Antagonism between Gefitinib and Cisplatin in Non-small Cell Lung Cancer Cells: Why Randomized Trials Failed?

Tsai, Chun Ming; Chen, Jen Ting; Stewart, David J.; Chiu, Chao Hua; Lai, Ching‐Huang; Hsiao, Shih Yin; Chen, Yuh Min; Chang, Kuo-Ting

doi:10.1097/jto.0b013e3182021ff5

Cited by 35 publications

(29 citation statements)

References 42 publications

(45 reference statements)

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“…Similarly, with pemetrexed, synergism was seen in NSCLC cell lines when erlotinib was administered concurrently with and/or following pemetrexed509, 510, while antagonism (associated with erlotinib-induced G1 blockade) was seen if erlotinib preceded pemetrexed510 or docetaxel513. In one series of NSCLC cell lines, gefitinib antagonized the effect of cisplatin in 13 of 15 lines tested, and was also antagonistic to cisplatin combined with paclitaxel516. The antagonism appeared to possibly be related to a gefitinib-induced reduction in cisplatin uptake at higher cisplatin doses, and was not seen if the gefitinib was delayed until 24 hours after the cisplatin516.…”

Section: 0 Apoptosis Inhibitorsmentioning

confidence: 93%

Tumor and host factors that may limit efficacy of chemotherapy in non-small cell and small cell lung cancer

Stewart

2010

Critical Reviews in Oncology/Hematology

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161

157

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While chemotherapy provides useful palliation, advanced lung cancer remains incurable since those tumors that are initially sensitive to therapy rapidly develop acquired resistance. Resistance may arise from impaired drug delivery, extracellular factors, decreased drug uptake into tumor cells, increased drug efflux, drug inactivation by detoxifying factors, decreased drug activation or binding to target, altered target, increased damage repair, tolerance of damage, decreased proapoptotic factors, increased antiapoptotic factors, or altered cell cycling or transcription factors. Factors for which there is now substantial clinical evidence of a link to small cell lung cancer (SCLC) resistance to chemotherapy include MRP (for platinum-based combination chemotherapy) and MDR1/P-gp (for non-platinum agents). SPECT MIBI and Tc-TF scanning appears to predict chemotherapy benefit in SCLC. In non-small cell lung cancer (NSCLC), the strongest clinical evidence is for taxane resistance with elevated expression or mutation of class III β-tubulin (and possibly α tubulin), platinum resistance and expression of ERCC1 or BCRP, gemcitabine resistance and RRM1 expression, and resistance to several agents and COX-2 expression (although COX-2 inhibitors have had minimal impact on drug efficacy clinically). Tumors expressing high BRCA1 may have increased resistance to platinums but increased sensitivity to taxanes. Limited early clinical data suggest that chemotherapy resistance in NSCLC may also be increased with decreased expression of cyclin B1 or of Eg5, or with increased expression of ICAM, matrilysin, osteopontin, DDH, survivin, PCDGF, caveolin-1, p21WAF1/CIP1, or 14-3-3sigma, and that IGF-1R inhibitors may increase efficacy of chemotherapy, particularly in squamous cell carcinomas. Equivocal data (with some positive studies but other negative studies) suggest that NSCLC tumors with some EGFR mutations may have increased sensitivity to chemotherapy, while K-ras mutations and expression of GST-pi, RB or p27kip1 may possibly confer resistance. While limited clinical data suggest that p53 mutations are associated with resistance to platinum-based therapies in NSCLC, data on p53 IHC positivity are equivocal. To date, resistance-modulating strategies have generally not proven clinically useful in lung cancer, although small randomized trials suggest a modest benefit of verapamil and related agents in NSCLC.

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Section: 0 Apoptosis Inhibitorsmentioning

confidence: 93%

Tumor and host factors that may limit efficacy of chemotherapy in non-small cell and small cell lung cancer

Stewart

2010

Critical Reviews in Oncology/Hematology

Self Cite

161

157

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“…Explanations could be that each of the agents is working against a susceptible subpopulation of tumor cells so that the effect is redundant rather than additive. Gefitinib might interfere with cisplatin cell entry [21] and act therefore as an antagonist. The synergistic effect of chemotherapy and gefitinib observed in preclinical models [18] could not be translated in clinical trials, probably because doses of drugs used in mice are often not pharmacokinetically equivalent in the clinical setting [22].…”

Section: Gefitinib In Combination With Chemotherapymentioning

confidence: 99%

Rationale of a relaunch of gefitinib in Caucasian non-small cell lung cancer patients

et al. 2010

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“…The combination of docetaxel and cisplatin has been reported to cause antagonism in treating NSCLC EBC-1 (squamous cell carcinoma) and RERF-LCMS cells (adenocarcinoma) [36]. Recently, the antagonism was also observed in 15 human NSCLC cell lines by the treatment of combining gefitinib and cisplatin [37]. …”

Section: Discussionmentioning

confidence: 99%

An Acetamide Derivative as a Camptothecin Sensitizer for Human Non‐Small‐Cell Lung Cancer Cells through Increased Oxidative Stress and JNK Activation

Chou

Fong

Lin

et al. 2016

Oxidative Medicine and Cellular Longevity

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In recent years, combination chemotherapy is a primary strategy for treating lung cancer; however, the issues of antagonism and side effects still limit its applications. The development of chemosensitizer aims to sensitize chemoresistant cancer cells to anticancer drugs and therefore improve the efficacy of chemotherapy. In this study, we examined whether N-[2-(morpholin-4-yl)phenyl]-2-{8-oxatricyclo[7.4.0.0,2,7]trideca-1(9),2(7),3,5,10,12-hexaen-4-yloxy}acetamide (NPOA), an acetamide derivative, sensitizes human non-small-cell lung cancer (NSCLC) H1299 cells towards camptothecin- (CPT-) induced apoptosis effects. Our results demonstrate that the combination of CPT and NPOA enhances anti-lung-cancer effect. The cytometer-based Annexin V/propidium iodide (PI) staining showed that CPT and NPOA cotreatment causes an increased population of apoptotic cells compared to CPT treatment alone. Moreover, Western blotting assay showed an enhancement of Bax expression and caspase cascade leading to cell death of H1299 cells. Besides, CPT and NPOA cotreatment-mediated disruption of mitochondrial membrane potential (MMP) in H1299 cells may function through increasing the activation of the stressed-associated c-Jun N-terminal kinase (JNK). These results showed that NPOA treatment sensitizes H1299 cells towards CPT-induced accumulation of cell cycle S phase and mitochondrial-mediated apoptosis through regulating endogenous ROS and JNK activation. Accordingly, NPOA could be a candidate chemosensitizer of CPT derivative agents such as irinotecan or topotecan in the future.

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Antagonism between Gefitinib and Cisplatin in Non-small Cell Lung Cancer Cells: Why Randomized Trials Failed?

Cited by 35 publications

References 42 publications

Tumor and host factors that may limit efficacy of chemotherapy in non-small cell and small cell lung cancer

Tumor and host factors that may limit efficacy of chemotherapy in non-small cell and small cell lung cancer

Rationale of a relaunch of gefitinib in Caucasian non-small cell lung cancer patients

An Acetamide Derivative as a Camptothecin Sensitizer for Human Non‐Small‐Cell Lung Cancer Cells through Increased Oxidative Stress and JNK Activation

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