Genetic polymorphisms and the efficacy and toxicity of cisplatin-based chemotherapy in ovarian cancer patients.
Platinum drugs are among the most active and widely used agents in the treatment of different cancers. However, the great individual variability in both outcome and toxicity of platinum chemotherapy requires the identification of genetic markers that can be used to screen patients before treatment. In this study, 21 polymorphisms in 10 genes, the protein activities of which may be addressed in different aspects of cisplatin metabolism, were tested for correlations with efficacy and toxicity of cisplatin-cyclophosphamide regimen in 104 ovarian cancer patients. The glutathione S-transferase P1 (GSTP1) Ile105Val polymorphism was strongly associated with progression-free survival (chi(2)=12.12, P=0.002). The allelic status of the GSTA1 -69 C>T polymorphism correlated with the overall survival: patients with T/T genotype survived longer than C/C carriers (P=0.044). Thrombocytopenia, anemia and neuropathy were less frequent among patients with the GSTM1-null or GSTM3 intron 6 AGG/AGG genotypes. Severe neutropenia was associated with the TP53 72 Pro/Pro, XPD 312 Asp/Asn and XRCC1 399 Arg/Arg genotypes. A higher risk of nephrotoxicity was noted for patients with the heterozygous ERCC1 19007 T/C and 8092 C/A genotypes. No correlations were found between genotypes and complete tumor responses.
Department of Molecular Bases of Human Genetics, Institute of Molecular Genetics, Russian Academy of Sciences, Moscow, Russia. khrunin@img.ras.ru
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Khrunin
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Moisseev
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Gorbunova
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Limborska
D000328:Adult; D002945:Cisplatin / Q000009:adverse effects / Q000627:therapeutic use*; D003520:Cyclophosphamide / Q000627:therapeutic use; D004268:DNA-Binding Proteins / Q000235:genetics; D018572:Disease-Free Survival; D005260:Female; D051549:Glutathione S-Transferase pi / Q000235:genetics*; D005982:Glutathione Transferase / Q000235:genetics; D006801:Humans; D008875:Middle Aged; D009503:Neutropenia / Q000139:chemically induced; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D000076105:X-ray Repair Cross Complementing Protein 1; D051759:Xeroderma Pigmentosum Group D Protein / Q000235:genetics
D002945:Cisplatin; D003520:Cyclophosphamide; D004268:DNA-Binding Proteins; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase; D016159:Tumor Suppressor Protein p53; D000076105:X-ray Repair Cross Complementing Protein 1; D051759:Xeroderma Pigmentosum Group D Protein; C495901:TP53 protein, human; C000619371:XRCC1 protein, human; C484555:GSTA1 protein, human; C483009:GSTM3 protein, human; C496556:GSTP1 protein, human; C497292:ERCC2 protein, human