Pharmacogenetics in chemotherapy of colorectal cancer.
Although in recent years, chemotherapeutic options for colorectal carcinoma have expanded, overall response rates are still too low, with high rates of toxicity. Pharmacogenetics aim at predicting both treatment response and adverse effects in individual patients. This review describes the current knowledge of pharmacogenetic markers in the systemic treatment of colorectal cancer. UGT1A1*28 leads to reduced conjugation of SN-38, the active metabolite of irinotecan, resulting in an increased rate of adverse effects, especially neutropenia. To a lesser extent, increased 5-FU toxicity is predicted by DPYD*2A. A variable number of tandem repeats polymorphism in the thymidylate synthase enhancer region, in combination with a single nucleotide polymorphism C>G, may predict poorer response to 5-FU. Efficacy of oxaliplatin is influenced by polymorphisms in components of DNA repair systems, such as ERCC1 and XRCC1. Polymorphic changes in the endothelial growth factor receptor probably predict cetuximab efficacy. Furthermore, the antibody-depended cell-mediated cytotoxic effect of cetuximab may be reduced by polymorphisms in the immunoglobin G fragment C receptors. Bevacizumab efficacy is suspected to be influenced by polymorphisms in the VEGF gene and the hypoxia inducible factor 1alpha gene. Although the interpretation of pharmacogenetic studies is complicated, results imply a promising way of pretreatment prediction of chemotherapy efficacy and toxicity.
Department of Clinical Oncology, Leiden University Medical Center, The Netherlands.
Lieke
L
Henriette Tanja
Henk-Jan
HJ
Guchelaar
Hans
H
Gelderblom
D000970:Antineoplastic Agents / Q000009:adverse effects / Q000378:metabolism / Q000627:therapeutic use*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D005820:Genetic Testing; D006801:Humans; D018579:Patient Selection; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic; D016896:Treatment Outcome
D000970:Antineoplastic Agents