Dihydropyrimidine dehydrogenase activity of cancerous and non-cancerous tissues in liver and large intestine.

Abstract

5-fluorouracil (5-FU) is a widely used chemotherapeutic agent for various carcinomas. However, the therapeutic effect of 5-FU differs among patients. The differences in the effectiveness of 5-FU are thought to be based on the different enzymatic activity which inactivates 5-FU of the host tissue. 5-FU is catabolized to 2-fluoro-beta-alanine by dihydropyrimidine dehydrogenase (DPD) in liver and tumors. In this study, we investigated the clinical significance of detecting DPD activity in patients with hepatocellular and colorectal carcinomas. DPD activity in 63 hepatocellular carcinomas (HCCs), 3 cholangiocellular carcinomas (CCCs), 63 non-cancerous liver tissues adjacent to HCCs (N-HCCs), 6 normal livers (NLs), 189 colorectal carcinomas (CRCs), and 189 non-cancerous colorectal mucosas (N-CRCs) was analyzed by enzyme-linked immunosorbent assay (ELISA). The mean DPD activities of these tissues were 209 +/- 187 Unit (U)/mg protein (HCC), 140 +/- 34 (CCC), 105 +/- 50 (N-HCC), 93 +/- 24 (NL), 58 +/- 45 (CRC), and 83 +/- 92 (N-CRC). DPD activity of HCC was higher than that of CRC (p < 0.0001). DPD activity of N-HCC was higher than that of N-CRC (p < 0.0001). DPD activity of HCC was higher than that of N-HCC (p = 0.0014), on the other hand, DPD activity of CRC was lower than that of N-CRC (p < 0.0001). Tumor DPD activity in HCC and CRC did not correlate with tumor differentiation or progression nor with patient survival. In 20 CRC patients with synchronous liver metastasis, who underwent post-operative 5-FU chemotherapy through the hepatic artery, the mean survival time (29 months) of 9 patients with high DPD was not significantly different from that of 11 patients with low DPD (18 months, p = 0.3412). These findings could provide an explanation for the relative 5-FU resistance of HCC compared with CRC. However, the DPD activities of tumors may not reveal tumor differentiation or progression in HCCs or in CRCs. Moreover, the DPD activity of primary CRC may not be a good indicator of the 5-FU chemosensitivity of synchronous liver metastasis.