Molecular Approach in Predicting 5-Fluorouracil Efficacy

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The advancement of the Human Genome Project along with the development of new techniques such as gene chips, automated gene-sequencers and real time quantitative PCR (RT -QPCR) have resulted in a rapidly expanding discipline devoted to the study of genetic differences that affect an individual's response to drugs tenned phannacogenomics. The long-term objective of this proposal is to examine if a phannacogenomic approach can be used to predict response and/or toxicity in patients with stage III colorectal cancer to the chemotherapy drug 5-Fluorouracil (5-FU). Initial efforts will follow up on a promising preliminary study in a small population of patients with disseminated colorectal cancer whose tumors were retrospectively examined using RT- PCR. This study suggested that over 90 percent of the responders to 5-FU therapy (with a median survival over 3 times longer than non-responders) could be identified by quantitating the expression levels of dihydropyrimidine dehydrogenase (DPD) and thymidylate synthase (TS). The specific aims of the current application include: Spec. Aim 1) Determine the role of intratumor DPD and TS expression in predicting response (time to relapse) to 5-FU in a prospective clinical study of patients presenting with stage III disease -subsequent studies will examine the additive value of other critical enzymes in the fluoropyrimidine pathway; Spec. Aim 2) Determine DPD and TS expression in normal tissues (e.g., normal intestine, liver, peripheral blood mononuclear cells) and compare with tumor expression levels and host toxicity; and Spec. Aim 3) Determine DPD and TS expression in paraffin embedded tissue samples compared to simultaneously collected snap frozen tissue in order to demonstrate the utility and validate this diagnostic approach in studies of archival tissue. If this pharmacogenomic approach is shown to be feasible with 5-FU, it could then be extended to potentially other cancer chemotherapy agents in the future, making possible alternative therapies tailored to the individual patient.