Bromodeoxyuridine improves the cytotoxic effect of cisplatin: a comparison with 5-fluorouracil

Abstract

We compared the effects of the radiosensitizers, 5-bromo-2′-deoxyuridine (BUdR) and 5-fluorouracil (5-FU) alone and in combination and cis-diamminedichloroplatinum (cisplatin, DDP) on the growth of Bl6 amelanotic melanoma (Bl6a) tumors in mice. In a preliminary study, tumor growth was significantly inhibited in the presence of BUdR and was further reduced with the combination of BudR and DDP. In a second experiment, BUdR was found to be more effective than 5-FU when used in combination with DDP. At the completion of the study, tumor volumes as a percentage of control values in mice treated with a single drug were as follows: 5-FU (50 mg/kg per day for 7 days) 76.5% (P < 0.05), BUdR (100 mg/kg per day for 7 days) 68% (P < 0.05) and DDP (5 mg/kg × 3) 54% (P< 0.01). Combining 5-FU and DDP at these dosages reduced volumes to 38% (P < 0.01), while BUdR + DDP-treated mice had tumor volumes only 28% (P < 0.001) the size of untreated controls. Furthermore, the toxicity, as demonstrated by a decrease in body weight and an increase in mortality, was more severe in mice receiving 5-FU than in those receiving in BUdR. DDP interacts synergistically with either BUdR or 5-FU in its cytotoxic action in vivo. No such relationship could be demonstrated in vitro, suggesting that the pharmacologic activity of these drugs may be responsible for the antitumor activity rather than direct cytotoxic effects. We propose that BUdR is more effective than 5-FU as a potentiator of DDP in this murine melanoma model.