ABSTRACT
The aim of the present study was to determine whether specific molecular parameters may serve as predictors of treatment outcomes and toxicity of oxaliplatin (OXA)based chemotherapy, which is used as an adjuvant treatment in resected gastric cancer. All gastric cancer patients examined in the study received an OXA/5fluorouracil chemotherapeutic regimen. Genetic polymorphisms of certain platinumrelated genes were determined by the TaqMan 5' nuclease assay and direct sequencing. Relapsefree survival (RFS), overall survival (OS) and toxicity were evaluated according to each genotype. Following adjustment for the most relevant clinical variables, excision repair crosscomplimentary group 1 (ERCC1)118 and X-ray repair cross-complementing protein 1 (XRCC1399) demonstrated significant predictive value for RFS and OS. We also demonstrated that carrying at least one variant XRCC1 Arg399Gln or glutathione S-transferase π 1 (GSTP1) Ile105Val allele significantly increased the risk of any grade 3 or 4 hematological toxicity. In particular, carrying at least one variant GSTP1 Ile105Val allele was also significantly correlated with an increased risk of grade 3 or 4 gastrointestinal toxicity and neurotoxicity. Our data suggested that gastric cancer patients harboring ERCC1118 C/C and XRCC1399 A/G or A/A genotypes may benefit from receiving OXAbased adjuvant chemotherapy, and carrying at least one variant XRCC1 Arg399Gln or GSTP1 Ile105Val allele may contribute to the occurrence of adverse drug effects associated with OXAbased chemotherapy.
Subject(s)
Antineoplastic Agents/therapeutic use , DNA-Binding Proteins/genetics , Endonucleases/genetics , Glutathione S-Transferase pi/genetics , Organoplatinum Compounds/therapeutic use , Polymorphism, Single Nucleotide , Stomach Neoplasms/drug therapy , Adult , Aged , Alleles , Chemotherapy, Adjuvant , Disease-Free Survival , Drug Therapy, Combination , Female , Fluorouracil/therapeutic use , Genotype , Humans , Male , Middle Aged , Neoplasm Grading , Oxaliplatin , Risk Factors , Stomach Neoplasms/genetics , Stomach Neoplasms/mortality , Treatment Outcome , X-ray Repair Cross Complementing Protein 1ABSTRACT
Excision repair cross-complementing 1 (ERCC1) is reported to be involved in the sensitivity of cancer cells to platinum-based chemotherapy. The present study was designed to evaluate the effects of ERCC1 expression on the chemosensitivity of platinum agents in gastric cancer cell lines, and on survival in gastric cancer patients treated with surgery followed by oxaliplatin-based adjuvant chemotherapy. ERCC1 expression levels were measured by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and western blot analysis, respectively. The chemosensitivity of a series of gastric cancer cell lines to platinum agents in vitro was evaluated using CellTiter 96 Aqueous One Solution Cell Proliferation Assay kit. The apoptotic effect of the drugs was evaluated by double staining with Annexin-V-fluorescein isothiocyanate (FITC) and propidium iodide (PI). The results demonstrated that the expression levels of ERCC1 mRNA were correlated with the chemosensitivity of platinum agents, and depletion of ERCC1 sensitized the relatively resistant MKN45 cells to cisplatin and oxaliplatin. Univariate analyses revealed that patients with low ERCC1 levels had longer relapse-free survival (RFS) and overall survival (OS) than those with high ERCC1 levels (median RFS, 18 vs. 7 months, P=0.001; median OS, 27 vs. 11 months, P=0.001). Multivariate analyses suggested that high ERCC1 expression is an independent prognostic marker of poor RFS [hazard ratio (HR), 2.16; 95% confidence interval (CI), 1.09-4.25; P= 0.026] and OS (HR, 2.21; 95% CI, 1.07-4.55; P=0.031). These results suggest that overexpression of ERCC1 is correlated with platinum drug resistance in gastric cancer cells, and that depletion of ERCC1 sensitizes gastric cancer cell lines to cisplatin and oxaliplatin. Gastric cancer patients with low levels of ERCC1 expression demonstrate a benefit from oxaliplatin-based adjuvant chemotherapy.