Phosphoribosyl pyrophosphate, pool size and tissue levels as a determinant of 5-fluorouracil response in murine colonic adenocarcinomas

Abstract

The antitumor activity of 5-fluorouracil (FUra) in four murine colonie adenocarcinomas was correlated with the basal pool sizes of phosphoribosyl pyrophosphate (PRPP). Mice inoculated with 20–30 mg fragments of murine colonic adenocarcinomas 26 and 38 (FUra-sensitive), and 51 and 11A (FUra-resistant), were treated approximately 2 weeks later with FUra (200 mg/kg, i.p.). In mice bearing adenocarcinomas 26 and 38, intravenous administrations on days 3, 10 and 17 of the highest nontoxic dose of 73 mg/kg produced a tumor growth delay of 14.8 and 11.8 days respectively. In contrast, mice bearing colonic adenocarcinomas 51 and 11A, treated with the same dose schedule of FUra, demonstrated a tumor growth delay of 5 and 5.4 days respectively. The basal levels of PRPP in FUra-sensitive tumors 26 and 38 were 8.7 and 4.0 μM, whereas those in FUra-resistant tumors 11A and 51 were 2.4 and 2.8 μM respectively. Two hours after i.p. injection of FUra (200 mg/kg), FUra-sensitive tumors (26 and 38) showed a substantial reduction in basal levels of PRPP to 1.30 and 2.80μM respectively; FUra-resistant tumors (51 and 11A) demonstrated a significantly smaller decrease in basal pool size levels. At 24 hr there was a full restitution of intratumoral PRPP to the previous basal levels. Four hours following i.p. injection of FUra at 200 mg/kg, the group of enzymes which could perturb PRPP pool size were assayed, namely PRPP synthetase (EC 2.7.6.1), hypoxanthine-guanine phosphoribosyl transferase (EC 2.4.2.8), adenine phosphoribosyl transferase (EC 2.4.2.7), and orotate phosphoribosyl transferase (EC 2.4.2.10). The specific activity of PRPP synthetase in the FUra-sensitive line (colon tumor 26) was 3-fold higher than in the FUra-resistant tumors examined (colon 51 and 11A); moreover, only in the sensitive line was the specific activity of orotate phosphoribosyl transferase increased significantly following treatment with FUra. Thus, these data suggest that measurement of the basal intratumoral PRPP levels, together with the determination of specific activities of PRPP synthetase and oratate phosphoribosyl transferase, should be tested for its potential clinical application as a means of selecting patients with gastrointestinal and breast carcinomas to be treated with FUra.