Determinants of prognosis and response to therapy in colorectal cancer.
Identification of the molecular determinants of 5-fluorouracil (5-FU) and irinotecan (CPT-11) efficacy and toxicity is critically important for the development of more efficient and less toxic treatment strategies for patients with colon cancer. We have identified molecular predictors of response to chemotherapy with 5-FU and survival in patients with advanced colorectal cancer. Low gene expression levels of thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), and thymidine phosphorylase (TP) are associated with response and survival. Preliminary data suggest that gene expression levels of topoisomerase I, p21, bcl-2, and ICE may be predictive of response to therapy with CPT-11. Increased toxicity seen in patients treated with CPT-11 may be explained by polymorphism in the UGT1A1 gene, which is responsible for glucuronidation of the active metabolite of CPT-11.
Iqbal
S
S
Division of Medical Oncology, University of Southern California/ Norris Comprehensive Cancer Center, 1441 Eastlake Avenue, Los Angeles, CA 90033-0804, USA. iqbal@hsc.usc.edu
Lenz
H J
HJ
D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000032:analysis*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D042943:Dihydrouracil Dehydrogenase (NADP); D005472:Fluorouracil / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic; D014453:Glucuronosyltransferase / Q000235:genetics; D006801:Humans; D000077146:Irinotecan; D009944:Organoplatinum Compounds / Q000494:pharmacology; D000077150:Oxaliplatin; D010088:Oxidoreductases / Q000032:analysis / Q000096:biosynthesis* / Q000378:metabolism; D011110:Polymorphism, Genetic; D011237:Predictive Value of Tests; D011379:Prognosis; D012680:Sensitivity and Specificity; D016019:Survival Analysis; D013939:Thymidine Phosphorylase / Q000032:analysis / Q000096:biosynthesis* / Q000378:metabolism; D013940:Thymidylate Synthase / Q000032:analysis / Q000096:biosynthesis* / Q000378:metabolism
D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D014408:Biomarkers, Tumor; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D000077146:Irinotecan; D010088:Oxidoreductases; D042943:Dihydrouracil Dehydrogenase (NADP); D013940:Thymidylate Synthase; D014453:Glucuronosyltransferase; D013939:Thymidine Phosphorylase; D005472:Fluorouracil; D002166:Camptothecin