Increased dihydropyrimidine dehydrogenase activity in breast cancer

Background and Objectives: Although studies have focused on modulating the bioavailability of 5-FU through inhibition of dihydropyrimidine dehydrogenase (DPD) to improve efficacy of the drug, activity of this enzyme in breast cancer has not been thoroughly examined. We measured DPD activity in primary and metastatic lesions and benign breast tumors to evaluate the clinical significance of this enzyme in the treatment of breast cancer. Methods: DPD activity was measured by catalytic assay and compared in 100 primary tumors (95 invasive carcinomas, 5 intraductal carcinomas), 26 uninvolved adjacent breast tissue specimens, 6 metastatic sites, and 7 intraductal papillomas. Results: The enzyme level in the carcinomas was 4-fold that of adjacent uninvolved breast tissues (101 vs 23 pmol/min/mg protein, P < 0.001). Enzyme activity in intraductal papilloma (120 pmol/min/mg protein) was comparable to that in invasive carcinoma. There were no significant differences in DPD activity related to clinicopathologic features, but a tendency toward increased DPD activity was observed in progesterone receptor-negative breast cancer (P = 0.09). There was marginal correlation in enzyme activity between primary and metastatic lesions (P = 0.07). Conclusions: DPD activity is substantially upregulated in breast cancer tissue and is higher than that reported previously. The clinical implications of DPD inhibitors in patients being treated for breast cancer with oral fluoropyrimidine chemotherapy should be further investigated. (C) 2003 Wiley-Liss, Inc.