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1
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Kaya Çakir H, Eroğlu O. Investigation of the synergic effect of mocetinostat and capecitabine in a triple-negative breast neoplasms mouse model. J Investig Med 2025; 73:320-327. [PMID: 39690705 DOI: 10.1177/10815589241309603] [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] [Indexed: 12/19/2024]
Abstract
Combined administration of two or more drugs is emerging as a new strategy in triple-negative breast neoplasms. This is the first study to investigate the combination of the histone deacetylase inhibitor mocetinostat and the antimetabolite drug capecitabine in triple-negative mammary neoplasms in a preclinical mouse model. Thirty-five female mice were grouped into the control group, capecitabine group, mocetinostat group, and combined drugs group. At the end of the experimental period, body weight, and tumor weight were measured and tumor tissue and lung tissue were histologically examined. The results showed that the body weight of mice in the drug-treated groups was reduced by about 18%. Tumor weights were also reduced by 21% in the mocetinostat group, 27.5% in the capecitabine group, and 45% in the combined group. The combination of mocetinostat and capecitabine decreased the formation of tumors and metastases in lung tissue. In summary, the combination of mocetinostat and capecitabine was more effective than either drug alone in reducing the size of triple-negative breast neoplasms in a mouse model.
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Affiliation(s)
- Hacer Kaya Çakir
- Department of Molecular Biology and Genetics, Faculty of Science, Bilecik Seyh Edebali University, Bilecik, Turkey
| | - Onur Eroğlu
- Department of Molecular Biology and Genetics, Faculty of Science, Bilecik Seyh Edebali University, Bilecik, Turkey
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2
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Wang X, Xu J, Chen J, Jin S, Yao J, Yu T, Wang W, Guo R. IL-22 Confers EGFR-TKI Resistance in NSCLC via the AKT and ERK Signaling Pathways. Front Oncol 2019; 9:1167. [PMID: 31750252 PMCID: PMC6848259 DOI: 10.3389/fonc.2019.01167] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2019] [Accepted: 10/17/2019] [Indexed: 01/01/2023] Open
Abstract
Background: The efficacy of an EGFR-targeted treatment strategy for non-small cell lung cancer (NSCLC) is reduced by drug resistance. IL-22 enhances tumor growth and induces chemotherapy resistance in human lung cancer cells. The present study elucidated the IL-22-induced mechanism underlying EGFR-tyrosine kinase inhibitor (TKI) resistance in NSCLC. Methods: The plasma and tissues of patients who received EGFR-TKIs were utilized to determine the association between IL-22 expression and gefitinib efficacy. The IL-22 effect on the EGFR/ERK/AKT pathways in NSCLC HCC827 and PC-9 cells was determined using the CCK-8 assay, western blot, and flow cytometric analysis. A PC-9 xenograft model of IL-22 exposure was established. Gefitinib was administered to mice in combination with IL-22 or vehicle. Results: We showed that IL-22 expression was higher in the EGFR-TKI-resistant group compared to EGFR-TKI-sensitive group. IL-22 expression was associated with EGFR-TKI efficacy in plasma. Additional treatment of IL-22 induced gefitinib resistance and reduced apoptosis in PC-9 and HCC827 cell lines. Furthermore, we showed that the effects of IL-22 attributed to p-ERK, p-EGFR, and p-AKT up-regulation. IL-22 neutralizing antibody completely abrogated the effects of IL-22 on apoptosis and AKT/EGFR/ERK signaling. Finally, we showed that IL-22 enhanced tumor growth and induced gefitinib resistance in the PC-9 xenograft model. Moreover, compared with gefitinib alone, the combination of IL-22 and gefitinib led to an increase in Ki67-positive staining and a reduction in TUNEL staining. Conclusions: Our findings indicate that IL-22 plays a role in tumor progression and EGFR-TKI resistance in NSCLC. Thus, IL-22 might serve as a novel biomarker to overcome resistance of EGFR-TKI.
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Affiliation(s)
- Xiaomeng Wang
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.,Department of Radiotherapy, II, The First People's Hospital of Shangqiu, Shangqiu, China
| | - Jiali Xu
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Jin Chen
- The Fourth Clinical Medical College, Nanjing Medical Universtiy, Nanjing, China
| | - Shidai Jin
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Jiaqi Yao
- The First Clinical Medical College, Nanjing Medical Universtiy, Nanjing, China
| | - Tongfu Yu
- Department of Radiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Wei Wang
- Department of Cardiothoracic Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Renhua Guo
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
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Siddiqui NS, Godara A, Byrne MM, Saif MW. Capecitabine for the treatment of pancreatic cancer. Expert Opin Pharmacother 2019; 20:399-409. [PMID: 30649964 DOI: 10.1080/14656566.2018.1560422] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
INTRODUCTION Capecitabine is an oral prodrug of 5-fluorouracil (5-FU) which is converted to 5FU by a series of reactions catalyzed by different enzymes, the last of the enzymes being thymidine phosphorylase (TP). TP is found to be elevated in tumor cells in comparison to normal cells, which consequently tumor-localizes the production of 5-FU, thereby limiting its systemic toxicity. Today, capecitabine is extensively used for the treatment of many solid malignancies, with a particular focus in breast and gastrointestinal tumors, but also in pancreatic cancer. Areas covered: This review summarizes the pharmacology and the clinical evidence relevant to the use of capecitabine in the treatment of pancreas cancer. The authors provide, furthermore, provide their expert perspectives on its use. Expert opinion: Capecitabine has the advantage over other therapeutics in so much that it has both convenient oral administration and a favorable toxicity profile. Current data has promised the use of capecitabine in all stages of pancreatic cancer. However, predictive markers for outcome and toxicity remain to be validated.
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Affiliation(s)
- Nauman S Siddiqui
- a Division of Hematology/Oncology , Tufts Medical Center - Tufts University School of Medicine , Boston , MA , USA
| | - Amandeep Godara
- a Division of Hematology/Oncology , Tufts Medical Center - Tufts University School of Medicine , Boston , MA , USA
| | - Margaret M Byrne
- a Division of Hematology/Oncology , Tufts Medical Center - Tufts University School of Medicine , Boston , MA , USA
| | - Muhammad Wasif Saif
- a Division of Hematology/Oncology , Tufts Medical Center - Tufts University School of Medicine , Boston , MA , USA.,b Department of Medical Oncology , Northwell Health Cancer Institute , New York , NY , USA
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Oberthür R, Seemann H, Gehrig J, Rave-Fränk M, Bremmer F, Halpape R, Conradi LC, Scharf JG, Burfeind P, Kaulfuß S. Simultaneous inhibition of IGF1R and EGFR enhances the efficacy of standard treatment for colorectal cancer by the impairment of DNA repair and the induction of cell death. Cancer Lett 2017; 407:93-105. [PMID: 28823963 DOI: 10.1016/j.canlet.2017.08.009] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2017] [Revised: 08/01/2017] [Accepted: 08/06/2017] [Indexed: 12/17/2022]
Abstract
Overexpression and activation of receptor tyrosine kinases (RTKs), such as the insulin-like growth factor 1 receptor (IGF1R) and the epidermal growth factor receptor (EGFR), are frequent phenomena in colorectal cancer (CRC). Here, we evaluated the effect and the cellular mechanisms of the simultaneous inhibition of these two RTKs both in vitro and in vivo in addition to a 5-fluoruracil (5-FU)-based radiochemotherapy (RCT), which is a standard treatment scheme for CRC. Using the small molecule inhibitors AEW541 and erlotinib, specific against IGF1R and EGFR, respectively, different CRC cell lines exhibited a reduced survival fraction after RCT, with the highest effect after the simultaneous inhibition of IGF1R/EGFR. In vivo, xenograft mice simultaneously treated with low dose AEW541/erlotinib plus RCT revealed a significant reduction in tumour volume and weight compared with the tumours of mice treated with either AEW541 or erlotinib alone. In vitro, the combined inhibition of IGF1R/EGFR resulted in a stronger reduction of downstream signalling, an increase in DNA double strand breaks (DSBs), apoptosis and mitotic catastrophe after RCT depending on the cell line. Moreover, the existence of IGF1R/EGFR heterodimers in CRC cells and human rectal cancer samples was proven. The heterodimerisation of these RTKs was dependent on the presence of both ligands, IGF-1 and EGF, and functional receptors. In conclusion, these results demonstrate that the strategy of targeting both IGF1R and EGFR, in addition to basic RCT, could be of intriguing importance in CRC therapy.
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Affiliation(s)
- Rabea Oberthür
- Institute of Human Genetics, University Medical Centre Göttingen, Germany
| | - Henning Seemann
- Institute of Human Genetics, University Medical Centre Göttingen, Germany
| | - Julia Gehrig
- Institute of Human Genetics, University Medical Centre Göttingen, Germany
| | - Margret Rave-Fränk
- Department of Radiotherapy and Radio Oncology, University Medical Centre Göttingen, Germany
| | - Felix Bremmer
- Institute of Pathology, University Medical Centre Göttingen, Germany
| | - Rovena Halpape
- Institute of Human Genetics, University Medical Centre Göttingen, Germany
| | - Lena-Christin Conradi
- Department of General, Visceral and Paediatric Surgery, University Medical Centre Göttingen, Germany
| | - Jens-Gerd Scharf
- 2nd Department of Internal Medicine, HELIOS Hospital Erfurt, Germany
| | - Peter Burfeind
- Institute of Human Genetics, University Medical Centre Göttingen, Germany
| | - Silke Kaulfuß
- Institute of Human Genetics, University Medical Centre Göttingen, Germany.
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5
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Kim YH, Kim MJ, Choe SW, Sprecher D, Lee YJ, Oh SP. Selective effects of oral antiangiogenic tyrosine kinase inhibitors on an animal model of hereditary hemorrhagic telangiectasia. J Thromb Haemost 2017; 15:1095-1102. [PMID: 28339142 PMCID: PMC5902312 DOI: 10.1111/jth.13683] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2016] [Indexed: 11/28/2022]
Abstract
Essentials Antiangiogenic drugs are indicated as therapies for hereditary hemorrhagic telangiectasia. We interrogated the response to four antiangiogenic drugs for anemia and intestinal bleeding. Sorafenib and a pazopanib analog significantly improved while erlotinib worsened anemia. Some oral antiangiogenic drugs were effective in reducing intestinal bleeding. SUMMARY Background Epistaxis and gastrointestinal (GI) tract hemorrhages are common symptoms of aged hereditary hemorrhagic telangiectasia (HHT) patients that result in anemia. Clinical as well as animal studies have suggested that vascular endothelial growth factor (VEGF) neutralizing antibodies lessen hemorrhage associated with adult-onset arteriovenous malformations (AVMs). Objectives The goal of this study is to evaluate potential therapeutic effects of oral delivery of four antiangiogenic tyrosine-kinase inhibitors (TKIs) in the development of adult-onset AVMs in a murine model of HHT. Methods An adult activin receptor-like kinase 1 (Alk1)-inducible knockout (iKO) model was utilized to evaluate the effect of oral administration of sorafenib, sunitinib, erlotinib and a pazopanib analog (GW771806) on hemoglobin level, GI hemorrhages and formation of wound-induced skin AVMs. Results and Conclusions Sorafenib and GW771806 significantly improved, yet erlotinib worsened, anemia and GI-bleeding in the Alk1-iKO model. However, none of these TKIs appeared to be effective for inhibiting the development of wound-induced skin AVMs. Taken together, these results suggest that oral delivery of antiangiogenic TKIs is selectively more effective for GI bleeding than mucocutaneous AVMs, and it may provide an experimental basis for selective therapeutic options depending on the symptoms of HHT.
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Affiliation(s)
- Yong Hwan Kim
- Department of Physiology and Functional genomics, College of Medicine, University of Florida, Gainesville, Florida 32610 USA
| | - Mi-Jung Kim
- Department of Aging, College of Medicine, University of Florida, Gainesville, Florida 32610 USA
- Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, Republic of Korea
| | - Se-woon Choe
- Department of Physiology and Functional genomics, College of Medicine, University of Florida, Gainesville, Florida 32610 USA
- Department of Medical IT Convergence Engineering, Kumoh National Institute of Technology, Gumi, Republic of Korea
| | - Dennis Sprecher
- GlaxoSmithKline Laboratories, Metabolic Pathways and Cardiovascular Unit, 709 Swedeland Road, King of Prussia, PA 19406, USA
| | - Young Jae Lee
- Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, Republic of Korea
| | - S. Paul Oh
- Department of Physiology and Functional genomics, College of Medicine, University of Florida, Gainesville, Florida 32610 USA
- Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, Republic of Korea
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Nedaeinia R, Avan A, Ahmadian M, Nia SN, Ranjbar M, Sharifi M, Goli M, Piroozmand A, Nourmohammadi E, Manian M, Ferns GA, Ghayour-Mobarhan M, Salehi R. Current Status and Perspectives Regarding LNA-Anti-miR Oligonucleotides and microRNA miR-21 Inhibitors as a Potential Therapeutic Option in Treatment of Colorectal Cancer. J Cell Biochem 2017; 118:4129-4140. [PMID: 28401648 DOI: 10.1002/jcb.26047] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2017] [Accepted: 04/10/2017] [Indexed: 02/06/2023]
Abstract
Colorectal cancer (CRC) is among the leading causes of cancer-related death, principally due to its metastatic spread and multifactorial chemoresistance. The therapeutic failure can also be explained by inter- or intra-tumor genetic heterogeneity and tumor stromal content. Thus, the identification of novel prognostic biomarkers and therapeutic options are warranted in the management of CRC patients. There are data showing that microRNA-21 is elevated in different types of cancer, particularly colon adenocarcinoma and that this is association with a poor prognosis. This suggests that microRNA-21 may be of value as a potential therapeutic target. Furthermore, locked nucleic acid (LNA)-modified oligonucleotides have recently emerged as a therapeutic option for targeting dysregulated miRNAs in cancer therapy, through antisense-based gene silencing. Further work is required to identify innovative anticancer drugs that improve the current therapy either through novel combinatorial approaches or with better efficacy than conventional drugs. We aimed to provide an overview of the preclinical and clinical studies targeting key dysregulated signaling pathways in CRC as well as the therapeutic application of LNA-modified oligonucleotides, and miR inhibitors in the treatment of CRC patients. J. Cell. Biochem. 118: 4129-4140, 2017. © 2017 Wiley Periodicals, Inc.
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Affiliation(s)
- Reza Nedaeinia
- Deputy of Food and Drug, Isfahan University of Medical Sciences, Isfahan, Iran.,Student Research Committee, Department of medical biotechnology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amir Avan
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.,Department of Modern Sciences and Technologies, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mehdi Ahmadian
- Department of Gastroentrology, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Sasan Nedaee Nia
- Department of Agricultural engineering and Weed science, Shiraz Branch, Islamic Azad University, Shiraz, Iran
| | - Maryam Ranjbar
- Deputy of Food and Drug, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Mohammadreza Sharifi
- Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Mohammad Goli
- Department of Food Science and Technology, Isfahan (Khorasgan) Branch, Islamic Azad University, Isfahan, Iran
| | - Ahmad Piroozmand
- School of Medicine, Kashan University of Medical Sciences, Autoimmune Diseases Research Center, Kashan, Iran
| | - Esmail Nourmohammadi
- Student Research Committee, Department of medical biotechnology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mostafa Manian
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Gordon A Ferns
- Brighton and Sussex Medical School, Division of Medical Education, Falmer, Brighton BN1 9PH, Sussex, UK
| | - Majid Ghayour-Mobarhan
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.,Department of Modern Sciences and Technologies, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Rasoul Salehi
- Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
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7
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West MA, Roman A, Sayan E, Primrose JN, Wedge SR, Underwood TJ, Mirnezami AH. A minimum core outcome dataset for the reporting of preclinical chemotherapeutic drug studies: Lessons learned from multiple discordant methodologies in the setting of colorectal cancer. Crit Rev Oncol Hematol 2017; 112:80-102. [PMID: 28325268 DOI: 10.1016/j.critrevonc.2017.02.008] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2016] [Revised: 01/11/2017] [Accepted: 02/13/2017] [Indexed: 12/27/2022] Open
Abstract
In vivo studies in animal models are critical tools necessary to study the fundamental complexity of carcinogenesis. A constant strive to improve animal models in cancer exists, especially those investigating the use of chemotherapeutic effectiveness. In the present systematic review, colorectal cancer (CRC) is used as an example to highlight and critically evaluate the range of reporting strategies used when investigating chemotherapeutic agents in the preclinical setting. A systematic review examining the methodology and reporting of preclinical chemotherapeutic drug studies using CRC murine models was conducted. A total of 45 studies were included in this systematic review. The literature was found to be highly heterogeneous with various cell lines, animal strains, animal ages and chemotherapeutic compounds/regimens tested, proving difficult to compare outcomes between similar studies or indeed gain any significant insight into which chemotherapeutic regimen caused adverse events. From this analysis we propose a minimum core outcome dataset that could be regarded as a standardised way of reporting results from in vivo experimentation.
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Affiliation(s)
- M A West
- University Surgery, University of Southampton, Southampton General Hospital, Southampton SO16 6YD, UK; Academic Unit of Cancer Sciences, Somers Cancer Research Building, University of Southampton, UK.
| | - A Roman
- University Surgery, University of Southampton, Southampton General Hospital, Southampton SO16 6YD, UK; Academic Unit of Cancer Sciences, Somers Cancer Research Building, University of Southampton, UK
| | - E Sayan
- Academic Unit of Cancer Sciences, Somers Cancer Research Building, University of Southampton, UK
| | - J N Primrose
- University Surgery, University of Southampton, Southampton General Hospital, Southampton SO16 6YD, UK; Academic Unit of Cancer Sciences, Somers Cancer Research Building, University of Southampton, UK
| | - S R Wedge
- Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK
| | - T J Underwood
- University Surgery, University of Southampton, Southampton General Hospital, Southampton SO16 6YD, UK; Academic Unit of Cancer Sciences, Somers Cancer Research Building, University of Southampton, UK
| | - A H Mirnezami
- University Surgery, University of Southampton, Southampton General Hospital, Southampton SO16 6YD, UK; Academic Unit of Cancer Sciences, Somers Cancer Research Building, University of Southampton, UK
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Chen J, Kaley K, Garcon MC, Rodriguez T, Saif MW. A novel schedule of erlotinib/capecitabine (7/7) as salvage therapy in previously treated advanced pancreatic adenocarcinoma: a case series. Therap Adv Gastroenterol 2016; 9:162-8. [PMID: 26929778 PMCID: PMC4749861 DOI: 10.1177/1756283x15622779] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND The objective of this study was to report a case series on the efficacy and safety of capecitabine 7/7 schedule combined with erlotinib (CAP-ERL) in patients with advanced pancreatic cancer (APC) who have failed prior therapies. METHODS We retrospectively evaluated 13 patients with locally advanced or metastatic pancreatic cancer previously treated with gemcitabine or oxaliplatin-irinotecan-based first-line regimens. Treatment consisted of capecitabine (Xeloda) at a flat dose of 1000 mg orally twice daily on days 1-7 out of 14 days (7/7 schedule) and erlotinib (Tarceva) 100 mg orally once daily until unacceptable toxicity or disease progression. Tumor assessments were repeated every two cycles (8 weeks) and serum tumor markers were measured every 4 weeks. RESULTS All patients (median age: 63 years; 7 female/3 male) had various previous lines of treatments of chemotherapies. Median number of cycles with CAP-ERL was 4 (range 2-12). The overall response rate was 20%. CA19-9 was reduced more than 25% in 40% patients. The median overall survival and progression-free survival from the start of CAP-ERL were 4.5 months (range 3-7.5) and 2 months (range 1.5-4), respectively. The most common grade 3 toxicities included hand-foot syndrome, nausea, vomiting, diarrhea, rash, and fatigue. CONCLUSIONS Our result suggests that the combination of a fixed low dose of CAP-ERL 7/7 schedule was tolerated with manageable toxicity and showed encouraging activity as salvage treatment in patients with refractory APC with ECOG performance status 0-2. Further prospective studies are warranted to evaluate this combination.
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Affiliation(s)
- Jiezhong Chen
- School of Biomedical Sciences and Australian Institute of Bioengineering and Nanotechnology, University of Queensland, QLD, Australia
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Harada S, Yanagisawa M, Kaneko S, Yorozu K, Yamamoto K, Moriya Y, Harada N. Superior antitumor activity of trastuzumab combined with capecitabine plus oxaliplatin in a human epidermal growth factor receptor 2-positive human gastric cancer xenograft model. Mol Clin Oncol 2015; 3:987-994. [PMID: 26623038 DOI: 10.3892/mco.2015.609] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2015] [Accepted: 06/04/2015] [Indexed: 01/28/2023] Open
Abstract
In the treatment of human epidermal growth factor receptor 2 (HER2)-positive advanced gastric or gastroesophageal junction cancer, it has been reported that the combination of trastuzumab with capecitabine plus cisplatin, or with 5-fluorouracil (5-FU) plus cisplatin, significantly increased overall survival compared with chemotherapy alone (ToGA trial). In addition, adjuvant therapy with capecitabine plus oxaliplatin (XELOX) improved the survival of patients who received curative D2 gastrectomy (CLASSIC trial). However, the efficacy of the combination of trastuzumab with XELOX for patients with HER2-positive gastric cancer remains unknown. The aim of this study, was to investigate the efficacy of the combination of trastuzumab with XELOX in a HER2-positive human gastric cancer xenograft model. Combination treatment with these three agents (trastuzumab 20 mg/kg, capecitabine 359 mg/kg and oxaliplatin 10 mg/kg), was found to exhibit a significantly stronger antitumor activity in NCI-N87 xenografts compared with either trastuzumab or XELOX alone. In this model, treatment with trastuzumab alone or trastuzumab plus oxaliplatin enhanced the expression of thymidine phosphorylase (TP), a key enzyme in the generation of 5-FU from capecitabine in tumor tissues. In in vitro experiments, trastuzumab induced TP mRNA expression in NCI-N87 cells. In addition, NCI-N87 cells co-cultured with the natural killer (NK) cell line CD16(158V)/NK-92 exhibited increased expression of TP mRNA. When NCI-N87 cells were cultured with CD16(158V)/NK-92 cells in the presence of trastuzumab, the mRNA expression of cytokines reported to have the ability to induce TP was upregulated in tumor cells. Furthermore, a medium conditioned by CD16(158V)/NK-92 cells also upregulated the expression of TP mRNA in NCI-N87 cells. These results suggest that trastuzumab promotes TP expression, either by acting directly on NCI-N87 cells, or indirectly via a mechanism that includes trastuzumab-mediated interactions between NK and NCI-N87 cells. Therefore, the combination of trastuzumab with XELOX may be a potent therapy for HER2-positive gastric cancer.
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Affiliation(s)
- Suguru Harada
- Product Research Department, Chugai Pharmaceutical Co., Ltd., Kamakura, Kanagawa 247-8530, Japan
| | - Mieko Yanagisawa
- Product Research Department, Chugai Pharmaceutical Co., Ltd., Kamakura, Kanagawa 247-8530, Japan
| | - Saori Kaneko
- Product Research Department, Chugai Pharmaceutical Co., Ltd., Kamakura, Kanagawa 247-8530, Japan
| | - Keigo Yorozu
- Product Research Department, Chugai Pharmaceutical Co., Ltd., Kamakura, Kanagawa 247-8530, Japan
| | - Kaname Yamamoto
- Product Research Department, Chugai Pharmaceutical Co., Ltd., Kamakura, Kanagawa 247-8530, Japan
| | - Yoichiro Moriya
- Product Research Department, Chugai Pharmaceutical Co., Ltd., Kamakura, Kanagawa 247-8530, Japan
| | - Naoki Harada
- Product Research Department, Chugai Pharmaceutical Co., Ltd., Kamakura, Kanagawa 247-8530, Japan
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10
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Li H, Wang S, Takayama K, Harada T, Okamoto I, Iwama E, Fujii A, Ota K, Hidaka N, Kawano Y, Nakanishi Y. Nicotine induces resistance to erlotinib via cross-talk between α 1 nAChR and EGFR in the non-small cell lung cancer xenograft model. Lung Cancer 2015; 88:1-8. [PMID: 25670150 DOI: 10.1016/j.lungcan.2015.01.017] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2014] [Revised: 12/26/2014] [Accepted: 01/20/2015] [Indexed: 12/18/2022]
Abstract
OBJECTIVES Given our previously published study, α 1 nicotinic acetylcholine receptor (nAChR) plays an essential role in nicotine-induced cell signaling and nicotine-induced resistance to epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) in non-small cell lung cancer (NSCLC) PC9 cells. The aim of this study was to investigate the potential mechanism between nAChR and EGFR for nicotine-induced resistance to EGFR-TKI erlotinib in the NSCLC xenograft model. MATERIALS AND METHODS We identified the role of nicotine to EGFR/AKT/ERK pathways and to erlotinib-resistance in NSCLC PC9 and HCC827 cells by MTS assay and western blot. Then, we established the PC9 xenograft model with nicotine exposure and treated mice with erlotinib combined with vehicle or nicotine. RESULTS We confirmed the effects of nicotine on EGFR/AKT/ERK pathways and determined nicotine's potential in preventing from the effect of erlotinib on NSCLC cells. Then, we showed that nicotine exposures can promote tumor growth and induce resistance to erlotinib in the PC9 xenograft model. Our results also indicated that chronic oral administration of nicotine can cause more significant erlotinib-resistance compared with acute i.v. injection of nicotine through activating α 1 nAChR and EGFR pathways. CONCLUSIONS These results suggest that nicotine contributes to the progression and erlotinib-resistance of the NSCLC xenograft model via the cooperation between nAChR and EGFR.
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Affiliation(s)
- Heyan Li
- Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Shuo Wang
- Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; Beijing Chest Hospital, Capital Medical University/Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, China
| | - Koichi Takayama
- Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
| | - Taishi Harada
- Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Isamu Okamoto
- Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Eiji Iwama
- Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Akiko Fujii
- Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Keiichi Ota
- Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Noriko Hidaka
- Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yuko Kawano
- Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yoichi Nakanishi
- Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
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Zhao HY, Chen GY, Huang Y, Li XL, Feng JF, Shi MQ, Cheng Y, Ma LX, Zhang YP, Gu CP, Song XQ, Zhou D, Zhang L. Erlotinib plus capecitabine as first-line treatment for older Chinese patients with advanced adenocarcinoma of the lung (C-TONG0807): an open-label, single arm, multicenter phase II study. Medicine (Baltimore) 2015; 94:e249. [PMID: 25590835 PMCID: PMC4602552 DOI: 10.1097/md.0000000000000249] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
Preclinical studies have shown synergism between epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors and antifolates in solid tumors. This study is to investigate the efficacy and tolerability of erlotinib plus capecitabine as first-line treatment in older Chinese patients (≥ 65 years) with lung adenocarcinoma. This is an open-label, single arm, multicenter phase II clinical trial. Sixty- two patients with previously untreated stage IIIB/IV adenocarcinoma and age 65 years or above were enrolled at four tertiary teaching hospitals and 2 provincial hospitals in China; 58 patients fulfilled the study requirements. Erlotinib (150 mg/day) and capecitabine (1000 mg/m2 twice daily on days 1-14) were administered during every 21-day cycle. The primary endpoint was the non-progression rate at 12 weeks. EGFR and K-ras mutation rates were determined using PCR. Tumor expression of different biomarkers was assessed using immunohistochemistry. In a cohort of 58 patients, 34 patients had no disease progression at 12 weeks following treatment. The objective response rate was 29.3%, and the disease control rate was 75.9%. The objective response rate was significantly higher in patients with EGFR mutations than in those with wild-type EGFR. Patients with thymidine phosphorylase-negative tumors had significantly longer overall survival after one year than patients with thymidine phosphorylase-positive tumors. Forty-four patients had at least one primary adverse events (AEs), including skin rash (n = 30), grade 3 AEs (n = 17), and grade 4 AEs (n = 7). This is the first phase II clinical trial to assess erlotinib plus capecitabine combination therapy as first-line treatment in older patients with lung adenocarcinoma. Erlotinib/capecitabine chemotherapy was significantly better in patients with EGFR mutations and in those with thymidine phosphorylase-negative tumors. The use of fluorouracil derivatives for the treatment of lung adenocarcinoma warrants further study.
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Affiliation(s)
- Hong-Yun Zhao
- From the Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, China (H-YZ, YH, LZ); Department of Internal Medicine, Cancer Hospital of Ha'erbin Medical University, Haerbin, Heilongjiang, China (G-YC, X-LL); Department of Oncology, Jiangsu Cancer Hospital, Nanjing, Jiangsu, China (J-FF, M-QS); Department of Oncology, Jilin Cancer Hospital, Changchun, Jilin, China (YC, L-XM); Chemotherapy Center, Zhejiang Cancer Hospital, Hangzhou, Zhejiang, China (Y-PZ, C-PG); and Department Chemotherapy, Cancer Hospital of Guangxi Medical University, Nanning, Guangxi, China (X-QS, DZ)
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Li H, Takayama K, Wang S, Shiraishi Y, Gotanda K, Harada T, Furuyama K, Iwama E, Ieiri I, Okamoto I, Nakanishi Y. Addition of bevacizumab enhances antitumor activity of erlotinib against non-small cell lung cancer xenografts depending on VEGF expression. Cancer Chemother Pharmacol 2014; 74:1297-305. [PMID: 25344762 PMCID: PMC4236614 DOI: 10.1007/s00280-014-2610-x] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2014] [Accepted: 10/14/2014] [Indexed: 12/31/2022]
Abstract
PURPOSE Erlotinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), and bevacizumab, an anti-vascular endothelial growth factor (VEGF) agent, are promising therapies for advanced non-small cell lung cancer (NSCLC). Our study was aimed to determine whether there were conditions under which the addition of bevacizumab would enhance the antitumor activity of erlotinib against NSCLC tumors in vitro and in vivo. METHODS MTS was for NSCLC cell (PC9, 11-18, H1975, H157, H460 and A549) growth assay in vitro. ELISA was for VEGF protein assay in cells and tumor tissues. Mouse xenograft models were established with H157, H460 and A549 with primary resistance to erlotinib and treated with erlotinib plus bevacizumab or each agent alone. Erlotinib concentrations in tumors were determined by high-performance liquid chromatography. RESULTS Bevacizumab alone did not inhibit NSCLC cell growth in vitro. In primarily erlotinib-resistant NSCLC cells, the levels of VEGF protein were highest in H157 cell followed in order by H460 and A549 cells. In vivo, bevacizumab alone significantly inhibited tumor growth only in xenograft models with high (H157) and/or moderate (H460) levels of VEGF protein. A combination of erlotinib and bevacizumab partially reversed resistance to erlotinib in H157 xenografts (high VEGF level) with increasing intratumoral erlotinib concentrations, but not in H460 (moderate) or A549 (low) xenografts. CONCLUSIONS These results support that combined with anti-VEGF therapy could enhance antitumor activity of anti-EGFR therapy and/or partially reverse resistance to EGFR TKI, by increasing EGFR TKI concentration in specific tumors that express high levels of VEGF protein.
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Affiliation(s)
- Heyan Li
- Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashiku, Fukuoka, 812-8582 Japan
| | - Koichi Takayama
- Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashiku, Fukuoka, 812-8582 Japan
| | - Shuo Wang
- Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashiku, Fukuoka, 812-8582 Japan
| | - Yoshimasa Shiraishi
- Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashiku, Fukuoka, 812-8582 Japan
| | - Keisuke Gotanda
- Department of Clinical Pharmacokinetics, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashiku, Fukuoka, 812-8582 Japan
| | - Taishi Harada
- Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashiku, Fukuoka, 812-8582 Japan
| | - Kazuto Furuyama
- Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashiku, Fukuoka, 812-8582 Japan
| | - Eiji Iwama
- Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashiku, Fukuoka, 812-8582 Japan
| | - Ichiro Ieiri
- Department of Clinical Pharmacokinetics, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashiku, Fukuoka, 812-8582 Japan
| | - Isamu Okamoto
- Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashiku, Fukuoka, 812-8582 Japan
| | - Yoichi Nakanishi
- Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashiku, Fukuoka, 812-8582 Japan
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Ko JC, Chiu HC, Syu JJ, Jian YJ, Chen CY, Jian YT, Huang YJ, Wo TY, Lin YW. Tamoxifen enhances erlotinib-induced cytotoxicity through down-regulating AKT-mediated thymidine phosphorylase expression in human non-small-cell lung cancer cells. Biochem Pharmacol 2014; 88:119-27. [DOI: 10.1016/j.bcp.2014.01.010] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2013] [Revised: 01/10/2014] [Accepted: 01/10/2014] [Indexed: 12/12/2022]
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Ma BBY, Chan SL, Ho WM, Lau W, Mo F, Hui EP, Chan C, Poon A, Dattatray RD, Wong SCC, To KF, King AD, Ahuja A, Chan ATC. Intermittent versus continuous erlotinib with concomitant modified “XELOX” (q3W) in first-line treatment of metastatic colorectal cancer. Cancer 2013; 119:4145-53. [DOI: 10.1002/cncr.28327] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2013] [Revised: 06/09/2013] [Accepted: 07/16/2013] [Indexed: 02/02/2023]
Affiliation(s)
- Brigette B. Y. Ma
- Department of Clinical Oncology, Sir Y.K. Pao Centre for Cancer, State Key Laboratory in Oncology in South China, Hong Kong Cancer Institute and Li Ka Shing Institute of Health Sciences; Chinese University of Hong Kong; Hong Kong SAR China
| | - Stephen L. Chan
- Department of Clinical Oncology, Sir Y.K. Pao Centre for Cancer, State Key Laboratory in Oncology in South China, Hong Kong Cancer Institute and Li Ka Shing Institute of Health Sciences; Chinese University of Hong Kong; Hong Kong SAR China
| | - Wing M. Ho
- Department of Clinical Oncology, Sir Y.K. Pao Centre for Cancer, State Key Laboratory in Oncology in South China, Hong Kong Cancer Institute and Li Ka Shing Institute of Health Sciences; Chinese University of Hong Kong; Hong Kong SAR China
| | - Wilson Lau
- Department of Clinical Oncology, Sir Y.K. Pao Centre for Cancer, State Key Laboratory in Oncology in South China, Hong Kong Cancer Institute and Li Ka Shing Institute of Health Sciences; Chinese University of Hong Kong; Hong Kong SAR China
| | - Frankie Mo
- Department of Clinical Oncology, Sir Y.K. Pao Centre for Cancer, State Key Laboratory in Oncology in South China, Hong Kong Cancer Institute and Li Ka Shing Institute of Health Sciences; Chinese University of Hong Kong; Hong Kong SAR China
| | - Edwin P. Hui
- Department of Clinical Oncology, Sir Y.K. Pao Centre for Cancer, State Key Laboratory in Oncology in South China, Hong Kong Cancer Institute and Li Ka Shing Institute of Health Sciences; Chinese University of Hong Kong; Hong Kong SAR China
| | - Charles Chan
- Department of Clinical Oncology, Sir Y.K. Pao Centre for Cancer, State Key Laboratory in Oncology in South China, Hong Kong Cancer Institute and Li Ka Shing Institute of Health Sciences; Chinese University of Hong Kong; Hong Kong SAR China
| | - Annette Poon
- Department of Clinical Oncology, Sir Y.K. Pao Centre for Cancer, State Key Laboratory in Oncology in South China, Hong Kong Cancer Institute and Li Ka Shing Institute of Health Sciences; Chinese University of Hong Kong; Hong Kong SAR China
| | - Rasalkar D. Dattatray
- Department of Imaging and Interventional Radiology; Prince of Wales Hospital; Hong Kong SAR China
| | - S. C. Cesar Wong
- Department of Health Technology and Informatics; the Hong Kong Polytechnic University; Hong Kong SAR China
| | - Ka F. To
- Department of Anatomical and Cellular Pathology, Prince of Wales Hospital; Chinese University of Hong Kong; Hong Kong SAR China
| | - Ann D. King
- Department of Imaging and Interventional Radiology; Prince of Wales Hospital; Hong Kong SAR China
| | - Anil Ahuja
- Department of Imaging and Interventional Radiology; Prince of Wales Hospital; Hong Kong SAR China
| | - Anthony T. C. Chan
- Department of Clinical Oncology, Sir Y.K. Pao Centre for Cancer, State Key Laboratory in Oncology in South China, Hong Kong Cancer Institute and Li Ka Shing Institute of Health Sciences; Chinese University of Hong Kong; Hong Kong SAR China
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Kim KB, Yang JY, Kwack SJ, Kim HS, Ryu DH, Kim YJ, Bae JY, Lim DS, Choi SM, Kwon MJ, Bang DY, Lim SK, Kim YW, Hwang GS, Lee BM. Potential metabolomic biomarkers for evaluation of adriamycin efficacy using a urinary 1H-NMR spectroscopy. J Appl Toxicol 2012; 33:1251-9. [PMID: 22782856 DOI: 10.1002/jat.2778] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2012] [Revised: 04/19/2012] [Accepted: 04/19/2012] [Indexed: 12/16/2022]
Abstract
A metabolomics approach using proton nuclear magnetic resonance (NMR) was applied to investigate metabolic alterations following adriamycin (ADR) treatment for gastric adenocarcinoma. After BALB/c-nu/nu mice were implanted with human gastric adenocarcinoma, ADR (1 or 3 mg kg(-1) per day) was intraperitoneally administered for 5 days. Urine was collected on days 2 and 5 and analyzed by NMR. The levels of trimethylamine oxide (TMAO, ×0.3), hippurate (×0.3) and taurine (×0.6) decreased significantly (P < 0.05), whereas the levels of 3-indoxylsulfate (×12.6), trigonelline (×1.5), citrate (×2.5), trimethylamine (TMA, ×2.0) and 2-oxoglutarate (×2.3) increased significantly (P < 0.05) in the tumor model. After ADR treatment, TMAO, hippuarte and taurine were increased significantly on day 5 compared with those of the tumor model. The levels of 2-oxoglutarate, 3-indoxylsulfate, trigonelline, TMA and citrate, which increased in the tumor model, significantly decreased to those of normal control by ADR treatment. Furthermore, the ratio between TMA and TMAO was dramatically altered in both tumor and ADR-treated groups. Overall, metabolites such as TMAO, TMA, 3-indoxylsulfate, hippurate, trigonelline, citrate and 2-oxoglutarate related to the tricarboxylic acid (TCA) cycle might be considered as therapeutic targets to potentiate the efficacy of ADR. Thus, these results suggest that the metabolomics analysis of tumor response to ADR treatment may be applicable for demonstrating the efficacy of anticancer agent, ADR and treatment adaptation.
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Affiliation(s)
- Kyu-Bong Kim
- College of Pharmacy, Dankook University, Dandae-ro, Cheonan, Chungnam, 330-714, Korea
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Li P, Torossian A, Zhang Q, Xu WC, Fu S. Inhibition of phosphoinositide 3-kinase enhances the cytotoxicity of AG1478, an epidermal growth factor receptor inhibitor, in breast cancer cells. Med Oncol 2012; 29:3258-64. [PMID: 22729368 DOI: 10.1007/s12032-012-0279-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2011] [Accepted: 06/07/2012] [Indexed: 01/01/2023]
Abstract
Aberrant activation and dysfunction of the EGFR/PI3K/Akt signaling pathways are commonly reported in breast cancer. Constitutive activation of the PI3K/Akt pathway by the lack of PTEN regulation is associated with resistance to novel targeted therapies including EGFR inhibitors. We aimed to study whether Ly294002, an inhibitor of PI3K, could enhance the cytotoxicity of AG1478, an inhibitor of EGFR, on breast cancer cells. We tested these agents in the MDA-MB-468 and MCF-7 breast cancer cell lines with different EGFR and PTEN profiles (MDA-MB-468: high expression of EGFR and PTEN mutation; MCF-7: low expression of EGFR and PTEN wild type). Simultaneous inhibition of EGFR and PI3K in MDA-MB-468 cells with combined Ly294002 and AG1478 treatment had a greater anti-proliferative effect and increased mitotic death than either treatment alone. In addition, more apoptosis and increased induction of cell arrest at G0/G1 phase were observed in MDA-MB-468 cells with the combined treatment. Phosphor-EGFR and its downstream signal transducer, phosphor-Akt, were fully attenuated only by simultaneous treatment with Ly294002 and AG1478. These data suggest that the inhibition of PI3K could enhance the cytotoxicity of EGFR inhibitors on breast cancer cells and tumors which overexpress EGFR and demonstrate mutated PTEN. This dual inhibition treatment protocol may have important therapeutic implication in the treatment of a subset of breast cancer patients with high expression of EGFR and deficient function of PTEN.
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Affiliation(s)
- Ping Li
- Department of Radiation Oncology, Sixth People's Hospital of Jiao Tong University, 600 Yi Shan Rd., Shanghai, 200233, People's Republic of China
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Marin JJG, Sanchez de Medina F, Castaño B, Bujanda L, Romero MR, Martinez-Augustin O, Moral-Avila RD, Briz O. Chemoprevention, chemotherapy, and chemoresistance in colorectal cancer. Drug Metab Rev 2012; 44:148-72. [PMID: 22497631 DOI: 10.3109/03602532.2011.638303] [Citation(s) in RCA: 107] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
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Bozec A, Sudaka A, Etienne-Grimaldi MC, Brunstein MC, Fischel JL, Milano G. Antitumor activity of cetuximab associated with the taxotere–cisplatin–fluorouracil (TPF) combination on an orthotopic head and neck cancer model. Oral Oncol 2011; 47:940-5. [DOI: 10.1016/j.oraloncology.2011.07.028] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2011] [Revised: 07/25/2011] [Accepted: 07/26/2011] [Indexed: 11/17/2022]
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Ueno NT, Zhang D. Targeting EGFR in Triple Negative Breast Cancer. J Cancer 2011; 2:324-8. [PMID: 21716849 PMCID: PMC3119395 DOI: 10.7150/jca.2.324] [Citation(s) in RCA: 119] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2011] [Accepted: 05/28/2011] [Indexed: 12/22/2022] Open
Abstract
Our preliminary data show that erlotinib inhibits Triple-negative breast cancer (TNBC) in a xenograft model. However, inhibition of metastasis by erlotinib is accompanied by nonspecific effects because erlotinib can inhibit other kinases; thus, more direct targets that regulate TNBC metastasis need to be identified to improve its therapeutic efficacy.
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Affiliation(s)
- Naoto T Ueno
- 1. Breast Cancer Translational Research Laboratory, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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20
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Ma WW, Herman JM, Jimeno A, Laheru D, Messersmith WA, Wolfgang CL, Cameron JL, Pawlik TM, Donehower RC, Rudek MA, Hidalgo M. A tolerability and pharmacokinetic study of adjuvant erlotinib and capecitabine with concurrent radiation in resected pancreatic cancer. Transl Oncol 2010; 3:373-9. [PMID: 21151476 PMCID: PMC3000462 DOI: 10.1593/tlo.10196] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2010] [Revised: 08/25/2010] [Accepted: 08/26/2010] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Erlotinib is approved for the treatment of advanced pancreas cancer. We conducted a prospective trial to determine the safety profile and recommended phase 2 dose of erlotinib and capecitabine given concurrently with intensity-modulated radiation therapy (IMRT) in resected pancreatic cancer patients. The pharmacokinetic profile of this combination was also evaluated. METHODS Patients with resected pancreatic adenocarcinoma received erlotinib and capecitabine concurrently with IMRT delivered at 1.8 Gy daily in 28 fractions (total = 50.4 Gy). The starting dose level (DL 1) was erlotinib 150mgdaily and capecitabine 800 mg/m(2) twice daily without interruption. The next lower dose level (DL -1) was erlotinib 100 mg daily and capecitabine 800 mg/m(2) twice daily (Monday to Friday). Plasma samples were obtained for pharmacokinetic analysis. RESULTS Thirteen patients were enrolled in total. At DL 1, six of the seven treated patients were evaluable for toxicities. Four completed planned treatment, but all required treatment interruption or dose reduction. The dose-limiting toxicities were neutropenia, diarrhea, and rash. Six patients were subsequently enrolled to and completed planned treatment in DL-1. Themost common toxicities were fatigue, elevated liver enzymes, and anorexia. The pharmacokinetic parameters of erlotinib and OSI-420 were not significantly different in the presence or absence of capecitabine and were consistent with historical controls. CONCLUSIONS When administered concurrently with IMRT, erlotinib 100 mg daily and capecitabine 800 mg/m(2) twice daily (Monday to Friday) can be administered safely in resected pancreas cancer patients, and is the recommended regimen for efficacy studies using this regimen.
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Affiliation(s)
- Wen Wee Ma
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA
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Chefrour M, Fischel JL, Formento P, Giacometti S, Ferri-Dessens RM, Marouani H, Francoual M, Renée N, Mercier C, Milano G, Ciccolini J. Erlotinib in combination with capecitabine (5'dFUR) in resistant pancreatic cancer cell lines. J Chemother 2010; 22:129-33. [PMID: 20435574 DOI: 10.1179/joc.2010.22.2.129] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/31/2022]
Abstract
The combination of capecitabine and the tyrosine kinase inhibitor erlotinib has recently been tested in patients with gemcitabine-refractory pancreatic tumors, with limited success. To understand this lack of efficacy, we studied the molecular effects of these agents in Capan-1 and Capan-2 human pancreatic resistant cancer cells. Erlotinib up-regulated thymidine phosphorylase (+50%) and downregulated dihydropyrimidine dehydrogenase (+55%) in a cell-dependent manner, thus suggesting that the combination should result in synergism. However, only mild additivity was achieved at best when combining both drugs, and several sequences tested even led to strong antagonism. Further experiments were performed to understand this lack of efficacy. We found that the fluoropyrimidine down-regulated EGFR expression by 30%, an unexpected finding resulting in a possible reduction in efficacy when cells were subsequently exposed to erlotinib. We also observed marked drug-induced over-expression of both cytosolic and extracellular vascular endothelial growth factor (VEGF) secretion, thus possibly triggering proliferation. These preliminary findings strongly suggest that these observations could be new mechanisms in the development of acquired drug resistance in pancreatic cancer cells.
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Affiliation(s)
- M Chefrour
- Oncopharmacology Unit, Centre Antoine Lacassagne, Nice, France
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Erlotinib 150 mg daily plus chemotherapy in advanced pancreatic cancer: an interim safety analysis of a multicenter, randomized, cross-over phase III trial of the 'Arbeitsgemeinschaft Internistische Onkologie'. Anticancer Drugs 2010; 21:94-100. [PMID: 19770635 DOI: 10.1097/cad.0b013e32833123ed] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
To date, only limited toxicity data are available for the combination of erlotinib with either capecitabine or gemcitabine as front-line therapy for advanced pancreatic cancer. Within a randomized phase III trial, 281 treatment-naive patients were randomly assigned between capecitabine (2000 mg/m/day, for 14 days, once every 3 weeks) plus erlotinib (150 mg/day, arm A) and gemcitabine (1000 mg/m as a 30-min infusion) plus erlotinib (150 mg/day, arm B). In case of treatment failure, patients were crossed over to a second-line treatment with the comparator cytostatic drug without erlotinib. The primary study endpoint was the time to treatment failure of second-line therapy (TTF2). This interim analysis of toxicity contains safety data from the first 127 randomized patients. During first-line therapy, patients received a median number of three treatment cycles (range 0-13) in both the arms. Regarding chemotherapy, a treatment delay was observed in 12% of the cycles in arm A and in 22% of the cycles in arm B. Dose reductions of the cytostatic drug were performed in 18 and 27% of treatment cycles, respectively. Erlotinib dose reductions were performed in 6 and 11% of all cycles. Grade 3/4 hematological toxicity was <10% in both the arms; major grade 3/4 toxicities in arms A and B were diarrhea (9 vs. 7%), skin rash (4 vs. 12%), and hand-foot syndrome (7 vs. 0%). No treatment-related death was observed. In conclusion, this interim safety analysis suggests that treatment with erlotinib 150 mg/day is feasible in combination with capecitabine or gemcitabine.
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Kim KB, Yang JY, Kwack SJ, Park KL, Kim HS, Ryu DH, Kim YJ, Hwang GS, Lee BM. Toxicometabolomics of urinary biomarkers for human gastric cancer in a mouse model. JOURNAL OF TOXICOLOGY AND ENVIRONMENTAL HEALTH. PART A 2010; 73:1420-1430. [PMID: 20954069 DOI: 10.1080/15287394.2010.511545] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/30/2023]
Abstract
Toxicometabolomics of urinary biomarkers for human gastric cancer in a mouse model was investigated using (1)H-nuclear magnetic resonance (NMR) spectroscopy. A human gastric adenocarcinoma cell line (1 × 10(7) cells/ml) was grafted onto the skin of the back of intact male BALB/c-nu/nu mice. After the xenografted tumors developed, urine was collected and analyzed for endogenous metabolites. Global profiling combined with principal components analysis (PCA), partial least squares-discriminant analysis (PLS-DA), and orthogonal projections to latent squares-discriminant analysis (OPLS-DA) showed distinct separation of clusters between control and tumor-bearing mice. Targeted profiling revealed significant changes in trimethylamine oxide (TMAO), 3-indoxylsulfate, hippurate, and citrate levels in mice carrying human gastric cancer cells compared to normal mice. The levels of TMAO (0.41-fold) and hippurate (0.26-fold) in tumor-bearing mice were significantly decreased, whereas the levels of 3-indoxylsulfate (3.39-fold), 2-oxoglutarate (2.32-fold), and citrate (1.9-fold) were significantly increased in urine samples of tumor-bearing mice. Data suggest that TMAO, hippurate, 3-indoxylsulfate, 2-oxoglutarate, and citrate may serve as useful urinary biomarkers for gastric tumorigenesis in a mouse model.
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Affiliation(s)
- Kyu-Bong Kim
- Department of Pharmaceutical Engineering, Inje University, Obang-dong, Gimhae, Gyungnam, Korea
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Yu X, Zhang Y, Chen C, Yao Q, Li M. Targeted drug delivery in pancreatic cancer. Biochim Biophys Acta Rev Cancer 2009; 1805:97-104. [PMID: 19853645 DOI: 10.1016/j.bbcan.2009.10.001] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2009] [Revised: 10/07/2009] [Accepted: 10/11/2009] [Indexed: 12/16/2022]
Abstract
Effective drug delivery in pancreatic cancer treatment remains a major challenge. Because of the high resistance to chemo and radiation therapy, the overall survival rate for pancreatic cancer is extremely low. Recent advances in drug delivery systems hold great promise for improving cancer therapy. Using liposomes, nanoparticles, and carbon nanotubes to deliver cancer drugs and other therapeutic agents such as siRNA, suicide gene, oncolytic virus, small molecule inhibitor, and antibody has been a success in recent preclinical trials. However, how to improve the specificity and stability of the delivered drug using ligand or antibody directed delivery represent a major problem. Therefore, developing novel, specific, tumor-targeted drug delivery systems is urgently needed for this terrible disease. This review summarizes the current progress on targeted drug delivery in pancreatic cancer and provides important information on potential therapeutic targets for pancreatic cancer treatment.
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Affiliation(s)
- Xianjun Yu
- Michael E. DeBakey Department of Surgery, Molecular Surgeon Research Center, Elkins Pancreas Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
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Zhang D, LaFortune TA, Krishnamurthy S, Esteva FJ, Cristofanilli M, Liu P, Lucci A, Singh B, Hung MC, Hortobagyi GN, Ueno NT. Epidermal growth factor receptor tyrosine kinase inhibitor reverses mesenchymal to epithelial phenotype and inhibits metastasis in inflammatory breast cancer. Clin Cancer Res 2009; 15:6639-48. [PMID: 19825949 DOI: 10.1158/1078-0432.ccr-09-0951] [Citation(s) in RCA: 92] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
PURPOSE Inflammatory breast cancer (IBC) is a rare but aggressive type of advanced breast cancer. Epidermal growth factor receptor (EGFR) expression is an independent poor prognostic factor in IBC. The purpose of this study was to determine the effect on IBC tumorigenicity and metastasis of blocking the EGFR pathway. EXPERIMENTAL DESIGN IBC cell lines, which express high level of EGFR, were treated with EGFR small interfering RNA and with the EGFR tyrosine kinase inhibitor erlotinib. The role of EGFR in IBC cell proliferation, motility, invasiveness, and change of the expression levels of epithelial-mesenchymal transition markers was examined. The role of extracellular signal-regulated kinase (ERK)-1/2 in erlotinib activity was also studied. The activity of erlotinib in tumor growth and metastasis was examined in an orthotopic xenograft model of IBC. RESULTS Erlotinib inhibited proliferation and anchorage-independent growth of IBC cells, and this inhibition was ERK dependent. Erlotinib inhibited cell motility and invasiveness and reversed the mesenchymal phenotype of IBC cells to epithelial phenotype in three-dimensional culture. Erlotinib dramatically inhibited IBC tumor growth in a xenograft model. Interestingly, erlotinib inhibited spontaneous lung metastasis, even at a low dose that had no significant effect on primary tumor growth. These erlotinib-treated tumors were converted to epithelial phenotype from mesenchymal phenotype. CONCLUSIONS The EGFR pathway is involved in tumor growth and metastasis of IBC. Targeting EGFR through the ERK pathway may represent an effective therapeutic approach to suppress tumorigenicity and prevent metastasis in EGFR-expressing IBC.
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Affiliation(s)
- Dongwei Zhang
- Breast Cancer Translational Research Laboratory, Department of Breast Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA
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Mayer EL, Partridge AH, Harris LN, Gelman RS, Schumer ST, Burstein HJ, Winer EP. Tolerability of and adherence to combination oral therapy with gefitinib and capecitabine in metastatic breast cancer. Breast Cancer Res Treat 2009; 117:615-23. [PMID: 19294501 DOI: 10.1007/s10549-009-0366-5] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2008] [Accepted: 03/05/2009] [Indexed: 10/21/2022]
Abstract
PURPOSE This phase I study explored gefitinib (G) and capecitabine (C) in metastatic breast cancer (MBC). METHODS Sequential cohorts (n = 3) received G and escalating C on a 14 day on/7 day off schedule, with a validation cohort (n = 10) at the maximum tolerated dose (MTD). Dose limiting toxicity (DLT) was defined in cycle 1. The primary endpoint was safety; secondary endpoints included response and adherence. RESULTS About 19 patients were treated for a median of 5 cycles. No patients in sequential cohorts experienced DLT; C MTD was 2,000 mg/m(2)/day when paired with daily G 250 mg. In the validation cohort, four experienced serious toxicities, including diarrhea, mucositis, and palmarplantar dysesthesia. At the MTD, 6 (46%) required a C dose reduction, and 3 (23%) came off study for toxicity. One partial response was observed (8%, 95% CI 0.2-38.5%); five had stable disease >24 weeks (26, 95% CI 9-51%). Patients missed few drug doses, with the suggestion of overadherence to therapy. CONCLUSIONS In this phase I study of G and C in MBC, a C MTD was identified, and significant toxicity was observed. About 8% demonstrated a response, with 26% maintaining stable disease. The possibility of overadherence, as suggested in this study, may have implications for other trials of oral antineoplastic therapy.
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Affiliation(s)
- E L Mayer
- Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney Street, Mayer 224, Boston, MA 02115, USA.
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Rivera F, López-Tarruella S, Vega-Villegas ME, Salcedo M. Treatment of advanced pancreatic cancer: from gemcitabine single agent to combinations and targeted therapy. Cancer Treat Rev 2009; 35:335-9. [PMID: 19131170 DOI: 10.1016/j.ctrv.2008.11.007] [Citation(s) in RCA: 83] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2008] [Revised: 10/17/2008] [Accepted: 11/27/2008] [Indexed: 01/03/2023]
Abstract
The prognosis of advanced pancreatic adenocarcinoma is still poor nowadays. Gemcitabine in monotherapy (30-min infusion) has been the standard of treatment during the last decade, and many clinical trials have failed to demonstrate an improvement in overall survival (OS) with the addition of different drugs to gemcitabine, including cetuximab and bevacizumab. Nevertheless, some modest but interesting advances have been provided by combinations such as gemcitabine-erlotinib, gemcitabine-capecitabine and gemcitabine plus a platinum salt. In spite of this, survival results remain disappointing. Further research focused on new combinations, incorporating the new targeted therapies and identifying potential predictive factors of response are required to be able to offer effective tailored therapies to these patients.
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Affiliation(s)
- Fernando Rivera
- Medical Oncology Department, Marqués de Valdecilla University Hospital, Cantabria, Spain.
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Dose finding study of erlotinib combined to capecitabine and irinotecan in pretreated advanced colorectal cancer patients. Cancer Chemother Pharmacol 2008; 64:67-72. [DOI: 10.1007/s00280-008-0852-1] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2008] [Accepted: 10/03/2008] [Indexed: 11/26/2022]
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Vasey PA, Gore M, Wilson R, Rustin G, Gabra H, Guastalla JP, Lauraine EP, Paul J, Carty K, Kaye S. A phase Ib trial of docetaxel, carboplatin and erlotinib in ovarian, fallopian tube and primary peritoneal cancers. Br J Cancer 2008; 98:1774-80. [PMID: 18506181 PMCID: PMC2410113 DOI: 10.1038/sj.bjc.6604371] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2007] [Revised: 03/25/2008] [Accepted: 03/28/2008] [Indexed: 11/09/2022] Open
Abstract
The safety and maximum tolerated dose (MTD) of erlotinib with docetaxel/carboplatin were assessed in patients with ovarian cancer. Chemonaive patients received intravenous docetaxel (75 mg m(-2)) and carboplatin (area under the curve 5) on day 1 of a 3-week cycle, and oral erlotinib at 50 (cohort 1), 100 (cohort 2a) or 75 mg day(-1) (cohort 2b) for up to six cycles. Dose-limiting toxicities were determined in cycle 1. Forty-five patients (median age 59 years) received treatment. Dose-limiting toxicities occurred in 1/5/5 patients (cohorts 1/2a/2b). The MTD of erlotinib in this regimen was determined to be 75 mg day(-1) (cohort 2b; the erlotinib dose was escalated to 100 mg day(-1) in 11 out of 19 patients from cycle 2 onwards). Neutropaenia was the predominant grade 3/4 haematological toxicity (85/100/95% respectively). Common non-haematological toxicities were diarrhoea, fatigue, nausea and rash. There were five complete and seven partial responses in 23 evaluable patients (52% response rate). Docetaxel/carboplatin had no measurable effect on erlotinib pharmacokinetics. In subsequent single-agent maintenance, erlotinib was given at 100-150 mg day(-1), with manageable toxicity, until tumour progression. Further investigation of erlotinib in epithelial ovarian carcinoma may be warranted, particularly as maintenance therapy.
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Affiliation(s)
- P A Vasey
- CR-UK Clinical Trials Unit, Beatson Oncology Centre, Western Infirmary, Dumbarton Road, Glasgow, Scotland G11 6NT, UK.
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Seierstad T, Røe K, Sitter B, Halgunset J, Flatmark K, Ree AH, Olsen DR, Gribbestad IS, Bathen TF. Principal component analysis for the comparison of metabolic profiles from human rectal cancer biopsies and colorectal xenografts using high-resolution magic angle spinning 1H magnetic resonance spectroscopy. Mol Cancer 2008; 7:33. [PMID: 18439252 PMCID: PMC2377266 DOI: 10.1186/1476-4598-7-33] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2007] [Accepted: 04/25/2008] [Indexed: 11/21/2022] Open
Abstract
Background This study was conducted in order to elucidate metabolic differences between human rectal cancer biopsies and colorectal HT29, HCT116 and SW620 xenografts by using high-resolution magnetic angle spinning (MAS) magnetic resonance spectroscopy (MRS) and for determination of the most appropriate human rectal xenograft model for preclinical MR spectroscopy studies. A further aim was to investigate metabolic changes following irradiation of HT29 xenografts. Methods HR MAS MRS of tissue samples from xenografts and rectal biopsies were obtained with a Bruker Avance DRX600 spectrometer and analyzed using principal component analysis (PCA) and partial least square (PLS) regression analysis. Results and conclusion HR MAS MRS enabled assignment of 27 metabolites. Score plots from PCA of spin-echo and single-pulse spectra revealed separate clusters of the different xenografts and rectal biopsies, reflecting underlying differences in metabolite composition. The loading profile indicated that clustering was mainly based on differences in relative amounts of lipids, lactate and choline-containing compounds, with HT29 exhibiting the metabolic profile most similar to human rectal cancers tissue. Due to high necrotic fractions in the HT29 xenografts, radiation-induced changes were not detected when comparing spectra from untreated and irradiated HT29 xenografts. However, PLS calibration relating spectral data to the necrotic fraction revealed a significant correlation, indicating that necrotic fraction can be assessed from the MR spectra.
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Affiliation(s)
- Therese Seierstad
- Department of Medical Physics, Rikshospitalet-Radiumhospitalet Medical Center, 0310 Oslo, Norway.
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The use of xenograft models for the selection of cancer treatments with the EGFR as an example. Crit Rev Oncol Hematol 2008; 65:200-11. [PMID: 18389522 DOI: 10.1016/j.critrevonc.2007.10.003] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023] Open
Abstract
Mouse models of cancer have consistently been used to qualify new anti-cancer drugs for development of human clinical trials. The most used models are xenografts of human tumors grown subcutaneously in immunodeficient mice such as athymic (nude) or severe combined immune deficient (SCID) mice. However, the number of anti-cancer agents that fail in the clinic far outweighs those considered effective, suggesting that the selection procedure for progression of molecules into the clinic requires improvement. This has provoked considerable skepticism about the value of using such preclinical models. As a result, a shift has occurred towards developing and using spontaneous mouse tumor arising in transgenic and/or knockout mice engineered to recapitulate various genetic alterations thought to be causative of specific types of human cancers. Alternatively, the option has been to improve human tumor xenograft models by using orthotopic transplantation and, therefore, promotion of metastatic spread of the resultant 'primary' tumors. Here we review the value and the limitations of xenograft models and their role in developing new anti-cancer treatments.
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Ponz-Sarvisé M, Rodríguez J, Viudez A, Chopitea A, Calvo A, García-Foncillas J, Gil-Bazo I. Epidermal growth factor receptor inhibitors in colorectal cancer treatment: what's new? World J Gastroenterol 2007; 13:5877-87. [PMID: 17990353 PMCID: PMC4205434 DOI: 10.3748/wjg.v13.i44.5877] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2007] [Revised: 08/01/2007] [Accepted: 10/22/2007] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer constitutes one of the most common malignancies and the second leading cause of death from cancer in the western world representing one million new cases and half a million deaths annually worldwide. The treatment of patients with metastatic colon cancer comprises different regimens of chemotherapeutic compounds (fluoropyrimidines, irinotecan and oxaliplatin) and new targeted therapies. Interestingly, most recent trials that attempt to expose patients to all five-drug classes (fluoropyrimidines, irinotecan, oxaliplatin, bevacizumab and cetuximab) achieve an overall survival well over 2 years. In this review we will focus on the main epidermal growth factor receptor inhibitors demonstrating clinical benefit for colorectal cancer mainly cetuximab, panitumumab, erlotinib and gefitinib. We will also describe briefly the molecular steps that lie beneath them and the different clinical or molecular mechanisms that are reported for resistance and response.
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Rodriguez J, Zarate R, Bandres E, Viudez A, Chopitea A, García-Foncillas J, Gil-Bazo I. Combining chemotherapy and targeted therapies in metastatic colorectal cancer. World J Gastroenterol 2007; 13:5867-76. [PMID: 17990352 PMCID: PMC4205433 DOI: 10.3748/wjg.v13.i44.5867] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2007] [Revised: 08/08/2007] [Accepted: 10/19/2007] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer remains one of the major causes of cancer death worldwide. During the past years, the development of new effective treatment options has led to a considerable improvement in the outcome of this disease. The advent of agents such as capecitabine, irinotecan, oxaliplatin, erbitux and bevacizumab has translated into median survival times in the range of 2 years. Intense efforts have focused on identifying novel agents targeting specific growth factor receptors, critical signal transduction pathways or mediators of angiogenesis. In addition, several clinical trials have suggested that some of these molecularly targeted drugs can be safely and effectively used in combination with conventional chemotherapy. In this article we review various treatment options combining cytotoxic and targeted therapies currently available for patients with metastatic colorectal cancer.
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Abstract
PURPOSE OF REVIEW This review summarizes the continuing value of some therapeutic drugs and new agents under development for the treatment of breast cancer. RECENT FINDINGS Overexpression and activation of various growth factor receptors occurs frequently in human breast cancer. Therapeutic approaches mainly involve the epidermal growth factor receptor family, insulin-like growth factor receptor and vascular endothelial growth factor receptor. Therapeutic agents targeting these receptors include the monoclonal antibodies trastuzumab and pertuzumab, and the small-molecule inhibitors gefitinib and erlotinib. Other small-molecule and dual inhibitors are in development, some of which have been demonstrated to have higher efficacy in the treatment of breast cancer. The selective estrogen receptor modulators and aromatase inhibitors continue to be valuable in the endocrine therapy of breast cancer. These drugs have been shown to have higher efficacy than conventional therapy agents, and to have extensive potential, especially in the treatment of postmenopausal women with advanced breast cancer. SUMMARY Approved agents including epidermal growth factor receptor-targeted inhibitor, selective estrogen receptor modulators and aromatase inhibitors continue to be valuable in treating breast cancer. To overcome the acquired resistance caused by these agents and to enhance the therapy effect, the development of new and specific dual inhibitors targeting various growth factor receptors will be important in the future.
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Affiliation(s)
- Xiao-ping Gao
- Institute of Materia Medica, KangHong Pharmaceutical Goup, Chengdu, People's Republic of China.
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Giatromanolaki A, Sivridis E, Koukourakis MI. Angiogenesis in colorectal cancer: prognostic and therapeutic implications. Am J Clin Oncol 2006; 29:408-17. [PMID: 16891872 DOI: 10.1097/01.coc.0000221317.56731.4e] [Citation(s) in RCA: 61] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Angiogenesis is important for tumor growth and metastasis. This account reviews the clinicopathological studies conducted in the field of angiogenesis in colorectal cancer, the methods of assessing vascular-related characteristics in tissue sections and provides a background for the usefulness of antiangiogenic policies along with chemotherapy and radiotherapy. Highly angiogenic colorectal tumors are associated with aggressive histopathological features and poor patients' survival. Similarly, factors stimulating angiogenesis, such as vascular endothelial growth factor (VEGF), thymidine phosphorylase (TP), and others, are commonly related to increased vascular density (VD) and, therefore, to an unfavorable clinical course. Anti-VEGF agents have improved prognosis in patients with metastatic colorectal cancer, when added to standard chemotherapy. It is expected that, in addition to adjuvant chemotherapy and radiotherapy, agents blocking the stimulatory effect of VEGF on endothelial cells would prove beneficial to the patient.
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Affiliation(s)
- Alexandra Giatromanolaki
- Department of Pathology, Democritus University of Thrace Medical School, Alexandroupolis, Greece
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