This investigation is designed to determine the clinical toxicity of a 24 hour thymidine infusion alone or in combination with carboplatin, compared to carboplatin alone. Thymidine preferentially kills neoplastic cells in vitro and induces complete and partial regressions of a variety of human rumor xenografts in nude mice. In clinical studies, prolonged thymidine infusions produced brief responses in heavily pre-treated patients. These prolonged, high dose infusions (5 to 29 days at 60 to 240 g/m2/day) are also quite myelosuppressive and clinical investigations of thymidine were abandoned. However, thymidine myelosuppression is proportional to the drug dose and duration. Accordingly, thymidine myelosuppression is minimal or zero when high doses are given for only one to two days in rats and mice, as well as an anecdotal report in man. Recent data demonstrates that 24-hour thymidine exposures have substantial antineoplastic efficacy in vitro. More importantly, thymidine exposures of 4 to 24 hours enhance carboplatin cytotoxicity in vitro for a variety of cell types, as well as cisplatin in human cell lines. Dose modifying factors range from approximately 2 to 3.5. The thymidine/carboplatin interaction increases with longer thymidine exposures up to 16 hours and then remains constant. This sensitization effect is the same for thymidine concentrations between 100 and 1000 mcg/ml, which is equal to the range of human serum thymidine levels of 60 to 240 grams thymidine/m2/day. In vivo studies show that 24 hour thymidine infusions are not myelosuppressive and also do not enhance hematologic or other normal tissue toxicities of carboplatin (This was at a dose corresponding to 75 grams thymidine/m2/day in man, the thymidine dose used as five-day infusions in phase II clinical studies). This observation suggests that 24 hour thymidine infusions could enhance carboplatin's antineoplastic effects without comparable increases in normal tissue toxicity.
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