Predicting chemosensitivity to gemcitabine and cisplatin based on gene polymorphisms and mRNA expression in non-small-cell lung cancer cells

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Date: Jan. 2015
From: Pharmacogenomics(Vol. 16, Issue 1)
Publisher: Future Medicine Ltd.
Document Type: Report
Length: 7,591 words
Lexile Measure: 1500L

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Author(s): Xiangning Meng aff1 , Geng Wang aff2 , Rongwei Guan aff1 , Xueyuan Jia aff1 , Wei Gao aff1 , Jie Wu aff1 , Jingcui Yu aff3 , Peng Liu aff1 , Yang Yu aff1 , Wenjing Sun aff1 , Haiying Dong aff4 , Songbin Fu [*] aff1 aff5


chemosensitivity; cisplatin; gemcitabine; non-small-cell lung cancer; polymorphisms

Cytotoxic chemotherapy is the standard of care for patients with advanced non-small-cell lung cancer (NSCLC) [1-3 ]. As with many cancer therapeutic agents, resistance is a significant problem with the use of cisplatin and gemcitabine to treat NSCLC. Therefore, the clinical integration of molecular biomarkers that predict responses to chemotherapeutic or molecularly targeted agents, leading ultimately to individualized chemotherapy, may be important for improving clinical outcomes in advanced NSCLC.

Cisplatin is a platinum agent that is known to act through the formation of DNA adducts that inhibit DNA synthesis and transcription. Although drug resistance is caused by multiple genetic factors, DNA repair genes play a key role in cisplatin resistance. DNA repair mechanisms are important determinants of the sensitivity to platinum-based chemotherapy, especially those involving the nucleotide excision repair (NER) pathway [4,5 ]. Gemcitabine, a potent and specific pyrimidine nucleoside antimetabolite agent, is active against NSCLC, especially when administered with platinum derivatives [3,6 ]. Evidence has shown that sequence variation in genes involved in gemcitabine and cisplatin transport, metabolism and bioactivation pathways contributes to the variation in gemcitabine and cisplatin response [ 7-13 ].

RRM1, a regulatory subunit of ribonucleotide reductase (RR), is required for deoxynucleotide production, which is the rate-limiting step in DNA synthesis and repair. Gemcitabine is a potent and widely used RR inhibitor. Gemcitabine (2′,2′-difluorodeoxycytidine) is a deoxycytidine analogue that is activated by deoxycytidine kinase to its monophosphate form. Subsequent phosphorylation by uridylate-cytidylate monophosphate kinase generates difluorodeoxycytidine diphosphate, which binds to the substrate binding site and inactivates the RRM1 subunit, reducing the pool of deoxyribonucleotide diphosphate available for DNA synthesis [14-16 ]. Retrospective studies of stage IV NSCLC patients treated with gemcitabine-based chemotherapy have shown that patients with low RRM1 mRNA levels live longer than patients with higher expression levels [ 17-20 ]. Preclinical studies have shown that the expression of RRM1 is involved in sensitivity to gemcitabine in NSCLC [21-23 ]. Zheng et al . [24 ] studied RRM1 and ERCC1 expression in vitro and in vivo and found that tumoral RRM1 expression is a major predictor of disease response to gemcitabine/platinum chemotherapy. Kwon et al . [7 ] have found that the RRM1 2464G[greater than]A polymorphism is associated with gemcitabine sensitivity using a panel of 62 human cancer cell lines. Thus, RRM1 expression and polymorphisms may be used to develop optimal, customized chemotherapy regimens in clinical practice.

ERCC1 is a DNA damage repair gene that encodes the 5′ endonuclease of the NER complex. An increase in ERCC1 expression is likely to cause the cisplatin resistance phenotype, which causes the cytotoxicity of cancer cells by forming adducts that result in DNA cross-links. The NER complex recognizes and removes these adducts, which may trigger resistance to platinum agents. High tumor tissue levels of ERCC1 mRNA have...

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Gale Document Number: GALE|A412067382