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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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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: 0] [Impact Index Per Article: 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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Luo J, Zheng Z, Yu R. Analysis of medical malpractice liability disputes related to novel antineoplastic drugs and research on risk prevention and control strategies. PLoS One 2023; 18:e0286623. [PMID: 37276214 DOI: 10.1371/journal.pone.0286623] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Accepted: 05/22/2023] [Indexed: 06/07/2023] Open
Abstract
OBJECTIVE To investigate the general characteristics of litigation cases of medical malpractice liability disputes (MMLDs) related to novel antineoplastic drugs (NADs), the drugs involved, as well as the common types of medical errors related to NADs and their damages in the process of diagnosis and treatment, with the aims of improving the level of rational medication use in the clinical application of NADs and actively prevent medical disputes. METHODS The China Judgments Online was searched for the cause of action using the key word "MMLDs" along with the name of 77 kinds of NADs. A total of 39 NAD litigation cases meeting the inclusion criteria from 1 January 2009 to 31 December 2021 were analyzed, and each potential adverse drug reaction (ADR) was reviewed to determine a causality assessment using the Naranjo algorithm for non-drug-induced liver injury (DILI) cases and the updated Roussel Uclaf Causality Assessment Method (RUCAM) for the DILI cases. Risk prevention and control strategies were recommended. RESULTS Cases that met the inclusion criteria increased substantially each year during the last six years, from three cases in 2009-2015 to 36 cases in 2016-2021. There were more cases in Eastern China than in other geographic regions. Most cases involved tertiary hospitals, patients between 25 and 60 years of age, and patients who were predominately male. There were 18 kinds of NADs involved in medical errors. The most common consequences of NADs were closely related to the death, disability, and increased treatment costs caused by ADRs, inadequate indications, delayed diagnosis and treatment, and misdiagnosis and mistreatment. The most frequent medical errors were medical technology errors, medical ethics errors and medical record writing/safekeeping errors. In two cases involving DILI, one case was unable to undergo further RUCAM scoring because the liver function indicators of the patient before and after treatment were not published. CONCLUSION The establishment of mechanisms to reduce the risks associated with the clinical application of NADs is warranted. Healthcare services must maintain strict adherence to the specific requirements of GPCANADs and drug instructions and strictly grasp the indications, contraindications, usage, and dosage of drugs, and strengthen the notification and management of off-label drug use. Monitoring patients for ADRs and preparing rescue and treatment measures for high-risk drugs may serve to reduce damages related to NADs. For DILI cases, medical and appraisal institutions should use RUCAM score to assess causal relationships.
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Affiliation(s)
- Jinyu Luo
- Division of Nursing, Hemopurification Center, Tongde Hospital of Zhejiang Province, Hangzhou, Zhejiang Province, People's Republic of China
| | - Zaoqian Zheng
- Department of Pharmacy, Tongde Hospital of Zhejiang Province, Hangzhou, Zhejiang, People's Republic of China
- Division of Medical Administration, Tongde Hospital of Zhejiang Province, Hangzhou, Zhejiang, People's Republic of China
- Division of Medical Administration, Zhejiang Academy of Traditional Chinese Medicine, Hangzhou, Zhejiang, People's Republic of China
| | - Rongliang Yu
- Division of Medical Administration, Tongde Hospital of Zhejiang Province, Hangzhou, Zhejiang, People's Republic of China
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Deng YY, Jiang DY, Zhu PF, Lu H, Liu Q, Zhang X, Pan SY, Chen ZL, Yang L. Apatinib combined with SOX regimen for conversion therapy in advanced gastric cancer patients: a retrospective cohort study. World J Surg Oncol 2023; 21:129. [PMID: 37041581 PMCID: PMC10088230 DOI: 10.1186/s12957-023-02973-3] [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: 10/20/2022] [Accepted: 02/27/2023] [Indexed: 04/13/2023] Open
Abstract
BACKGROUND Recently, many studies have shown that the progress of conversion therapy can provide surgical opportunities for patients with advanced gastric cancer (GC) and bring survival benefits. However, the results of the current study show that the regimen used in conversion therapy is still controversial. Apatinib, as the standard third-line treatment for GC, has an inconclusive status in conversion therapy. METHODS This study retrospectively analyzed GC patients admitted to Zhejiang Provincial People's Hospital from June 2016 to November 2019. All patients were pathologically diagnosed, had unresectable factors, and received SOX regimen with or without apatinib as conversion therapy. RESULTS A total of 50 patients were enrolled in the study. Altogether 33 patients (66%) received conversion surgery and 17 patients (34%) received conversion therapy without surgery. The median progression-free survival (PFS) between surgery group and non-surgery group were 21.0 versus 4.0 months (p < 0.0001), and the median overall survival (OS) were 29.0 versus 14.0 months (p < 0.0001). In conversion surgery group, 16 patients (16/33) were treated with SOX plus apatinib, and the R0 resection rate was 81.3%; 17 patients (17/33) were treated with SOX regimen along, and the R0 resection rate was 41.2% (p = 0.032). The PFS in the SOX combined with apatinib group was significantly longer than that of SOX group (25.5 versus 16 months, p = 0.045), and the median OS were 34.0 versus 23.0 months (p = 0.048). The addition of apatinib did not increase the incidence of serious adverse reactions throughout the preoperative therapy period. CONCLUSIONS Patients with advanced inoperable gastric cancer could benefit probably from conversion chemotherapy and subsequence conversion surgery. Apatinib-targeted therapy combined with SOX chemotherapy may be a safe and feasible option for conversion therapy.
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Affiliation(s)
- Ya-Ya Deng
- Cancer Center, Department of Medical Oncology, Zhejiang Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical College), Hangzhou, Zhejiang, 310014, China
- The Qingdao University Medical College, Qingdao, Shandong Province, 260075, China
| | - Ding-Yi Jiang
- Cancer Center, Department of Medical Oncology, Zhejiang Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical College), Hangzhou, Zhejiang, 310014, China
- The Qingdao University Medical College, Qingdao, Shandong Province, 260075, China
| | - Peng-Fei Zhu
- The Qingdao University Medical College, Qingdao, Shandong Province, 260075, China
- Graduate School of Clinical Medicine, Bengbu Medical College, Bengbu, 233000, Anhui Province, China
| | - Hongrui Lu
- The Qingdao University Medical College, Qingdao, Shandong Province, 260075, China
- Graduate School of Clinical Medicine, Bengbu Medical College, Bengbu, 233000, Anhui Province, China
| | - Qian Liu
- The Qingdao University Medical College, Qingdao, Shandong Province, 260075, China
| | - Xinyue Zhang
- Cancer Center, Department of Medical Oncology, Zhejiang Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical College), Hangzhou, Zhejiang, 310014, China
- The Qingdao University Medical College, Qingdao, Shandong Province, 260075, China
| | - Shuang-Yue Pan
- The Qingdao University Medical College, Qingdao, Shandong Province, 260075, China
- Graduate School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, 310014, Zhejiang Province, China
| | - Zhe-Ling Chen
- The Qingdao University Medical College, Qingdao, Shandong Province, 260075, China.
| | - Liu Yang
- Cancer Center, Department of Medical Oncology, Zhejiang Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical College), Hangzhou, Zhejiang, 310014, China.
- The Qingdao University Medical College, Qingdao, Shandong Province, 260075, China.
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Zhang L, Wang W, Ge S, Li H, Bai M, Duan J, Yang Y, Ning T, Liu R, Wang X, Ji Z, Wang F, Zhang H, Ba Y, Deng T. Sintilimab Plus Apatinib and Chemotherapy as Second‑/Third-Line treatment for Advanced Gastric or Gastroesophageal Junction Adenocarcinoma: a prospective, Single-Arm, phase II trial. BMC Cancer 2023; 23:211. [PMID: 36872337 PMCID: PMC9985926 DOI: 10.1186/s12885-023-10661-4] [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: 09/10/2022] [Accepted: 02/20/2023] [Indexed: 03/07/2023] Open
Abstract
BACKGROUND The prognosis of patients with previously treated advanced gastric or gastroesophageal junction (GEJ) cancer remains poor. Given the robust development of immunotherapy and targeted therapy during the last decades, we aimed to investigate if the combination of traditional second-line chemotherapy with sintilimab and apatinib could bring survival benefits for these patients. METHODS In this single-center, single-arm, phase II trial, patients with previously treated advanced gastric or GEJ adenocarcinoma received specific dose level of intravenous paclitaxel or irinotecan (investigator's choice), 200 mg intravenous sintilimab on day 1, and 250 mg oral apatinib once daily continuously in each cycle until disease progression, intolerable toxicity, or withdrawal of consent. The primary endpoints were objective response rate and progression-free survival. The secondary endpoints were mainly overall survival and safety. RESULTS From May 2019 to May 2021, 30 patients were enrolled. At the data cutoff date (March 19, 2022), the median follow-up duration was 12.3 months and 53.6% (95% CI, 33.9-72.5%) patients achieved objective response. The median progression-free survival and overall survival were 8.5 months (95% CI, 5.4-11.5) and 12.5 months (95% CI, 3.7-21.3), respectively. Grade 3-4 adverse events included hematological toxicities, elevated alanine aminotransferase, elevated aspartate aminotransferase, elevated alkaline phosphatase, elevated gamma-glutamyl transpeptidase, hyperbilirubinemia and proteinuria. The most frequent grade 3-4 adverse event was neutropenia (13.3%). No serious treatment-related adverse events or treatment-related deaths occurred. CONCLUSION Sintilimab plus apatinib and chemotherapy demonstrates promising anti-tumor activity with manageable safety profile in patients with previously treated advanced gastric or GEJ cancer. TRIAL REGISTRATION ClinicalTrials.gov: NCT05025033, 27/08/2021.
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Affiliation(s)
- Le Zhang
- Department of GI Medical Oncology, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, 300060, Tianjin, China
| | - Weixue Wang
- Department of GI Medical Oncology, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, 300060, Tianjin, China
| | - Shaohua Ge
- Department of GI Medical Oncology, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, 300060, Tianjin, China
| | - Hongli Li
- Department of GI Medical Oncology, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, 300060, Tianjin, China
| | - Ming Bai
- Department of GI Medical Oncology, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, 300060, Tianjin, China
| | - Jingjing Duan
- Department of GI Medical Oncology, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, 300060, Tianjin, China
| | - Yuchong Yang
- Department of GI Medical Oncology, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, 300060, Tianjin, China
| | - Tao Ning
- Department of GI Medical Oncology, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, 300060, Tianjin, China
| | - Rui Liu
- Department of GI Medical Oncology, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, 300060, Tianjin, China
| | - Xia Wang
- Department of GI Medical Oncology, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, 300060, Tianjin, China
| | - Zhi Ji
- Department of GI Medical Oncology, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, 300060, Tianjin, China
| | - Feixue Wang
- Department of GI Medical Oncology, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, 300060, Tianjin, China
| | - Haiyang Zhang
- Department of GI Medical Oncology, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, 300060, Tianjin, China
| | - Yi Ba
- Department of GI Medical Oncology, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, 300060, Tianjin, China.
| | - Ting Deng
- Department of GI Medical Oncology, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, 300060, Tianjin, China.
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Doganlar O, Doganlar ZB, Erdogan S, Delen E. Antineoplastic multi-drug chemotherapy to sensitize tumors triggers multi-drug resistance and inhibits efficiency of maintenance treatment inglioblastoma cells. EXCLI JOURNAL 2023; 22:35-52. [PMID: 36660193 PMCID: PMC9837385 DOI: 10.17179/excli2022-5556] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Figures] [Subscribe] [Scholar Register] [Received: 10/28/2022] [Accepted: 12/08/2022] [Indexed: 01/21/2023]
Abstract
Combinations of the well-known antineoplastic agents 5-fluorouracil (5-Fu), cisplatin, and paclitaxel are employed to increase radiotherapy/immunotherapy efficacy against persistent and resistant tumors. However, data remains needed on the hormetic, chronic, and long-term side effects of these aggressive combination chemotherapies. Here we investigated cellular and molecular responses associated with these combined agents, and their potential to induce multi-drug resistance against the temozolomide (TMZ) and etoposide (EP) used in glioblastoma maintenance treatment. We analyzed resistance and survival signals in U87 MG cells using molecular probes, fluorescent staining, qRT-PCR, and immunoblot. Repeated treatment with combined 5-Fu, cisplatin, and paclitaxel induced cross-resistance against TMZ and EP. Resistant cells exhibited elevated gene/protein expression of MRP1/ABCC1, ABCC2, BRCP/ABCG2, and GST. Moreover, they managed oxidative stress, cell cycle, apoptosis, and autophagy signaling to ensure survival. In these groups TMZ and etoposide efficiency dramatically reduced. Our result suggests that combined high-dose treatments of classical antineoplastic agents to sensitize tumors may trigger multi-drug resistance and inhibit maintenance treatment. When deciding on antineoplastic combination therapy for persistent/resistant glioblastoma, we recommend analyzing the long-term hormetic and chronic effects on cross-resistance and multi-drug resistance in primary cell cultures from patients. See also the Graphical Abstract(Fig. 1).
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Affiliation(s)
- Oguzhan Doganlar
- Faculty of Medicine, Department of Medical Biology, Trakya University, Edirne, Turkiye
| | - Zeynep Banu Doganlar
- Faculty of Medicine, Department of Medical Biology, Trakya University, Edirne, Turkiye
| | - Suat Erdogan
- Faculty of Medicine, Department of Medical Biology, Trakya University, Edirne, Turkiye
| | - Emre Delen
- Faculty of Medicine, Department of Neurosurgery, Trakya University, Edirne, Turkiye
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Wang X, Zhong D, Zhang J, Du N, Ren Y, Gao J, Liu L, Yu J, Li X, Ma L, Zang A, Yang M, Zhang Y, Guo J, Liu Z, Fu Z, Jia J, Diao J, Fan Z, Song X, Li G, Wang H, Bai C, Guan M, Ren X, Zhang R. Safety and effectiveness of apatinib in elderly patients with metastatic gastric cancer: a sub-analysis from the large-scale, prospective observational study of apatinib for gastric cancer treatment in a real-world clinical setting (AHEAD-G202). J Gastrointest Oncol 2022; 13:1679-1689. [PMID: 36092345 PMCID: PMC9459208 DOI: 10.21037/jgo-22-727] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2022] [Accepted: 08/11/2022] [Indexed: 11/06/2022] Open
Abstract
Background Apatinib was shown to improve the survival of Chinese patients with refractory metastatic gastric cancer (mGC). As an orally administered drug, it has been widely used in elderly patients because the dosing schedule can be adjusted flexibly. However, data on the efficacy and safety of apatinib in elderly patients is scarce. The aim of this study was to evaluate the toxicity and effectiveness of apatinib for elderly patients with mGC in a real-world setting. Methods Data from the sub-population of patients who were ≥65 years enrolled in the AHEAD-G202 trial were analyzed. Patients with mGC were prospectively registered and initially received ≤850 mg oral apatinib daily combined or not combined with chemotherapy, at the investigator's discretion. The primary endpoint was safety. The secondary endpoints were overall survival (OS) and progression-free survival (PFS). Results A total of 117 patients were included. There were 51 (43.59%) patients in the low-dose (250 mg) group, 60 (51.28%) patients in the mid-dose (425 to 500 mg) group, and 6 (5.13%) patients in the high-dose (850 mg) group according to the initial daily doses. Hypertension (6.84%) was the only grade 3-4 adverse event (AE) with a prevalence of more than 5% and across the low-dose (11.76%), mid-dose (3.33%) and high-dose group (0%). The median OS and PFS were 7.13 months (95% CI: 5.04 to 9.22 months) and 4.27 months (95% CI: 3.24 to 5.29 months), respectively. The OS and PFS were similar among the 65-74 and ≥75 years groups (χ2=1.406, P=0.306; χ2=0.378, P=0.066, respectively). The OS and PFS were also comparable among the 3 dose groups. Conclusions Elderly patients with mGC can tolerate and benefit from apatinib therapy. A lower initial daily dosing strategy may be a suitable choice for elderly patients in clinical practice.
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Affiliation(s)
- Xiang Wang
- Department of Medical Oncology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China
| | - Diansheng Zhong
- Department of Medical Oncology, Tianjin Medical University General Hospital, Tianjin, China
| | - Junping Zhang
- Department of Medical Oncology, Shanxi Academy of Medical Sciences, Shanxi Dayi Hospital, Taiyuan, China
| | - Nan Du
- Department of Medical Oncology, Fourth Medical Center of PLA General Hospital, Beijing, China
| | - Yuchuan Ren
- Department of Oncology, Yangquan First People’s Hospital, Yangquan, China
| | - Jinghua Gao
- Department of Medical Oncology, Cangzhou Central Hospital, Cangzhou, China
| | - Likun Liu
- Oncology Department, Shanxi Provincial Hospital of Traditional Chinese Medicine, Taiyuan, China
| | - Junyan Yu
- Department of Oncology, Peace Hospital of Changzhi Medical College, Changzhi, China
| | - Xiaomei Li
- Department of Medical Oncology, Chinese PLA General Hospital, Medical School of Chinese PLA, Beijing, China
| | - Liwen Ma
- Department of Tumor Chemotherapy and Radiology, Peking University Third Hospital, Beijing, China
| | - Aimin Zang
- Department of Medical Oncology, Affiliated Hospital of Hebei University, Baoding, China
| | - Mudan Yang
- Digestive Department of Oncology, Shanxi Tumor Hospital, Taiyuan, China
| | - Yan Zhang
- Department of Medical Oncology, Shijiazhuang People’s Hospital, Shijiazhuang, China
| | - Jun Guo
- Department of Medical Oncology, Xingtai People’s Hospital, Hebei Medical University Affiliated Hospital, Xingtai, China
| | - Zheng Liu
- Department of Radiology, Handan Central Hospital, Handan, China
| | - Zhanzhao Fu
- Department of Medical Oncology, First Hospital of Qinhuangdao, Qinhuangdao, China
| | - Junmei Jia
- Department of Medical Oncology, First Hospital of Shanxi Medical University, Taiyuan, China
| | - Jianfeng Diao
- Department of Medical Oncology, Datong Second People’s Hospital, Datong, China
| | - Zaiwen Fan
- Department of Medical Oncology, Air Force General Hospital, PLA, Beijing, China
| | - Xiang Song
- Department of Medical Oncology, Second Hospital of Shanxi Medical University, Taiyuan, China
| | - Guozhong Li
- Department of Medical Oncology, Peking University Binhai Hospital, Tianjin, China
| | - Huaqing Wang
- Department of Medical Oncology, Tianjin People’s Hospital, Tianjin, China
| | - Chunmei Bai
- Department of Medical Oncology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China
| | - Mei Guan
- Department of Medical Oncology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China
| | - Xiubao Ren
- Department of Biotherapy, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Ruixing Zhang
- Department of Gastroenterology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
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Apatinib plus chemotherapy versus chemotherapy alone as neoadjuvant therapy in locally advanced gastric carcinoma patients: a prospective, cohort study. Ir J Med Sci 2022:10.1007/s11845-022-03075-x. [PMID: 35819743 DOI: 10.1007/s11845-022-03075-x] [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: 05/24/2022] [Accepted: 06/15/2022] [Indexed: 02/03/2023]
Abstract
BACKGROUND Apatinib, a small molecule targeting VEGFR2, is commonly used for advanced gastric cancer treatment. This prospective cohort study further investigated the efficacy and safety of neoadjuvant apatinib plus chemotherapy in locally advanced gastric carcinoma patients. METHODS Ninety-six locally advanced gastric carcinoma patients were divided into the apatinib plus chemotherapy group (N = 45) and chemotherapy group (N = 51) according to their chosen treatment. Apatinib was administered (375 mg/day), and S-1 plus oxaliplatin (SOX) or oxaliplatin plus capecitabine (CapOx) was given as chemotherapy, for 3 cycles with 3 weeks a cycle before surgery. RESULTS The objective response rate (62.2% vs. 37.3%, P = 0.015) and pathological response grade (P = 0.011) were better; meanwhile, the tumor-resection rate (95.6% vs. 84.3%, P = 0.143) and pathological complete response rate (23.3% vs. 9.3%, P = 0.080) exhibited increasing trends (without statistical significance) in the apatinib plus chemotherapy group compared with the chemotherapy group. Additionally, the apatinib plus chemotherapy group achieved prolonged disease-free survival (DFS) (P = 0.019) and overall survival (OS) (P = 0.047) compared with the chemotherapy group. After adjusted by multivariate Cox's regression analysis, neoadjuvant apatinib plus chemotherapy was still superior to chemotherapy regarding DFS (hazard ratio (HR): 0.277, P = 0.014) and OS (HR: 0.316, P = 0.038). Notably, the incidences of adverse events between the two groups were not different (P > 0.050). Moreover, the most common adverse events of neoadjuvant apatinib plus chemotherapy were leukopenia (42.2%), fatigue (37.8%), hypertension (37.8%), and anemia (31.1%). CONCLUSION Neoadjuvant apatinib plus chemotherapy realizes better clinical response, pathological response, survival profile, and non-inferior safety profile compared to chemotherapy in locally advanced gastric carcinoma.
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9
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Wu JQ, Fan RY, Zhai J, Li CY, Wei P, Shen LZ, He MF, Wang P, Huang XE. Docetaxel and 5-FU enhanced the inhibitory effects of apatinib and ramucirumab on growth and migration of gastric cancer. Life Sci 2022; 296:120439. [PMID: 35235851 DOI: 10.1016/j.lfs.2022.120439] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Revised: 02/22/2022] [Accepted: 02/23/2022] [Indexed: 11/20/2022]
Abstract
BACKGROUND Gastric cancer (GC) is one of the most common malignant tumors in the world. The clinical benefit of anti-angiogenic strategy as a single drug is limited. Some studies showed that the combination of anti-angiogenic therapy and chemotherapy exhibited synergistic effect and reduced the side effects of chemotherapy drugs. We investigated the combined effects of these two types of drugs in gastric cancer cells in vitro and in vivo. METHODS cell viability, migration, invasion, and apoptosis were evaluated by CCK-8, wound-healing, transwell, and Annexin V-FITC/PI assay, respectively. In vivo anti-cancer efficacy was tested for the cell proliferation and metastasis in cell line derived tumor xenograft (CDX) model and patient derived tumor xenografted (PDX) model based on Tg (fli-1: EGFP) zebrafish embryos; RESULTS: In the cell experiments, the combination of the two types of drugs could inhibit the proliferation and metastasis of gastric cancer cells and promote apoptosis through VEGFR-2/AKT/ERK1/2 signal. In the zebrafish CDX (zCDX) model and zebrafish PDX (zPDX) model, the combination of the two treatment also showed a synergistic effect in inhibiting gastric cancer cell metastasis and cell proliferation. CONCLUSIONS Apatinib/ramucirumab targeted therapy combined with docetaxel or 5-fluorouracil (5-FU) may serve as an effective treatment strategy for patients with advanced gastric cancer.
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Affiliation(s)
- Jia-Qi Wu
- College of Biotechnology and Pharmaceutical Engineering, Nanjing Tech University, Nanjing 211800, China
| | - Ruo-Yue Fan
- College of Biotechnology and Pharmaceutical Engineering, Nanjing Tech University, Nanjing 211800, China
| | - Jing Zhai
- Department of Surgical Oncology, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, China
| | - Chong-Yong Li
- College of Biotechnology and Pharmaceutical Engineering, Nanjing Tech University, Nanjing 211800, China
| | - Ping Wei
- College of Biotechnology and Pharmaceutical Engineering, Nanjing Tech University, Nanjing 211800, China
| | - Li-Zong Shen
- Department of Surgical Oncology, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, China
| | - Ming-Fang He
- College of Biotechnology and Pharmaceutical Engineering, Nanjing Tech University, Nanjing 211800, China.
| | - Ping Wang
- Department of Medical Oncology, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, 210009, China.
| | - Xin-En Huang
- Department of Medical Oncology, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, 210009, China.
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Cascallar M, Alijas S, Pensado-López A, Vázquez-Ríos AJ, Sánchez L, Piñeiro R, de la Fuente M. What Zebrafish and Nanotechnology Can Offer for Cancer Treatments in the Age of Personalized Medicine. Cancers (Basel) 2022; 14:cancers14092238. [PMID: 35565373 PMCID: PMC9099873 DOI: 10.3390/cancers14092238] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2022] [Revised: 04/27/2022] [Accepted: 04/28/2022] [Indexed: 12/12/2022] Open
Abstract
Cancer causes millions of deaths each year and thus urgently requires the development of new therapeutic strategies. Nanotechnology-based anticancer therapies are a promising approach, with several formulations already approved and in clinical use. The evaluation of these therapies requires efficient in vivo models to study their behavior and interaction with cancer cells, and to optimize their properties to ensure maximum efficacy and safety. In this way, zebrafish is an important candidate due to its high homology with the human genoma, its large offspring, and the ease in developing specific cancer models. The role of zebrafish as a model for anticancer therapy studies has been highly evidenced, allowing researchers not only to perform drug screenings but also to evaluate novel therapies such as immunotherapies and nanotherapies. Beyond that, zebrafish can be used as an “avatar” model for performing patient-derived xenografts for personalized medicine. These characteristics place zebrafish in an attractive position as a role model for evaluating novel therapies for cancer treatment, such as nanomedicine.
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Affiliation(s)
- María Cascallar
- Nano-Oncology and Translational Therapeutics Group, Health Research Institute of Santiago de Compostela (IDIS), SERGAS, 15706 Santiago de Compostela, Spain; (M.C.); (S.A.); (A.J.V.-R.)
- Centro de Investigación Biomédica en Red Cáncer (CIBERONC), 28029 Madrid, Spain;
- Department of Zoology, Genetics and Physical Anthropology, Universidade de Santiago de Compostela, Campus de Lugo, 27002 Lugo, Spain; (A.P.-L.); (L.S.)
| | - Sandra Alijas
- Nano-Oncology and Translational Therapeutics Group, Health Research Institute of Santiago de Compostela (IDIS), SERGAS, 15706 Santiago de Compostela, Spain; (M.C.); (S.A.); (A.J.V.-R.)
| | - Alba Pensado-López
- Department of Zoology, Genetics and Physical Anthropology, Universidade de Santiago de Compostela, Campus de Lugo, 27002 Lugo, Spain; (A.P.-L.); (L.S.)
- Center for Research in Molecular Medicine & Chronic Diseases (CIMUS), Campus Vida, Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain
| | - Abi Judit Vázquez-Ríos
- Nano-Oncology and Translational Therapeutics Group, Health Research Institute of Santiago de Compostela (IDIS), SERGAS, 15706 Santiago de Compostela, Spain; (M.C.); (S.A.); (A.J.V.-R.)
- Centro de Investigación Biomédica en Red Cáncer (CIBERONC), 28029 Madrid, Spain;
- DIVERSA Technologies S.L., 15782 Santiago de Compostela, Spain
| | - Laura Sánchez
- Department of Zoology, Genetics and Physical Anthropology, Universidade de Santiago de Compostela, Campus de Lugo, 27002 Lugo, Spain; (A.P.-L.); (L.S.)
- Preclinical Animal Models Group, Health Research Institute of Santiago de Compostela (IDIS), 15706 Santiago de Compostela, Spain
| | - Roberto Piñeiro
- Centro de Investigación Biomédica en Red Cáncer (CIBERONC), 28029 Madrid, Spain;
- Roche-Chus Joint Unit, Translational Medical Oncology Group, Oncomet, Health Research Institute of Santiago de Compostela, Travesía da Choupana s/n, 15706 Santiago de Compostela, Spain
| | - María de la Fuente
- Nano-Oncology and Translational Therapeutics Group, Health Research Institute of Santiago de Compostela (IDIS), SERGAS, 15706 Santiago de Compostela, Spain; (M.C.); (S.A.); (A.J.V.-R.)
- Centro de Investigación Biomédica en Red Cáncer (CIBERONC), 28029 Madrid, Spain;
- DIVERSA Technologies S.L., 15782 Santiago de Compostela, Spain
- Correspondence: ; Tel.: +34-981-955-704
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11
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Dai Y, Sun L, Zhuang L, Zhang M, Zou Y, Yuan X, Qiu H. Efficacy and safety of low-dose apatinib plus S-1 versus regorafenib and fruquintinib for refractory metastatic colorectal cancer: a retrospective cohort study. J Gastrointest Oncol 2022; 13:722-731. [PMID: 35557597 PMCID: PMC9086039 DOI: 10.21037/jgo-22-285] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2022] [Accepted: 04/15/2022] [Indexed: 09/17/2023] Open
Abstract
Background At present, regorafenib and fruquintinib are the standard regimens for refractory metastatic colorectal cancer patients in China, but both options have limited efficacy. The aim of this study was to investigate the efficacy and safety of low-dose apatinib plus S-1 compared with regorafenib and fruquintinib in patients with metastatic colorectal cancer (mCRC) refractory to standard therapies. Methods The records of 114 patients with refractory mCRC in our center from April 2016 to September 2020 were retrospectively reviewed. Among these patients, 43 received apatinib 250 mg/day combined with S-1, 36 received regorafenib starting at 80 mg/day with weekly escalation, and 35 received fruquintinib 5 mg/day orally. Patients received radiographic examination every 1.5-2 months during the treatment period, progression-free survival time and overall survival time were analyzed and recorded. Results The baseline clinical characteristics of the patients were broadly similar among the three groups. The median progression-free survival (mPFS) was 3.9 months [95% confidence interval (CI): 2.5-5.3] in the apatinib plus S-1 group, 3.1 months (95% CI: 1.9-4.2) in the fruquintinib group, and 2.4 months (95% CI: 2.1-2.7) in the regorafenib group, the mPFS of apatinib plus S-1 was significantly longer than that of regorafenib (HR =0.49, P=0.003) and fruquintinib (HR =0.60, P=0.048). The median overall survival (OS) was 8.2 months (95% CI: 5.4-11.0) in the apatinib plus S-1 group, 7.8 months (95% CI: 5.3-10.3) in the fruquintinib group, and 7.5 months (95% CI: 4.2-10.7) in the regorafenib group, which was comparable among the 3 groups. There was no statistical difference in disease control rate (DCR) among the three groups. Patients in the apatinib plus S-1 group had a higher incidence of hematological toxicity including anemia (62.8%), neutropenia (30.2%), and thrombocytopenia (39.5%), and the hand-foot skin reaction (58.3%) was more prevalent in the regorafenib group, while the adverse reaction of hypertension (45.7%) in the fruquintinib group was very significant. Conclusions Low-dose apatinib plus S-1 prolonged PFS compared with regorafenib and fruquintinib, and is a potential alternative regimen for the treatment of refractory mCRC with tolerable and controlled toxicity.
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Affiliation(s)
- Yuhong Dai
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Li Sun
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Liang Zhuang
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Mingsheng Zhang
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yanmei Zou
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xianglin Yuan
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Hong Qiu
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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12
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Yan Y, Li H, Wu S, Wang G, Luo H, Niu J, Cao L, Hu X, Xu H, Jia W, Sun Y, Yao Y, Chen W, Ke L, Hu B, Ji C, Sun Y, Chen J, Li M, He Y. Efficacy and safety of intermittent versus continuous dose apatinib plus docetaxel as second-line therapy in patients with advanced gastric cancer or gastroesophageal junction adenocarcinoma: a randomized controlled study. ANNALS OF TRANSLATIONAL MEDICINE 2022; 10:205. [PMID: 35280426 PMCID: PMC8908117 DOI: 10.21037/atm-22-546] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Accepted: 02/18/2022] [Indexed: 12/24/2022]
Abstract
Background Previous studies of the second-line treatment for advanced gastric cancer or gastroesophageal junction adenocarcinoma (GC/GEJAC) had reported that apatinib combined with chemotherapy improved the treatment outcomes. However, the benefits were sometimes limited due to the tolerance of continuous dose regimen. This randomized controlled study aimed to investigate the efficacy and safety of intermittent or continuous dose apatinib plus docetaxel as a second-line therapy in patients with advanced GC/GEJAC. Methods Advanced GC/GEJAC patients who failed first-line chemotherapy were recruited (enrollment time: from September 15, 2017 to July 21, 2019), and randomly assigned to either the intermittent dose group (IG group) or the continuous dose group (CG group) (1:1 ratio) using the block randomization method. In the IG group, patients received apatinib 500 mg/d for 5 consecutive days then held for 2 days plus docetaxel 60 mg/m2 q3w, in a 3-week cycle. In the CG group, patients received apatinib 500 mg daily plus docetaxel 60 mg/m2 q3w, in a 3-week cycle. The progression free survival (PFS) was evaluated every two cycles and follow-ups were performed monthly. The primary endpoint was PFS, and the secondary endpoints were objective response rate (ORR), disease control rate (DCR), overall survival (OS), and safety. Results In total, 76 eligible patients were enrolled and randomly assigned (1:1 ratio). The IG group exhibited similar PFS compared to the CG group [median PFS: 3.88 (95% CI: 1.72–6.03) months vs. 3.98 (95% CI: 1.06–6.90) months, P=0.546] and OS [median OS: 9.00 (95% CI: 5.31–12.70) months vs. 9.40 (95% CI: 5.20–13.59) months, P=0.310]. ORR (21.1% vs. 18.4%, P=0.773) and DCR (60.5% vs. 60.5%, P=1.000) were of not statistically different between the IG and CG groups. As for safety, the IG group exhibited less frequent hypoproteinemia (31.6% vs. 55.3%, P=0.037) and lactate dehydrogenase increased (18.4% vs. 44.7%, P=0.014), while no differences in other adverse events were observed between the two groups. Conclusions Intermittent dose apatinib plus docetaxel was equally effective and more tolerable than continuous dose apatinib plus docetaxel as a second-line therapy in patients with advanced GC/GEJAC. Trial Registration ClinicalTrials.gov NCT03334591.
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Affiliation(s)
- Ying Yan
- Department of Medical Oncology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Huimin Li
- Department of Medical Oncology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Shusheng Wu
- Department of Medical Oncology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Gang Wang
- Department of Medical Oncology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Huiqin Luo
- Department of Medical Oncology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Jiayu Niu
- Department of Medical Oncology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Lulu Cao
- Department of Medical Oncology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Xiaoxiu Hu
- Department of Medical Oncology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Huijun Xu
- Department of Medical Oncology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Wei Jia
- Department of Medical Oncology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Yubei Sun
- Department of Medical Oncology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Yiwei Yao
- Department of Medical Oncology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Wenju Chen
- Department of Medical Oncology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Lihong Ke
- Department of Medical Oncology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Bing Hu
- Department of Medical Oncology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Chushu Ji
- Department of Medical Oncology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Yancai Sun
- Department of Pharmacy, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Jian Chen
- Department of Medical Oncology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Mengge Li
- Department of Medical Oncology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Yifu He
- Department of Medical Oncology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
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13
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Zhang HC, Wen T, Cai YZ. Overexpression of miR-146a promotes cell proliferation and migration in a model of diabetic foot ulcers by regulating the AKAP12 axis. Endocr J 2022; 69:85-94. [PMID: 34483150 DOI: 10.1507/endocrj.ej21-0177] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
In the current study, we aimed to study the effect of miR-146a on proliferation and migration in an in vitro diabetic foot ulcer (DFU) model by targeting A-kinase-anchoring protein 12 (AKAP12). An in vitro DFU model was initially established using HaCaT cells derived from human keratinocytes and induced by advanced glycation end products (AGEs). The effects of overexpression of miR-146a on proliferation and migration ability were analysed. The expression levels of miR-146a and AKAP12 were measured by quantitative real-time polymerase chain reaction (qRT-PCR), and AKAP12, hypoxia-inducible factor-1α (HIF-1α), Wnt3a and β-catenin protein levels were measured by western blotting. The cell proliferation ability was measured by MTT, and the migration ability was analysed by a cell scratch assay. The binding between miR-146a and AKAP12 was identified using a luciferase reporter assay. The results demonstrated that AGEs significantly suppressed cell proliferation and migration, while the expression of miR-146a decreased and the expression of AKAP12 increased. A luciferase reporter assay revealed that miR-146a could directly target AKAP12. Overexpression of miR-146a promoted cell proliferation and migration in an in vitro DFU model and also promoted the expression of HIF-1α, Wnt3a and β-catenin but suppressed the expression of AKAP12. Co-overexpression of miR-146a and AKAP12 reversed the effect of miR-146a on cell proliferation and migration. Our findings revealed that miR-146a directly targeted AKAP12 and promoted cell proliferation and migration in an in vitro DFU model. This study provides a new perspective for the study of miR-146a in the treatment of DFU.
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Affiliation(s)
- Han-Chong Zhang
- Department of Emergency Medicine, Second Xiangya Hospital, Central South University, Changsha 410011, Hunan Province, P.R. China
- Emergency Medicine and Difficult Diseases Institute, Second Xiangya Hospital, Central South University, Changsha 410011, Hunan Province, P.R. China
| | - Tie Wen
- Department of Emergency Medicine, Second Xiangya Hospital, Central South University, Changsha 410011, Hunan Province, P.R. China
- Emergency Medicine and Difficult Diseases Institute, Second Xiangya Hospital, Central South University, Changsha 410011, Hunan Province, P.R. China
| | - Yu-Zhong Cai
- Department of Emergency Medicine, Second Xiangya Hospital, Central South University, Changsha 410011, Hunan Province, P.R. China
- Emergency Medicine and Difficult Diseases Institute, Second Xiangya Hospital, Central South University, Changsha 410011, Hunan Province, P.R. China
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14
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Tao S, Ren Z, Yang Z, Duan S, Wan Z, Huang J, Liu C, Wei G. Effects of Different Molecular Weight Polysaccharides From Dendrobium officinale Kimura & Migo on Human Colorectal Cancer and Transcriptome Analysis of Differentially Expressed Genes. Front Pharmacol 2021; 12:704486. [PMID: 34925000 PMCID: PMC8678483 DOI: 10.3389/fphar.2021.704486] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2021] [Accepted: 10/27/2021] [Indexed: 12/13/2022] Open
Abstract
We investigated the antitumor effects of four fractions of Dendrobium officinale Kimura & Migo (D. officinale) polysaccharides with different molecular weights (Mw), Astragalus membranaceus polysaccharides (APS) and Lentinus edodes polysaccharides (LNT) on colorectal cancer (CRC) using a zebrafish xenograft model. Transcriptome sequencing was performed to further explore the possible antitumor mechanisms of D. officinale polysaccharides. Fractions of D. officinale polysaccharides, LNT, and APS could significantly inhibit the growth of HT-29 cells in a zebrafish xenograft model. One fraction of D. officinale polysaccharides called DOPW-1 (Mw of 389.98 kDa) exhibited the strongest tumor inhibition. Compared with the control group, RNA-seq revealed that the DOPW-1–treated experimental group had 119 differentially expressed genes (DEGs), of which 45 had upregulated expression and 74 had downregulated expression. Analyses using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes suggested that the pathway “apoptosis-multiple species” was the most significantly enriched. Our data indicated that 1) fractions of D. officinale polysaccharides of Mw 389.98 kDa were most suitable against CRC; 2) DOPW-1 could be developed into a clinical agent against CRC; and 3) an apoptosis pathway is important for DOPW-1 to inhibit the proliferation of HT-29 cells.
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Affiliation(s)
- Shengchang Tao
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China.,Department of Pharmacy, Affiliated Dongguan Hospital, Southern Medical University, Dongguan, China
| | - Zhiyao Ren
- Department of Systems Biomedical Sciences, School of Medicine, Jinan University, Guangzhou, China.,NHC Key Laboratory of Male Reproduction and Genetics, Guangzhou, China.,Department of Central Laboratory, Family Planning Research Institute of Guangdong Province, Guangzhou, China
| | - Zerui Yang
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Shuna Duan
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China.,Shaoguan Institute of Danxia Dendrobium Officinale, Shaoguan, China
| | - Zhongxian Wan
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Jiahui Huang
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China.,Shaoguan Institute of Danxia Dendrobium Officinale, Shaoguan, China
| | - Chenxing Liu
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China.,Shaoguan Institute of Danxia Dendrobium Officinale, Shaoguan, China
| | - Gang Wei
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
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15
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Nuplazid suppresses esophageal squamous cell carcinoma growth in vitro and in vivo by targeting PAK4. Br J Cancer 2021; 126:1037-1046. [PMID: 34912075 PMCID: PMC8980085 DOI: 10.1038/s41416-021-01651-z] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2021] [Revised: 10/31/2021] [Accepted: 11/22/2021] [Indexed: 11/09/2022] Open
Abstract
Background Due to the high recurrence and low 5-year survival rates of esophageal squamous cell carcinoma (ESCC) after treatment, the discovery of novel drugs for recurrence chemoprevention is of particular importance. Methods We screened the FDA-approved drug library and found that Nuplazid, an atypical antipsychotic that acts as an effective 5-HT 2 A receptor inverse agonist, could potentially exert anticancer effects in vitro and in vivo on ESCC. Results Pull-down results indicated that Nuplazid binds with p21-activated kinase 4 (PAK4), and a kinase assay showed that Nuplazid strongly suppressed PAK4 kinase activity. Moreover, Nuplazid exhibited inhibitory effects on ESCC in vivo. Conclusions Our findings indicate that Nuplazid can suppress ESCC progression through targeting PAK4.
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16
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Bei Y, Chen X, Xu Q, Lv J, Hu J, Yang S. Apatinib weakens resistance of gastric cancer cells to paclitaxel by suppressing JAK/STAT3 signaling pathway. Drug Dev Res 2021; 83:379-388. [PMID: 34405891 DOI: 10.1002/ddr.21867] [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: 03/25/2021] [Revised: 08/03/2021] [Accepted: 08/05/2021] [Indexed: 01/16/2023]
Abstract
Apatinib has experienced a long-term study in enhancing the sensitivity of various cancer cells to chemotherapy drugs. Currently, researches show that apatinib could attenuate the resistance of gastric cancer (GC) cells to paclitaxel (PTX), but the mechanism has not been fully elucidated, which therefore was explored in this study. PTX-resistant GC cell, namely HGC-27R, was established by exposure to stepwise-increasing PTX. The cell viability of HGC-27 and HGC-27R under PTX or apatinib at different concentrations was assessed by CCK-8 assay, while scratching test and invasion assay were used for investigating the harmful influence of GC cells resistance to PTX. The function of apatinib in HGC-27R was studied by performing functional experiments (flow cytometry, scratching test, and invasion assay). Western blot was performed to measure the expressions of proteins concerning apoptosis, epithelial-mesenchymal transition and janus-activated kinase (JAK)/signal transducer and activator of transcription (STAT) pathway. PTX-resistant GC cell, namely HGC-27R, was successively constructed. HGC-27R cells showed resistance to PTX by promoting migratory and invasive capabilities. Apatinib not only inhibited cell viability of HGC-27 and HGC-27R, but also combined with PTX to suppress that of HGC-27R. Apatinib enhanced apoptosis, diminished migration and invasion of HGC-27R cells, elevated proapoptotic protein expression, and reduced Bcl-2, vimentin, snail, MMP-3, MMP-2, and MMP-9 expressions. The phosphorylation of JAK2 and STAT3 was repressed by apatinib. JAK2 partially reversed the effect of apatinib on enhancing sensitivity of GC cells to PTX. Apatinib strengthened sensitivity of GC cells to PTX by inhibiting JAK/STAT3 signaling pathway.
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Affiliation(s)
- Yanping Bei
- Department of Radiotherapy, Ningbo Medical Center Lihuili Hospital, Ningbo, China
| | - Xue Chen
- Department of Radiotherapy, Ningbo Medical Center Lihuili Hospital, Ningbo, China
| | - Quan Xu
- Department of Radiotherapy, Ningbo Medical Center Lihuili Hospital, Ningbo, China
| | - Jiaming Lv
- Department of Radiotherapy, Ningbo Medical Center Lihuili Hospital, Ningbo, China
| | - Jing Hu
- Department of Radiotherapy, Ningbo Medical Center Lihuili Hospital, Ningbo, China
| | - Shaohui Yang
- Department of Anorectal Surgery, Ningbo Medical Center Lihuili Hospital, Ningbo, China
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17
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Wang YM, Xu X, Tang J, Sun ZY, Fu YJ, Zhao XJ, Ma XM, Ye Q. Apatinib induces endoplasmic reticulum stress-mediated apoptosis and autophagy and potentiates cell sensitivity to paclitaxel via the IRE-1α-AKT-mTOR pathway in esophageal squamous cell carcinoma. Cell Biosci 2021; 11:124. [PMID: 34229754 PMCID: PMC8261945 DOI: 10.1186/s13578-021-00640-2] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2021] [Accepted: 06/27/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Apatinib, a novel vascular endothelial growth factor receptor-2 (VEGFR-2) tyrosine kinase inhibitor, has been approved for the treatment of metastatic gastric cancer and other tumors. Apatinib exerts antiproliferative and proapoptotic effects in different kinds of cancer cells. However, the molecular mechanisms by which apatinib effective against esophageal squamous cell carcinoma (ESCC) have only been partially researched and whether it has a sensitizing effect on paclitaxel remains unclear. MATERIALS AND METHODS The effects of apatinib or paclitaxel on endoplasmic reticulum (ER) stress, autophagy, apoptosis and proliferation of ESCC cell lines were evaluated. Western blot and immunohistochemistry analyses were performed to detect the expression of related genes. The weight and volume of xenograft tumors in mice were measured. RESULTS In the current study, we elucidated the antiproliferative and ER-stress-mediated autophagy-inducing effects of apatinib on ECA-109 and KYSE-150 esophageal squamous cancer cells and identified the underlying mechanisms of its action. We demonstrated that apatinib not only inhibited the proliferation and induced the apoptosis of ESCC cells, but also activated ER stress and triggered protective autophagy. Moreover, inhibiting autophagy by chloroquine (CQ) enhanced the apatinib-induced apoptosis of ESCC cells through the IRE-1α-AKT-mTOR pathway. In addition, we showed, for the first time, the paclitaxel combined with apatinib and CQ exhibited the best antitumor effect on ESCC both in vivo and in vitro via the IRE-1α-AKT-mTOR pathway. CONCLUSIONS Our data showed that apatinib induced ER stress, autophagy and apoptosis in ESCC. Inhibiting autophagy by CQ enhanced apatinib-induced apoptosis. The combination of apatinib and CQ sensitized ESCC cells to paclitaxel to induce apoptosis through the IRE-1α-AKT-mTOR signaling pathway, thus providing the basis for its use in innovative anticancer therapeutic strategies.
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Affiliation(s)
- Yu-Ming Wang
- Department of Thoracic Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, People's Republic of China
| | - Xin Xu
- Department of Radiation Oncology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, People's Republic of China
| | - Jian Tang
- Department of Thoracic Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, People's Republic of China
| | - Zhi-Yong Sun
- Department of Thoracic Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, People's Republic of China
| | - Yu-Jie Fu
- Department of Thoracic Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, People's Republic of China
| | - Xiao-Jing Zhao
- Department of Thoracic Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, People's Republic of China
| | - Xiu-Mei Ma
- Department of Radiation Oncology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, People's Republic of China.
| | - Qing Ye
- Department of Thoracic Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, People's Republic of China.
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18
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Hermanowicz JM, Szymanowska A, Sieklucka B, Czarnomysy R, Pawlak K, Bielawska A, Bielawski K, Kalafut J, Przybyszewska A, Surazynski A, Rivero-Muller A, Mojzych M, Pawlak D. Exploration of novel heterofused 1,2,4-triazine derivative in colorectal cancer. J Enzyme Inhib Med Chem 2021; 36:535-548. [PMID: 33522320 PMCID: PMC7850456 DOI: 10.1080/14756366.2021.1879803] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Colorectal cancer (CRC) is the third leading cause of cancer-related deaths in men and in women. The impact of the new pyrazolo[4,3-e]tetrazolo[1,5-b][1,2,4]triazine sulphonamide (MM-129) was evaluated against human colon cancer in vitro and in zebrafish xenografts. Our results show that this new synthesised compound effectively inhibits cell survival in BTK-dependent mechanism. Its effectiveness is much higher at a relatively low concentration as compared with the standard chemotherapy used for CRC, i.e. 5-fluorouracil (5-FU). Flow cytometry analysis after annexin V-FITC and propidium iodide staining revealed that apoptosis was the main response of CRC cells to MM-129 treatment. We also found that MM-129 effectively inhibits tumour development in zebrafish embryo xenograft model, where it showed a markedly synergistic anticancer effect when used in combination with 5-FU. The above results suggest that this novel heterofused 1,2,4-triazine derivative may be a promising candidate for further evaluation as chemotherapeutic agent against CRC.
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Affiliation(s)
- Justyna Magdalena Hermanowicz
- Department of Pharmacodynamics, Medical University of Bialystok, Bialystok, Poland.,Department of Clinical Pharmacy, Medical University of Bialystok, Bialystok, Poland
| | - Anna Szymanowska
- Department of Biotechnology, Medical University of Bialystok, Bialystok, Poland
| | - Beata Sieklucka
- Department of Pharmacodynamics, Medical University of Bialystok, Bialystok, Poland
| | - Robert Czarnomysy
- Department of Synthesis and Technology of Drugs, Medical University of Bialystok, Bialystok, Poland
| | - Krystyna Pawlak
- Department of Monitored Pharmacotherapy, Medical University of Bialystok, Bialystok, Poland
| | - Anna Bielawska
- Department of Biotechnology, Medical University of Bialystok, Bialystok, Poland
| | - Krzysztof Bielawski
- Department of Synthesis and Technology of Drugs, Medical University of Bialystok, Bialystok, Poland
| | - Joanna Kalafut
- Department of Biochemistry and Molecular Biology, Medical University of Lublin, Lublin, Poland
| | - Alicja Przybyszewska
- Department of Biochemistry and Molecular Biology, Medical University of Lublin, Lublin, Poland
| | - Arkadiusz Surazynski
- Department of Medicinal Chemistry, Medical University of Bialystok, Bialystok, Poland
| | - Adolfo Rivero-Muller
- Department of Biochemistry and Molecular Biology, Medical University of Lublin, Lublin, Poland
| | - Mariusz Mojzych
- Department of Chemistry, Siedlce University of Natural Sciences and Humanities, Siedlce, Poland
| | - Dariusz Pawlak
- Department of Pharmacodynamics, Medical University of Bialystok, Bialystok, Poland.,Department of Pharmacology and Toxicology, Faculty of Medicine, University of Warmia and Mazury in Olsztyn, Olsztyn, Poland
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19
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Effect of the polysaccharides derived from Dendrobium officinale stems on human HT-29 colorectal cancer cells and a zebrafish model. FOOD BIOSCI 2021. [DOI: 10.1016/j.fbio.2021.100995] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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20
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Matsuoka T, Yashiro M. Molecular-targeted therapy toward precision medicine for gastrointestinal cancer: Current progress and challenges. World J Gastrointest Oncol 2021; 13:366-390. [PMID: 34040699 PMCID: PMC8131909 DOI: 10.4251/wjgo.v13.i5.366] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Revised: 03/04/2021] [Accepted: 04/22/2021] [Indexed: 02/06/2023] Open
Abstract
Gastrointestinal (GI) cancer remains the deadliest cancer in the world. The current standard treatment for GI cancer focuses on 5-fluorouracil-based chemotherapeutic regimens and surgery, and molecular-targeted therapy is expected to be a more effective and less toxic therapeutic strategy for GI cancer. There is well-established evidence for the use of epidermal growth factor receptor-targeted and vascular endothelial growth factor-targeted antibodies, which should routinely be incorporated into treatment strategies for GI cancer. Other potential therapeutic targets involve the PI3K/AKT pathway, tumor growth factor-β pathway, mesenchymal-epithelial transition pathway, WNT pathway, poly (ADP-ribose) polymerase, and immune checkpoints. Many clinical trials assessing the agents of targeted therapy are underway and have presented promising and thought-provoking results. With the development of molecular biology techniques, we can identify more targetable molecular alterations in larger patient populations with GI cancer. Targeting these molecules will allow us to reach the goal of precision medicine and improve the outcomes of patients with GI cancer.
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Affiliation(s)
- Tasuku Matsuoka
- Department of Surgical Oncology, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan
| | - Masakazu Yashiro
- Department of Surgical Oncology, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan
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21
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Wang T, Zhang J, Cui L. Apatinib inhibits gastric carcinoma development by regulating the expression levels of IL-17 via the Bax/Bcl-2 signaling pathway. Exp Ther Med 2021; 21:654. [PMID: 33968184 PMCID: PMC8097188 DOI: 10.3892/etm.2021.10086] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2020] [Accepted: 09/16/2020] [Indexed: 12/13/2022] Open
Abstract
Gastric carcinoma is a common type of gastrointestinal tumor with high morbidity and mortality rates. IL-17 is a newly discovered cytokine that has been reported to serve an important role in the development of gastric carcinoma. The potential effect of apatinib on IL-17 expression levels in the development of gastric carcinoma has been rarely reported. The present study aimed to investigate the potential mechanism of IL-17 and apatinib in the development of gastric carcinoma. A total of 30 tumor and para-carcinoma tissues were collected from 30 patients with gastric carcinoma between January 2019 and December 2019 and the expression levels of IL-17 in the tissues were analyzed by reverse transcription-quantitative PCR and western blotting. An in vitro model of gastric carcinoma was also established using the HGC-27 cell line, in which the cells were divided into control, IL-17, IL-17-apatinib and apatinib groups. The expression levels of IL-17, Bax, Bcl-2 and caspase-3 were analyzed using reverse transcription-quantitative PCR and western blotting. An MTT assay and flow cytometry were used to analyze the proliferation and apoptosis of HGC-27 cells, respectively, and a Transwell assay was used to analyze the invasive ability of HGC-27 cells. The results revealed that the expression levels of IL-17 were significantly upregulated in the gastric carcinoma tissues compared with the para-carcinoma tissues. In vitro, IL-17 treatment promoted the proliferation and invasive ability of HGC-27 cells, but inhibited the apoptosis with the significantly downregulated expression levels of Bax and caspase-3 and the upregulated expression levels of Bcl-2 than control group. Conversely, apatinib treatment significantly inhibited the proliferative and invasive abilities of HGC-27 cells, but promoted cell apoptosis in the IL-17 and IL-17-apatinib groups.. Collectively, the present results suggested that the upregulation of IL-17 may be associated with the occurrence and development of gastric carcinoma. The findings indicated that apatinib may inhibit gastric carcinoma development by regulating IL-17 expression via the Bax/Bcl-2 signaling pathway. Therefore, the present findings may enhance the current knowledge of the effect of apatinib on gastric carcinoma cells.
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Affiliation(s)
- Tianxi Wang
- Department of Gastroenterology, Tianjin Nankai Hospital, Tianjin 300100, P.R. China
| | - Jun Zhang
- Department of General Medicine, Tianjin Beichen Hospital, Tianjin 300401, P.R. China
| | - Lihong Cui
- Department of Gastroenterology, Tianjin Nankai Hospital, Tianjin 300100, P.R. China
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22
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Zhang X, Ren X, Tang J, Wang J, Zhang X, He P, Yao C, Bian W, Sun L. Hyaluronic acid reduction-sensitive polymeric micelles achieving co-delivery of tumor-targeting paclitaxel/apatinib effectively reverse cancer multidrug resistance. Drug Deliv 2021; 27:825-835. [PMID: 32489129 PMCID: PMC8216478 DOI: 10.1080/10717544.2020.1770373] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
Abstract
Multidrug resistance (MDR) of cancer cells is a significant challenge in chemotherapy, highlighting the urgent medical need for simple and reproducible strategies to reverse this process. Here, we report the development of an active tumor-targeting and redox-responsive nanoplatform (PA-ss-NP) using hyaluronic acid-g-cystamine dihydrochloride-poly-ε-(benzyloxycarbonyl)-L-lysine (HA-ss-PLLZ) to co-deliver paclitaxel (PTX) and apatinib (APA) for effective reversal of MDR. This smart nanoplatform specifically bound to CD44 receptors, leading to selective accumulation at the tumor site and uptake by MCF-7/ADR cells. Under high concentrations of cellular glutathione (GSH), the nanocarrier was degraded rapidly with complete release of its encapsulated drugs. Released APA effectively inhibited the function of the P-glycoprotein (P-gp) drug pump and improved the sensitivity of MDR cells to chemotherapeutic agents, leading to the recovery of PTX chemosensitivity in MDR cells. As expected, this newly developed intelligent drug delivery system could effectively control MDR, both in vitro and in vivo.
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Affiliation(s)
- Xiaoqing Zhang
- Department of Mastopathy, The Affiliated Hospital of Nanjing University of Chinese Medicine (Jiangsu Province Hospital of TCM), Nanjing, China
| | - Xiaomei Ren
- Department of Mastopathy, The Affiliated Hospital of Nanjing University of Chinese Medicine (Jiangsu Province Hospital of TCM), Nanjing, China
| | - Jiayin Tang
- Department of Mastopathy, The Affiliated Hospital of Nanjing University of Chinese Medicine (Jiangsu Province Hospital of TCM), Nanjing, China
| | - Jiangtao Wang
- Department of Mastopathy, The Affiliated Hospital of Nanjing University of Chinese Medicine (Jiangsu Province Hospital of TCM), Nanjing, China
| | - Xiang Zhang
- The Department of Oncology, The Affiliated Shuyang Hospital of Xuzhou Medical University, Suqian, China
| | - Peng He
- Department of Mastopathy, The Affiliated Hospital of Nanjing University of Chinese Medicine (Jiangsu Province Hospital of TCM), Nanjing, China
| | - Chang Yao
- Department of Mastopathy, The Affiliated Hospital of Nanjing University of Chinese Medicine (Jiangsu Province Hospital of TCM), Nanjing, China
| | - Weihe Bian
- Department of Mastopathy, The Affiliated Hospital of Nanjing University of Chinese Medicine (Jiangsu Province Hospital of TCM), Nanjing, China
| | - Lizhu Sun
- The Department of Oncology, The Affiliated Shuyang Hospital of Xuzhou Medical University, Suqian, China
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23
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Xu Z, Hu C, Yu J, Du Y, Hu P, Yu G, Hu C, Zhang Y, Mao W, Chen S, Cheng X. Efficacy of Conversion Surgery Following Apatinib Plus Paclitaxel/S1 for Advanced Gastric Cancer With Unresectable Factors: A Multicenter, Single-Arm, Phase II Trial. Front Pharmacol 2021; 12:642511. [PMID: 33815124 PMCID: PMC8017219 DOI: 10.3389/fphar.2021.642511] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Accepted: 02/12/2021] [Indexed: 12/18/2022] Open
Abstract
Objective: Conversion therapy (surgical resection after chemotherapy) is a promising option for unresectable gastric cancer (GC) patients. Addition of anti-angiogenesis drug improves response to chemotherapy. Hence, this study explored the feasibility and efficacy of preoperative paclitaxel (PTX)/S1 chemotherapy combined with apatinib for unresectable GC. Methods: Thirty-one eligible patients with a single unresectable factor were enrolled in this multi-center, single-arm trial. Apatinib (500 mg qd) was administered continuously, while PTX (130 mg/m2) on day 1 and S1 (80 mg/m2) on day 1-14 were given every 3 weeks. The treatment was given for three cycles preoperatively, but the last cycle did not include apatinib. The primary objective measurements included R0 resection rate, objective response rate (ORR) and morbidity of preoperative treatment. Results: Among the 31 patients, 30 patients were evaluable for tumor response, the ORR to preoperative treatment was 73.3%. Eighteen of 30 patients underwent surgery, and R0 resection was achieved in 17 patients. The patients who underwent the conversion surgery had a superior OS compared with those who did not (3 years OS: 52.9 vs 8.3%, p = 0.001). The surgery was operated after apatinib had stopped for a median duration of 4 weeks. Neither anastomotic leakage nor wound healing complications was observed. No increased bleeding event was observed compared with historical data. During preoperative treatment, grade 3 or 4 toxicities were experienced by 58.1% of the patients. Conclusion: Chemotherapy in combination with apatinib demonstrated higher rates of conversion and R0 resection and a superior survival benefit in initial unresectable GC. It is safe and reasonable to suspend apatinib for 4 weeks before the gastrectomy.
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Affiliation(s)
- Zhiyuan Xu
- Department of Gastric Surgery, Institute of Cancer Research and Basic Medical Sciences of Chinese Academy of Sciences, Cancer Hospital of University of Chinese Academy of Sciences, Zhejiang Cancer Hospital, Hangzhou, China
| | - Can Hu
- The 2nd Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, China
| | - Jianfa Yu
- Department of Gastrointestinal Surgery, the First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China
| | - Yian Du
- Department of Gastric Surgery, Institute of Cancer Research and Basic Medical Sciences of Chinese Academy of Sciences, Cancer Hospital of University of Chinese Academy of Sciences, Zhejiang Cancer Hospital, Hangzhou, China
| | - Ping Hu
- Department of Gastrointestinal Surgery, the Central Hospital of Lishui City, Lishui, China
| | - Guofa Yu
- Department of General Surgery, Shengzhou People's Hospital, Shengzhou, China
| | - Conggang Hu
- Department of Abdominal Surgery, GuangFu Hospital, Jinhua, China
| | - Yu Zhang
- Department of Gastrointestinal Surgery, the First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China
| | - Wei Mao
- Department of Gastrointestinal Surgery, the First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China
| | - Shanqi Chen
- Department of Gastrointestinal Surgery, the First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China
| | - Xiangdong Cheng
- Department of Gastric Surgery, Institute of Cancer Research and Basic Medical Sciences of Chinese Academy of Sciences, Cancer Hospital of University of Chinese Academy of Sciences, Zhejiang Cancer Hospital, Hangzhou, China
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24
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Chi D, Chen B, Guo S, Bai K, Ma H, Hu Y, Li Q, Zhu Y. Oral maintenance therapy using apatinib combined with S-1/capecitabine for esophageal squamous cell carcinoma with residual disease after definitive chemoradiotherapy. Aging (Albany NY) 2021; 13:8408-8420. [PMID: 33713398 PMCID: PMC8034932 DOI: 10.18632/aging.202652] [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: 08/24/2020] [Accepted: 01/21/2021] [Indexed: 01/20/2023]
Abstract
Background: A substantial number of patients with esophageal squamous cell carcinoma (ESCC) do not achieve complete remission after definitive concurrent chemoradiotherapy (dCRT). We performed this retrospective study to evaluate the efficacy and safety of apatinib combined with S-1/capecitabine as the oral maintenance therapy for these patients. Methods: Thirty-nine ESCC patients with residual disease after dCRT were included. Patients were treated with apatinib combined with S-1 /capecitabine after dCRT. Efficacy, toxicity, and survival were analyzed. Results: Of the 39 patients, 5 (12.8%) achieved a partial response and 29 (74.4%) achieved stable disease, yielding a disease control rate of 87.2%. The median progression-free survival (PFS) and overall survival (OS) were 27.5 (95%CI: 14.9 - 40.1) and 38.1 (95%CI: 31.3 - 44.8) months. Most frequent adverse events were of grade 1 to 2. Multivariate analysis revealed the occurrence of any adverse events (HR = 0.274, 95%[CI] = 0.119 - 0.630) correlated to better PFS and occurrence of proteinuria (HR = 0.108, 95%[CI] = 0.025 - 0.456) predicted better OS. Conclusion: The oral combination therapy consisting of apatinib and S-1/capecitabine showed a tolerable toxicity profile and achieved satisfactory disease control in ESCC patients with residual disease after dCRT.
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Affiliation(s)
- Dongmei Chi
- Department of Radiation Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, Guangdong, P.R. China.,Guangdong Esophageal Cancer Research Institute, Guangzhou, Guangdong, P. R. China.,Department of Anesthesiology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, P.R. China
| | - Baoqing Chen
- Department of Radiation Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, Guangdong, P.R. China.,Guangdong Esophageal Cancer Research Institute, Guangzhou, Guangdong, P. R. China
| | - Suping Guo
- Department of Radiation Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, Guangdong, P.R. China.,Guangdong Esophageal Cancer Research Institute, Guangzhou, Guangdong, P. R. China
| | - Kunhao Bai
- Department of Endoscopy, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, Guangdong, P.R. China
| | - Huali Ma
- Department of Radiology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, Guangdong, P.R. China
| | - Yonghong Hu
- Department of Radiation Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, Guangdong, P.R. China.,Guangdong Esophageal Cancer Research Institute, Guangzhou, Guangdong, P. R. China
| | - Qiaoqiao Li
- Department of Radiation Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, Guangdong, P.R. China.,Guangdong Esophageal Cancer Research Institute, Guangzhou, Guangdong, P. R. China
| | - Yujia Zhu
- Department of Radiation Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, Guangdong, P.R. China.,Guangdong Esophageal Cancer Research Institute, Guangzhou, Guangdong, P. R. China
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25
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Zhao S, Fan N, Li H, Liu J, Huang F, Chen Y, Zhou M, Yu J, Lin R. Apatinib combined with paclitaxel-based chemotherapy in patients with taxane-resistant advanced gastric cancer: a single-arm exploratory study. ANNALS OF TRANSLATIONAL MEDICINE 2020; 8:1233. [PMID: 33178765 PMCID: PMC7607108 DOI: 10.21037/atm-20-5841] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Background Apatinib combined with chemotherapy might be effective and safe for the management of advanced gastric cancer, but the available data are limited. To investigate the efficacy and safety of apatinib in combination with paclitaxel (PTX) alone or POF (PTX, oxaliplatin, and 5-fluorouracil) in patients with taxane-resistant advanced gastric cancer. Methods Patients with taxane-resistant advanced gastric cancer were enrolled in the single-center, open-labeled, single-arm, exploratory study (ClinicalTrials.gov #NCT02697838). Apatinib was administered at 850 mg po in combination with weekly PTX or the POF regimen. The primary endpoint was the objective response rate (ORR). The secondary endpoints included disease control rate (DCR), progression-free survival (PFS), overall survival (OS), the time to tumor progression (TTP), and safety. Results Twenty participants were recruited from 08/2016 to 01/2018. The duration of the study treatment was 2.07 (0.03–16.2) months. The median follow-up was 24.8 (0.3–26.0) months. The reasons for termination of treatment were disease progression (n=6), adverse events (AEs) (n=5), and patients’ will (n=9). The ORR was 11.1% (95% CI: 1.4–34.7%) and the DCR was 77.8% (95% CI: 52.4–93.6%). The median PFS was 3.5 (95% CI: 1.9–5.1) months, the median OS was 4.7 (95% CI: 2.0–7.3) months, and the median TTP was 4.2 (95% CI: 0.562–7.838) months. All 20 (100%) patients had AEs, 17 (85%) had apatinib treatment-emergent AEs (TEAEs), and 18 (90%) had chemotherapy TEAEs. The main grade 3–4 TEAEs were neutropenia, leukopenia, hypertension, and anemia. Conclusions This preliminary study suggests that apatinib combined with PTX or POF might be effective and tolerable in patients with chemotherapy-refractory gastric cancer. Studies are necessary to confirm the results. Trial registration ClinicalTrials.gov #NCT02697838.
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Affiliation(s)
- Shen Zhao
- Department of Gastrointestinal Medical Oncology, Fujian Cancer Hospital, Fuzhou, Fujian, China.,Fujian Medical University Cancer Hospital, Fuzhou, Fujian, China.,Fujian Key Laboratory of Translational Cancer Medicine, Fuzhou, Fujian, China
| | - Nanfeng Fan
- Department of Gastrointestinal Medical Oncology, Fujian Cancer Hospital, Fuzhou, Fujian, China.,Fujian Medical University Cancer Hospital, Fuzhou, Fujian, China
| | - Hui Li
- Department of Gastrointestinal Medical Oncology, Fujian Cancer Hospital, Fuzhou, Fujian, China.,Fujian Medical University Cancer Hospital, Fuzhou, Fujian, China
| | - Jie Liu
- Department of Gastrointestinal Medical Oncology, Fujian Cancer Hospital, Fuzhou, Fujian, China.,Fujian Medical University Cancer Hospital, Fuzhou, Fujian, China
| | - Feng Huang
- Department of Gastrointestinal Medical Oncology, Fujian Cancer Hospital, Fuzhou, Fujian, China.,Fujian Medical University Cancer Hospital, Fuzhou, Fujian, China
| | - Yigui Chen
- Department of Gastrointestinal Medical Oncology, Fujian Cancer Hospital, Fuzhou, Fujian, China.,Fujian Medical University Cancer Hospital, Fuzhou, Fujian, China
| | - Min Zhou
- Department of Gastrointestinal Medical Oncology, Fujian Cancer Hospital, Fuzhou, Fujian, China.,Fujian Medical University Cancer Hospital, Fuzhou, Fujian, China
| | - Jiaqing Yu
- Department of Gastrointestinal Medical Oncology, Fujian Cancer Hospital, Fuzhou, Fujian, China.,Fujian Medical University Cancer Hospital, Fuzhou, Fujian, China
| | - Rongbo Lin
- Department of Gastrointestinal Medical Oncology, Fujian Cancer Hospital, Fuzhou, Fujian, China.,Fujian Medical University Cancer Hospital, Fuzhou, Fujian, China.,Fujian Key Laboratory of Translational Cancer Medicine, Fuzhou, Fujian, China
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26
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Khalafi S, Lockhart AC, Livingstone AS, El-Rifai W. Targeted Molecular Therapies in the Treatment of Esophageal Adenocarcinoma, Are We There Yet? Cancers (Basel) 2020; 12:E3077. [PMID: 33105560 PMCID: PMC7690268 DOI: 10.3390/cancers12113077] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Revised: 10/14/2020] [Accepted: 10/20/2020] [Indexed: 02/07/2023] Open
Abstract
Esophageal adenocarcinoma is one of the leading causes of cancer-related deaths worldwide. The incidence of esophageal adenocarcinoma has increased at an alarming rate in the Western world and long-term survival remains poor. Current treatment approaches involve a combination of surgery, chemotherapy, and radiotherapy. Unfortunately, standard first-line approaches are met with high rates of recurrence and metastasis. More recent investigations into the distinct molecular composition of these tumors have uncovered key genetic and epigenetic alterations involved in tumorigenesis and progression. These discoveries have driven the development of targeted therapeutic agents in esophageal adenocarcinoma. While many agents have been studied, therapeutics targeting the human epidermal growth factor receptor (HER2) and vascular endothelial growth factor (VEGF) pathways have demonstrated improved survival. More recent advances in immunotherapies have also demonstrated survival advantages with monoclonal antibodies targeting the programmed death ligand 1 (PD-L1). In this review we highlight recent advances of targeted therapies, specifically agents targeting receptor tyrosine kinases, small molecule kinase inhibitors, and immune checkpoint inhibitors. While targeted therapeutics and immunotherapies have significantly improved survival, the benefits are limited to patients whose tumors express biomarkers such as PD-L1 and HER2. Survival remains poor for the remainder of patients with esophageal adenocarcinoma, underscoring the critical need for development of novel treatment strategies.
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Affiliation(s)
- Shayan Khalafi
- Department of Surgery, Miler School of Medicine, University of Miami, Miami, FL 33136, USA; (S.K.); (A.S.L.)
| | - Albert Craig Lockhart
- Department of Medicine, Miler School of Medicine, University of Miami, Miami, FL 33136, USA;
- Sylvester Comprehensive Cancer Center, Miler School of Medicine, University of Miami, Miami, FL 33136, USA
| | - Alan S. Livingstone
- Department of Surgery, Miler School of Medicine, University of Miami, Miami, FL 33136, USA; (S.K.); (A.S.L.)
| | - Wael El-Rifai
- Department of Surgery, Miler School of Medicine, University of Miami, Miami, FL 33136, USA; (S.K.); (A.S.L.)
- Department of Medicine, Miler School of Medicine, University of Miami, Miami, FL 33136, USA;
- Department of Veterans Affairs, Miami Healthcare System, Miami, FL 33136, USA
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27
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Li C, Wu R, Xing Y. MAFG-AS1 is a novel clinical biomarker for clinical progression and unfavorable prognosis in gastric cancer. Cell Cycle 2020; 19:601-609. [PMID: 32079456 DOI: 10.1080/15384101.2020.1728017] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
MAFG antisense 1 (MAFG-AS1) is recently identified as a novel lncRNA and serves as a tumor promoter in several types of human tumor. However, no prior study has been performed to evaluate the role of MAFG-AS1 in gastric cancer. In our study, we found MAFG-AS1 expression was increased in gastric cancer tissue samples compared with normal gastric mucosa tissue samples, and associated with poor overall survival in gastric cancer patients at The Cancer Genome Atlas database. Furthermore, we confirmed the clinical and prognostic significance of MAFG-AS1 in gastric cancer. We found gastric cancer tissues and cell lines had remarkably increased MAFG-AS1 expression in comparison to normal gastric mucosa tissues and normal human gastric epithelial cell line, and high MAFG-AS1 expression was positively associated with diffuse type, advanced clinical stage, extensive depth of invasion, more lymph node metastasis, and present distant metastasis in gastric cancer patients. Moreover, high MAFG-AS1 expression acted as one of the independent poor prognostic factors for overall survival in gastric cancer patients. The loss-of-function study showed knocking down MAFG-AS1 expression inhibited gastric cancer cell proliferation, migration and invasion in vitro. In conclusion, MAFG-AS1 is probable to be a valuable prognostic biomarker, and a novel potential target for gastric cancer.
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Affiliation(s)
- Chao Li
- Department of Laboratory, Shandong University Hospital, Jinan, Shandong, China
| | - Rongfang Wu
- Department of Gastroenterology, Taishan Sanatorium of Shandong Province, Tai'an, Shandong, China
| | - Youzhong Xing
- Department of Blood Transfusion, Jinan Central Hospital, Jinan, Shandong, China
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28
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Sun H, Feng F, Xie H, Li X, Jiang Q, Chai Y, Wang Z, Yang R, Li R, Hou J. Quantitative examination of the inhibitory activation of molecular targeting agents in hepatocellular carcinoma patient-derived cell invasion via a novel in vivo tumor model. Animal Model Exp Med 2019; 2:259-268. [PMID: 31942558 PMCID: PMC6930997 DOI: 10.1002/ame2.12085] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2019] [Revised: 08/31/2019] [Accepted: 09/03/2019] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND The outcomes for patients with advanced hepatocellular carcinoma (HCC) receiving sorafenib are far from satisfactory because of treatment resistance to sorafenib. However, the exact mechanism of resistance to sorafenib remains unclear and it is valuable to establish a novel mouse model to quantitatively analyze the inhibition rates of sorafenib on the invasive growth of HCC cells in the liver. METHODS HCC tissue microblocks derived from patients were cultured and mixed with hydrogel drops. Then, hydrogel drops containing microblocks of HCC tissue were attached onto the surface of the livers of nude mice to form lesions or nodules of HCC. The mice received molecular targeting agents through oral administration. Livers with tumor nodules were harvested for H&E staining (hematoxylin-eosin staining) analysis and H&E staining images were quantitatively analyzed using image J software. The invasive growth of HCC cells into the liver was calculated using the depth of the lesions compared with the total thickness of the liver. RESULTS Microblocks containing cells derived from HCC patients can form lesions in the liver of nude mice. Oral administration of molecular targeting agents inhibited the invasive growth of HCC cells in the liver of nude mice. CONCLUSIONS The model established in this study involves the invasive growth of HCC cells in the liver of nude mice, and the model allows for the quantitative analysis of the inhibitory effect of molecular targeting agents on the invasion of HCC cells in vivo.
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Affiliation(s)
- Huiwei Sun
- Research Center for Clinical and Translational MedicineThe Fifth Medical CenterGeneral Hospital of Chinese PLABeijingChina
| | - Fan Feng
- Research Center for Clinical and Translational MedicineThe Fifth Medical CenterGeneral Hospital of Chinese PLABeijingChina
- Center for Clinical LaboratoryThe Fifth Medical CenterGeneral Hospital of Chinese PLABeijingChina
| | - Hui Xie
- Department of Interventional TherapyThe Fifth Medical CenterGeneral Hospital of Chinese PLABeijingChina
| | - Xiaojuan Li
- Research Center for Clinical and Translational MedicineThe Fifth Medical CenterGeneral Hospital of Chinese PLABeijingChina
- Medical School of Chinese PLABeijingChina
| | - Qiyu Jiang
- Research Center for Clinical and Translational MedicineThe Fifth Medical CenterGeneral Hospital of Chinese PLABeijingChina
| | - Yantao Chai
- Research Center for Clinical and Translational MedicineThe Fifth Medical CenterGeneral Hospital of Chinese PLABeijingChina
| | - Zhijie Wang
- Research Center for Clinical and Translational MedicineThe Fifth Medical CenterGeneral Hospital of Chinese PLABeijingChina
| | - Ruichuang Yang
- Research Center for Clinical and Translational MedicineThe Fifth Medical CenterGeneral Hospital of Chinese PLABeijingChina
| | - Ruisheng Li
- Research Center for Clinical and Translational MedicineThe Fifth Medical CenterGeneral Hospital of Chinese PLABeijingChina
| | - Jun Hou
- Research Center for Clinical and Translational MedicineThe Fifth Medical CenterGeneral Hospital of Chinese PLABeijingChina
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