The goal of this proposal is to identify the molecular determinants of CPT-11 metabolism and molecular predictors of response and survival in patients with disseminated colorectal cancer treated with CPT-11. Identification of molecular determinants of CPT-11 efficacy and toxicity is of critical importance for the development of more efficient and less toxic treatment strategies for patients with colon cancer. Since its introduction as a second line of treatment for colon cancer, we have seen significant clinical toxicity in Hispanic patients treated with CPT-11. One possible explanation for he increased clinical toxicity is a high frequency of a genetic polymorphism of UGT1A1, the critical enzyme essential for inactivation CPT-11 metabolites. Our preliminary data suggest that up to 60% of Hispanics have a genetic polymorphism associated with decreased enzyme activity, which is associated with high risk of significant clinical toxicity. These data facilitate the design of treatment strategies for CPT-11 that avoids life-threatening toxicity. We have also identified potential molecular determinants of response to CPT-11 in patients with colorectal cancer. Preliminary preclinical and clinical data suggest that topoisomerase I, the target enzyme of CPT-11, and genes involved in DNA repair and apoptosis may be predictors of chemosensitivity to CPT-11 treatment. The understanding of the molecular mechanism of resistance to CPT-11 will have a significant impact on the clinical management of patients with colorectal cancer. To our knowledge, molecular determinants of clinical outcome and metabolism of anticancer drugs have not been systematically studied and there are no data available in Hispanics. At USC/Norris we will be able to perform these studies because the Los Angeles County population is among the most ethnically diverse in the US. The cultural and ethnic variety provides a great """"""""natural laboratory"""""""" for the study of colon cancer genes in most ethnic groups. We will test the hypotheses, 1) that Hispanic patients have more frequent UGT1A1 polymorphism associated with decreased UGT1A1 activity than Caucasian, 2) clinical toxicity and pharmokinetic/ dynamics are associated with the genotype of UGT1A1, 3) the newly identified polymorphism are associated with decreased enzyme activity, 4) gene expression of topoismerase 1, bcl-2, bcl-xL, bcl-xS, bax, ICE, and p21 are predictors of response to and survival after treatment with CPT-11, and 4) that the status of DNA mismatch repair and p53 will predict for response and survival.
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