Dihydropyrimidine dehydrogenase activity and messenger RNA level may be related to the antitumor effect of 5-fluorouracil on human tumor xenografts in nude mice

We investigated the correlation between tumor sensitivity to 5-fluorouracil (5-FU) and the enzymatic activity and mRNA levels of thymidylate synthetas e (TS) and dihydropyrimidine dehydrogenase (DPD) using human tumor xenograf ts in nude mice. Three gastric carcinoma xenografts (SC-1-NU, St-4, and H-1 11), two colon carcinoma xenografts (Co-4 and Col-3-JCK), one pancreatic ca rcinoma xenograft (PAN-3-JCK), and one breast carcinoma xenograft (MX-1) we re inoculated into nude mice. When the resultant tumors reached 100-300 mg, 5-FU was administered i.p. at a dose of 60 mg/kg in a schedule of three ti mes every 4 days, and the antitumor activity of 5-FU was evaluated as the r elative mean tumor weight in treated mice compared to control mice. Xenogra fts were also inoculated into untreated nude mice. When tumors weighed 200- 300 mg, tumor tissues were resected for measurement of tumoral TS and DPD, TS and DPD activities were detected by the TS-binding assay and a radioenzy matic assay, respectively. mRNA levels were measured by semiquantitative re verse transcription-PCR, with glyceraldehyde-3-phosphate dehydrogenase coam plified as an internal standard. TS and DPD activities ranged from 84.7 to 775.5 fmol/mg protein and from not detectable to 79.7 pmol/min/mg protein, respectively. TS and DPD mRNA levels ranged from 0.51 to 9.90 and from not detectable to 0.93, respectively. The enzymatic activities of TS and DPD we re correlated with observed mRNA levels. DPD levels were significantly corr elated with 5-FU sensitivity, with high DPD activity and high DPD mRNA leve l resulting in low sensitivity to 5-FU, In contrast, no correlation between TS level and 5-FU sensitivity was observed. Tumoral DPD activity and DPD m RNA level may be useful indicators in predicting the antitumor activity of 5-FU.