Dihydropyrimidine dehydrogenase activity in hepatocellular carcinoma: implication in 5-fluorouracil-based chemotherapy.
Dihydropyrimidine dehydrogenase (DPD) is the initial, rate-limiting enzyme in the catabolism of 5-fluorouracil, one of the most widely used cancer chemotherapeutic agents. Previous studies have demonstrated the clinical importance of determination of DPD in cancer patients, suggesting that the efficacy and toxicity of 5-fluorouracil may directly relate to the DPD activity in both tumor and host tissues. In the present study, DPD activity was determined in 50 pairs of tumor and uninvolved liver specimens in Chinese cancer patients with hepatocellular carcinoma. Mean enzyme activity in uninvolved liver tissues (0.45 +/- 0.02 nmol/min/mg protein) was significantly higher than that in tumor specimens (0.34 +/- 0.03 nmol/min/mg protein). Statistical analysis revealed no significant differences in DPD activity of tumor and uninvolved liver specimens among different age and gender groups. Compared to previously reported tumor studies, hepatomas were found to have relatively high DPD activity. Since high levels of DPD would be expected to metabolize 5-fluorouracil, these findings may provide an explanation for the relative 5-fluorouracil resistance of hepatoma and may have implications for designing a new therapeutic strategy such as modulation of 5-fluorouracil chemotherapy by DPD inhibitors.
Jiang
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Department of Pharmacology and Toxicology, Division of Clinical Pharmacology, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA.
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D000328:Adult; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology / Q000601:surgery; D002681:China; D042943:Dihydrouracil Dehydrogenase (NADP); D005260:Female; D005472:Fluorouracil / Q000627:therapeutic use*; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology / Q000601:surgery; D008297:Male; D008875:Middle Aged; D010088:Oxidoreductases / Q000378:metabolism*; D011379:Prognosis
D000964:Antimetabolites, Antineoplastic; D010088:Oxidoreductases; D042943:Dihydrouracil Dehydrogenase (NADP); D005472:Fluorouracil