The long term objective of this project is to improve the effectiveness of the widely used cancer chemotherapy drug 5-fluorouracil (5-FU) by better understanding the genetic factors controlling the rate-limiting enzyme in pyrimidine catabolism, dihydropyrimidine dehydrogenase (DPD). Studies in the applicant's laboratory have demonstrated the critical role that DPD has in regulating 5-FU catabolism and hence 5-FU available for anabolism. Thus, while anabolism of 5-FU is directly responsible for toxicity in both tumor and host cells, regulation of catabolism will have major effects on both host cell toxicity and antitumor effects. Patients with significantly decreased DPD activity (DPD deficiency) in their host cells (e.g., hematopoietic and mucosal cells) are at increased risk of 5-FU toxicity. On the other hand, patients with increased DPD activity in their tumor tissue are likely to have tumor resistance to 5-FU. The recent availability of the DPD cDNA as well as a preliminary structural characterization of the DPD gene makes possible now a more complete examination of the genetic factors controlling DPD enzyme activity, including both natural regulatory elements as well as mutations that can alter DPD activity. The applicant proposes during the next grant period to examine the following: Spec.
Aim 1) Population Analysis of DPD Deficiency and Known DPD Mutations; Spec.
Aim 2) Determine the mechanism by which Previously Characterized Mutations Produce DPD Deficiency; Spec.
Aim 3) Identify Other Specific Molecular Defects Associated with DPD Deficiency; and Spec.
Aim 4) Identify and Characterize Transcriptional Regulatory Elements of the Human DPD Gene. These studies should improve understanding of the molecular regulation of DPD and be useful in the development of specific molecular diagnostic tests that may predict both host toxicity and tumor response before administration of 5-FU.
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