Dihydropyrimidine Dehydrogenase Activity and Thymidylate Synthase Level Are Associated with Response to 5-fluorouracil in Human Colorectal Cancer.

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Abstract
In the recent studies associated with the modulation of 5-fluorouracil (5-FU) and the development of new antifolates, attentions have been focused on the expression of the target enzymes, thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPD), that affect tumor sensitivity and resistance to drugs. In order to evaluate predictability of therapeutic efficacy by intratumoral enzyme activity, we investigated the role of TS content and DPD activity in tumor sensitivity of 5-FU. Surgical specimens were obtained from 51 patients with colorectal cancer and used to measure TS content and DPD activity. TS content and DPD activity in tissues were measured by [3H]-FdUMP binding assay and radioenzymatic assay, respectively. The sensitivity to 5-FU in tumor specimens was determined by collagen-gel droplet embedded-drug sensitivity test (CD-DST). The TS content and DPD activity did not correlate with Dukes' staging. There was no correlation between TS content and DPD activity in any tumors. Simple linear regression analysis showed that neither DPD activity (r = -0.267, p > 0.05) nor TS content (r = -0.277, p > 0.05) in tumors had a significant correlation with 5-FU effectiveness independently. Four out of 24 patients, highly responsive to 5-FU, showed low levels in both DPD and TS. The patients with high value in either DPD activity or TS content proved not to respond to 5-FU. In conclusion, these results demonstrate that both tumor DPD activity and TS content are the factors predicting 5-FU responsiveness in colorectal cancer.

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