEGFR inhibitors, focusing on BC treatment reported in the last two decades.
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Affiliation(s)
- Mohammad Malekan
- Student Research Committee, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
| | - Mohammad Ali Ebrahimzadeh
- Pharmaceutical Sciences Research Center, School of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran
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44
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Boichuk S, Dunaev P, Mustafin I, Mani S, Syuzov K, Valeeva E, Bikinieva F, Galembikova A. Infigratinib (BGJ 398), a Pan-FGFR Inhibitor, Targets P-Glycoprotein and Increases Chemotherapeutic-Induced Mortality of Multidrug-Resistant Tumor Cells. Biomedicines 2022; 10:biomedicines10030601. [PMID: 35327403 PMCID: PMC8945560 DOI: 10.3390/biomedicines10030601] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Revised: 02/24/2022] [Accepted: 02/28/2022] [Indexed: 02/01/2023] Open
Abstract
The microtubule-targeting agents (MTAs) are well-known chemotherapeutic agents commonly used for therapy of a broad spectrum of human malignancies, exhibiting epithelial origin, including breast, lung, and prostate cancer. Despite the impressive response rates shortly after initiation of MTA-based therapy, the vast majority of human malignancies develop resistance to MTAs due to the different mechanisms. Here, we report that infigratinib (BGJ 398), a potent FGFR1-4 inhibitor, restores sensitivity of a broad spectrum of ABCB1-overexpressing cancer cells to certain chemotherapeutic agents, including paclitaxel (PTX) and doxorubicin (Dox). This was evidenced for the triple-negative breast cancer (TNBC), and gastrointestinal stromal tumor (GIST) cell lines, as well. Indeed, when MDR-overexpressing cancer cells were treated with a combination of BGJ 398 and PTX (or Dox), we observed a significant increase of apoptosis which was evidenced by an increased expression of cleaved forms of PARP, caspase-3, and increased numbers of Annexin V-positive cells, as well. Moreover, BGJ 398 used in combination with PTX significantly decreased the viability and proliferation of the resistant cancer cells. As expected, no apoptosis was found in ABCB1-overexpressing cancer cells treated with PTX, Dox, or BGJ 398 alone. Inhibition of FGFR-signaling by BGJ 398 was evidenced by the decreased expression of phosphorylated (i.e., activated) forms of FGFR and FRS-2, a well-known adaptor protein of FGFR signaling, and downstream signaling molecules (e.g., STAT-1, -3, and S6). In contrast, expression of MDR-related ABC-transporters did not change after BGJ 398 treatment, thereby suggesting an impaired function of MDR-related ABC-transporters. By using the fluorescent-labeled chemotherapeutic agent PTX-Alexa488 (Flutax-2) and doxorubicin, exhibiting an intrinsic fluorescence, we found that BGJ 398 substantially impairs their efflux from MDR-overexpressing TNBC cells. Moreover, the efflux of Calcein AM, a well-known substrate for ABCB1, was also significantly impaired in BGJ 398-treated cancer cells, thereby suggesting the ABCB1 as a novel molecular target for BGJ 398. Of note, PD 173074, a potent FGFR1 and VEGFR2 inhibitor failed to retain chemotherapeutic agents inside ABCB1-overexpressing cells. This was consistent with the inability of PD 173074 to sensitize Tx-R cancer cells to PTX and Dox. Collectively, we show here for the first time that BGJ 398 reverses the sensitivity of MDR-overexpressing cancer cells to certain chemotherapeutic agents due to inhibition of their efflux from cancer cells via ABCB1-mediated mechanism.
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Affiliation(s)
- Sergei Boichuk
- Department of Pathology, Kazan State Medical University, 420012 Kazan, Russia; (P.D.); (S.M.); (K.S.); (F.B.); (A.G.)
- Сentral Research Laboratory, Kazan State Medical University, 420012 Kazan, Russia;
- Department of Radiotherapy and Radiology, Faculty of Surgery, Russian Medical Academy of Continuous Professional Education, 125993 Moscow, Russia
- Correspondence: ; Tel.: +7-917-397-80-93; Fax: +7-843-236-06-52
| | - Pavel Dunaev
- Department of Pathology, Kazan State Medical University, 420012 Kazan, Russia; (P.D.); (S.M.); (K.S.); (F.B.); (A.G.)
| | - Ilshat Mustafin
- Department of Biochemistry, Kazan State Medical University, 420012 Kazan, Russia;
| | - Shinjit Mani
- Department of Pathology, Kazan State Medical University, 420012 Kazan, Russia; (P.D.); (S.M.); (K.S.); (F.B.); (A.G.)
| | - Kirill Syuzov
- Department of Pathology, Kazan State Medical University, 420012 Kazan, Russia; (P.D.); (S.M.); (K.S.); (F.B.); (A.G.)
| | - Elena Valeeva
- Сentral Research Laboratory, Kazan State Medical University, 420012 Kazan, Russia;
| | - Firuza Bikinieva
- Department of Pathology, Kazan State Medical University, 420012 Kazan, Russia; (P.D.); (S.M.); (K.S.); (F.B.); (A.G.)
| | - Aigul Galembikova
- Department of Pathology, Kazan State Medical University, 420012 Kazan, Russia; (P.D.); (S.M.); (K.S.); (F.B.); (A.G.)
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45
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Exploration of novel phthalazinone derivatives as potential efflux transporter inhibitors for reversing multidrug resistance and improving the oral absorption of paclitaxel. Eur J Med Chem 2022; 233:114231. [PMID: 35247755 DOI: 10.1016/j.ejmech.2022.114231] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2021] [Revised: 02/21/2022] [Accepted: 02/22/2022] [Indexed: 11/23/2022]
Abstract
Chemotherapy is an important means of cancer treatment. However, overexpression of efflux transporters (including but not limited to P-gp and BCRP) can lead to resistance to cancer chemotherapy. Multiple-target inhibitors of efflux transporter can be overcome the resistance and improve the oral bioavailability of chemotherapy drugs. Therefore, we designed and synthesized a series of phthalazinone ring derivatives (1-20) with different aromatic heterocycles substituents on the amide bond for dual inhibition of P-gp and BCRP. Most target compounds significantly increased the accumulation of P-gp substrates in the chemo-resistant cancer cell lines by inhibiting the efflux of transporters. Compound 19 in particular showed stronger MDR reversal compared to Gefitinib and Verapamil, and comparable to that of the BCRP inhibitor Ko143. In addition, compound 19 improved intestinal absorption of paclitaxel (PTX) and enhanced the bioavailability of the orally administered drug in vivo.
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46
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Wang G, Cao L, Jiang Y, Zhang T, Wang H, Wang Z, Xu J, Mao M, Hua Y, Cai Z, Ma X, Hu S, Zhou C. Anlotinib Reverses Multidrug Resistance (MDR) in Osteosarcoma by Inhibiting P-Glycoprotein (PGP1) Function In Vitro and In Vivo. Front Pharmacol 2022; 12:798837. [PMID: 35111065 PMCID: PMC8801797 DOI: 10.3389/fphar.2021.798837] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2021] [Accepted: 12/28/2021] [Indexed: 12/26/2022] Open
Abstract
Overexpression of the multidrug resistance (MDR)-related protein P-glycoprotein (PGP1), which actively extrudes chemotherapeutic agents from cells and significantly decreases the efficacy of chemotherapy, is viewed as a major obstacle in osteosarcoma chemotherapy. Anlotinib, a novel tyrosine kinase inhibitor (TKI), has good anti-tumor effects in a variety of solid tumors. However, there are few studies on the mechanism of anlotinib reversing chemotherapy resistance in osteosarcoma. In this study, cellular assays were performed in vitro and in vivo to evaluate the MDR reversal effects of anlotinib on multidrug-resistant osteosarcoma cell lines. Drug efflux and intracellular drug accumulation were measured by flow cytometry. The vanadate-sensitive ATPase activity of PGP1 was measured in the presence of a range of anlotinib concentrations. The protein expression level of ABCB1 was detected by Western blotting and immunofluorescence analysis. Our results showed that anlotinib significantly increased the sensitivity of KHOSR2 and U2OSR2 cells (which overexpress PGP1) to chemotherapeutic agents in vitro and in a KHOSR2 xenograft nude mouse model in vivo. Mechanistically, anlotinib increases the intracellular accumulation of PGP1 substrates by inhibiting the efflux function of PGP1 in multidrug-resistant cell lines. Furthermore, anlotinib stimulated the ATPase activity of PGP1 but affected neither the protein expression level nor the localization of PGP1. In animal studies, anlotinib in combination with doxorubicin (DOX) significantly decreased the tumor growth rate and the tumor size in the KHOSR2 xenograft nude mouse model. Overall, our findings suggest that anlotinib may be useful for circumventing MDR to other conventional antineoplastic drugs.
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Affiliation(s)
- Gangyang Wang
- Department of Orthopaedics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Shanghai Bone Tumor Institute, Shanghai, China
| | - Lingling Cao
- Department of Rehabilitation, Shanghai Fifth Rehabilitation Hospital, Shanghai, China
| | - Yafei Jiang
- Department of Orthopaedics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Shanghai Bone Tumor Institute, Shanghai, China
| | - Tao Zhang
- Department of Orthopaedics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Shanghai Bone Tumor Institute, Shanghai, China
| | - Hongsheng Wang
- Department of Orthopaedics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Shanghai Bone Tumor Institute, Shanghai, China
| | - Zhuoying Wang
- Department of Orthopaedics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Shanghai Bone Tumor Institute, Shanghai, China
| | - Jing Xu
- Department of Orthopaedics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Shanghai Bone Tumor Institute, Shanghai, China
| | - Min Mao
- Department of Orthopaedics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Shanghai Bone Tumor Institute, Shanghai, China
| | - Yingqi Hua
- Department of Orthopaedics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Shanghai Bone Tumor Institute, Shanghai, China
| | - Zhengdong Cai
- Department of Orthopaedics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Shanghai Bone Tumor Institute, Shanghai, China
| | - Xiaojun Ma
- Department of Orthopaedics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Shanghai Bone Tumor Institute, Shanghai, China
| | - Shuo Hu
- Department of Orthopaedics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Shanghai Bone Tumor Institute, Shanghai, China
| | - Chenghao Zhou
- Department of Orthopaedics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Shanghai Bone Tumor Institute, Shanghai, China
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Teng F, Xing P, Yang K, Gao L, Tian Z, Li J. Apatinib as maintenance therapy following standard first-line chemotherapy in extensive disease small cell lung cancer: A phase II single-arm trial. Thorac Cancer 2022; 13:557-562. [PMID: 35029038 PMCID: PMC8841707 DOI: 10.1111/1759-7714.14298] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2021] [Revised: 12/13/2021] [Accepted: 12/14/2021] [Indexed: 12/03/2022] Open
Abstract
BACKGROUND There is a need for the development of therapies to delay cancer progression and prolong survival after initial chemotherapy for the treatment of small cell lung cancer (SCLC). Since apatinib has been found to exert promising effects on cancer patients after standard first-line chemotherapy, this study aimed to investigate apatinib as a maintenance treatment following first-line chemotherapy in extensive disease (ED)-SCLC. METHODS The primary endpoints were overall survival (OS) and progression-free survival (PFS). The secondary endpoints included toxicity and safety. Apatinib (250 mg/day) was administered during the chemotherapy interval and as maintenance therapy after 4-6 cycles until the patient's disease progressed, the patient died, or became intolerant to the drug's toxicity. RESULTS The patients who received apatinib maintenance treatment had a median PFS of 3.7 months (95% CI: 1.3-6.2 months). The median OS was 16.3 months (95% CI: 9.7-22.8 months). The objective response rate and disease control rate were 50.0% and 66.7%, respectively. Two patients required dose reduction due to adverse effects (AEs). The most common AEs included hypertension (n = 4, 33.3%) and hand-foot-skin reaction (n = 2, 16.7%). One patient developed diarrhea, while another patient developed hemoptysis. The most serious AE was intestinal obstruction. CONCLUSIONS Apatinib maintenance therapy showed promising efficacy and safety to extend the OS/PFS of patients with ED-SCLC, thus making it a potent therapeutic option in future clinical practice. Given the small sample size of this study, further studies with large sample sizes are needed to validate the findings of the present study.
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Affiliation(s)
- Fei Teng
- Department of Medical OncologyNational Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Puyuan Xing
- Department of Medical OncologyNational Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Ke Yang
- Department of Medical OncologyCancer Hospital of Huanxing ChaoYang District BeijingBeijingChina
| | - Lizhen Gao
- Department of Medical OncologyCancer Hospital of Huanxing ChaoYang District BeijingBeijingChina
| | - Zhongqiu Tian
- Department of Medical OncologyCancer Hospital of Huanxing ChaoYang District BeijingBeijingChina
| | - Junling Li
- Department of Medical OncologyNational Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
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48
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Aytatli A, Barlak N, Sanli F, Caglar HO, Gundogdu B, Tatar A, Ittmann M, Karatas OF. AZD4547 targets the FGFR/Akt/SOX2 axis to overcome paclitaxel resistance in head and neck cancer. Cell Oncol (Dordr) 2022; 45:41-56. [PMID: 34837170 DOI: 10.1007/s13402-021-00645-6] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/25/2021] [Indexed: 12/22/2022] Open
Abstract
PURPOSE Development of chemoresistance is one of the major obstacles to the treatment of head and neck squamous cell carcinoma (HNSCC). The PI3K/Akt pathway, involved in drug resistance, has been found to be overactivated in > 90% of HNSCCs. Aberrant activation of the FGF receptors (FGFRs) has been reported to cause overactivation of the PI3K/Akt pathway and to be associated with the maintenance of stem cell features, which is controlled via SOX2 expression. In this study, we aimed at investigating the potential of using AZD4547, an orally bioavailable FGFR inhibitor, to overcome taxol-resistance by targeting the FGFR/Akt/SOX2 axis in HNSCC. METHODS We initially evaluated FGFR2 and SOX2 expression using in silico tools. We analyzed the FGFR/Akt/SOX2 axis in normal/tumor tissue pairs and in recombinant FGF2 treated HNSCC cells. Next, we explored the effects of AZD4547 alone and in combination with taxol on the proliferation, migration and colony forming capacities of parental/taxol-resistant cells using in vitro models. RESULTS We found that the p-FGFR, p-AKT, p-GSK-3β and SOX2 expression levels were higher in tumor tissues than in its corresponding normal tissues, and that AZD4547 effectively suppressed the expression of FGFR and its downstream targets in recombinant FGF2 treated HNSCC cells. We also found that AZD4547 diminished the viability, migration and colony forming capacity of HNSCC cells, and that co-treatment with taxol potentiated the impact of taxol on these cells. Finally, we found that AZD4547 inhibited the overexpressed FGFR/Akt/SOX2 axis and profoundly suppressed cancer-related phenotypes in taxol-resistant HNSCC cells. CONCLUSION From our data we conclude that AZD4547 may increase the impact of taxol during HNSCC treatment. We suggest AZD4547 as a therapeutic agent to overcome taxol-resistance.
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Affiliation(s)
- Abdulmelik Aytatli
- Department of Molecular Biology and Genetics, Erzurum Technical University, Omer Nasuhi Bilmen Mah. Havaalani Yolu Cad. No: 53 Yakutiye, Erzurum, Turkey
- Molecular Cancer Biology Laboratory, High Technology Application and Research Center, Erzurum Technical University, Erzurum, Turkey
| | - Neslisah Barlak
- Department of Molecular Biology and Genetics, Erzurum Technical University, Omer Nasuhi Bilmen Mah. Havaalani Yolu Cad. No: 53 Yakutiye, Erzurum, Turkey
- Molecular Cancer Biology Laboratory, High Technology Application and Research Center, Erzurum Technical University, Erzurum, Turkey
| | - Fatma Sanli
- Department of Molecular Biology and Genetics, Erzurum Technical University, Omer Nasuhi Bilmen Mah. Havaalani Yolu Cad. No: 53 Yakutiye, Erzurum, Turkey
- Molecular Cancer Biology Laboratory, High Technology Application and Research Center, Erzurum Technical University, Erzurum, Turkey
| | - Hasan Onur Caglar
- Department of Molecular Biology and Genetics, Erzurum Technical University, Omer Nasuhi Bilmen Mah. Havaalani Yolu Cad. No: 53 Yakutiye, Erzurum, Turkey
| | - Betul Gundogdu
- Department of Medical Pathology, Faculty of Medicine, Ataturk University, Erzurum, Turkey
| | - Arzu Tatar
- Department of Otorhinolaryngology Diseases, Faculty of Medicine, Ataturk University, Erzurum, Turkey
| | - Michael Ittmann
- Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX, 77030, USA
- Michael E. DeBakey VAMC, Houston, TX, 77030, USA
| | - Omer Faruk Karatas
- Department of Molecular Biology and Genetics, Erzurum Technical University, Omer Nasuhi Bilmen Mah. Havaalani Yolu Cad. No: 53 Yakutiye, Erzurum, Turkey.
- Molecular Cancer Biology Laboratory, High Technology Application and Research Center, Erzurum Technical University, Erzurum, Turkey.
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Xie Q, Wang J, Wu W, Zhao Y. Apatinib inhibits paclitaxel resistance of gastric carcinoma cells through VEGFR2 pathway. Am J Transl Res 2022; 14:421-431. [PMID: 35173861 PMCID: PMC8829625] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2021] [Accepted: 11/09/2021] [Indexed: 06/14/2023]
Abstract
Drug resistance of gastric carcinoma (GC) is a burning question in the medical field. This study aimed to investigating the ameliorative effect of apatinib (Apa) on paclitaxel (PTX) resistance in GC. In this research, PTX-resistant MGC803 cells were intervened by Apa. Cell proliferation was detected by cell counting kit-8 (CCK-8) assay, and cell migration and invasion was determined by Transwell assays. The levels of apoptosis-related proteins (Bcl-2, Bax), drug resistance-related proteins (MDR1, P-gp) and VEGFR2 protein were measure by Western blot, and the mRNA expression of VEGFR2 was tested by real-time quantitative polymerase chain reaction (RT-qPCR). Then VEGFR2 was overexpressed to examine the role of Apa in PTX-resistant MGC803 cells. The results identified a significantly reduced growth rate of MGC803/PTX cells after PTX induction, obviously increased invasive and migrated cells, and evidently enhanced proliferation capacity of MGC803/PTX cells as compared to MGC803 cells. In MGC803/PTX cells, VEGFR2, MDR1, P-gp and Bcl-2 were all up-regulated while Bax was down-regulated. After Apa intervention, PTX-resistant MGC803 cells showed decreased cell migration, invasion and proliferation, reduced MDR1, P-gp and VEGFR2 levels, and increased Bax protein level. Overexpression of VEGFR2 can offset the rescue effect of Apa on PTX-induced drug resistance of MGC803 cells. Taken together, Apa may inhibit PTX resistance of MGC803 cells via the VEGFR2 signaling pathway.
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Affiliation(s)
- Qian Xie
- Kindos Pharmaceuticals Co., Ltd.Chengdu 611731, Sichuan, China
| | - Jing Wang
- Kindos Pharmaceuticals Co., Ltd.Chengdu 611731, Sichuan, China
| | - Wenwen Wu
- Sichuan Institute of Food InspectionChengdu 610097, Sichuan, China
| | - Ye Zhao
- Chengdu Medical College, School of Bioscience and TechnologyChengdu 610500, Sichuan, China
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Dong S, Ou W, Zhong Y, Zhu X, Cai Q, Zhang J, Ran F, Qian Y, Wang J, Hu S. A single-arm, prospective study of apatinib mesylate plus pemetrexed in patients of advanced non-squamous non-small cell lung cancer after failure of previous chemotherapy. ANNALS OF TRANSLATIONAL MEDICINE 2022; 10:101. [PMID: 35282037 PMCID: PMC8848392 DOI: 10.21037/atm-22-79] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Accepted: 01/18/2022] [Indexed: 11/14/2022]
Abstract
Background The outcomes of advanced non-small cell lung cancer (NSCLC) patients after first- or second-line therapy are still discouraging due to a lack of effective treatment strategies. As a novel oral anti-angiogenesis drug, apatinib, approved by the National Medical Products Administration of China only for advanced gastric cancer, has been increasingly used in off-label treatment across various cancer types in recent years, especially advanced NSCLC. It has shown strong anti-tumor efficacy and acceptable safety. Methods This prospective study (NCT02974933) was conducted in patients with advanced NSCLC, who had suffered disease progression from the first- or second-line treatment, in Hubei Cancer Hospital. Eligible patients were enrolled and administrated with apatinib mesylate (500 mg qd) in combination with pemetrexed (500 mg/m2, every 4 weeks). The primary endpoint was progression-free survival (PFS). Results From September 2016 to September 2019, a total of 21 advanced NSCLC patients were enrolled in Hubei Cancer Hospital. As of January 2021, treatment was discontinued in all patients, with 1 still in follow-up. There were 7/21 (33.3%) patients who achieved objective response. The median PFS and median overall survival (OS) were 7.0 months (95% CI: 6.15-7.85 months) and 13.0 months (95% CI: 7.39-18.6 months), respectively. Toxicities were tolerable or could be clinically managed. The most common grade 3-4 adverse events (AEs) were hypertension (14.3%, 3/21), hand-foot syndrome (4.7%, 1/21), and proteinuria (4.7%, 1/21). Hematological toxicities were moderate, with rare occurrences of grade 3/4 toxicities. During the period of treatment, there was no occurrence of treatment-related death. Conclusions Apatinib plus pemetrexed demonstrated promising efficacy and a high level of safety profile in previously heavily-treated NSCLC patients. More definitive studies on the combination of apatinib and pemetrexed are warranted.
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Affiliation(s)
- Shuang Dong
- Department of Medical Oncology, Hubei Cancer Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Wuling Ou
- Department of Medical Oncology, Hubei Cancer Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yi Zhong
- Department of Medical Oncology, Hubei Cancer Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xianmin Zhu
- Department of Medical Oncology, Hubei Cancer Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Qian Cai
- Department of Medical Oncology, Hubei Cancer Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jing Zhang
- Department of Medical Oncology, Hubei Cancer Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Fengming Ran
- Department of Medical Oncology, Hubei Cancer Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yu Qian
- Department of Medical Oncology, Hubei Cancer Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jun Wang
- Department of Medical Oncology, Hubei Cancer Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Sheng Hu
- Department of Medical Oncology, Hubei Cancer Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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