For more than 40 years, thymidylate metabolism has been an important biochemical target for widely utilized anti-cancer agents. Inhibitors of this pathway such as the fluoropyrimidines and antifolates induce a severe depletion of TTP pools resulting in nucleotide pool imbalance and cell killing through a process termed """"""""thymineless death."""""""" Investigation of the underlying mechanisms of this process suggest that aberrant uracil-DNA metabolism may be an important mediator of DNA damage and cell killing. The broad objectives of this proposal are to better understand the role of key enzymes involved in dUTP metabolism in modulating chemosensitivity. In this study, we propose to investigate the prognostic value of the enzyme deoxyuridine triphosphate nucleotidohydrolase (dUTPase) as a marker for overall survival and response to fluoropyrimidine-based chemotherapy in metastatic colon cancer. dUTPase catalyzes the hydrolysis of dUTP to form dUMP and PPi, thereby eliminating dUTP from the DNA biosynthetic pathway. We hypothesize that dUTPase overexpression counters the cytotoxic effect of fluoropyrimidine treatment by limiting the expansion of dUTP pools. Although there is significant evidence suggesting that uracil-DNA metabolism may be a critical factor in mediating cytotoxicity, there have been few clinical studies performed to clarify the role of human dUTPase expression in modulating chemosensitivity.
Specific aim 1 investigates the significance of dUTPase expression in predicting patient response to fluoropyrimidine-based chemotherapy and overall survival in metastatic colon cancer.
Specific aim 2 compares the prognostic ability of intratumoral dUTPase expression with other known prognostic markers of colorectal cancer including, thymidylate synthase (TS), thymidine phosphorylase (TP), dihydropyrimidine dehydrogenase (DPD) and p53. Clinical analysis of dUTPase expression as a prognostic marker will not only provide a useful tool for the evaluation and treatment of colon cancer patients, but will also provide additional insight into the role of aberrant uracil-DNA metabolism in chemotherapies that inhibit thymidylate metabolism.
