5-Fluorouracil enhances azidothymidine cytotoxicity: in vitro, in vivo, and biochemical studies.

摘要: Preliminary in vitro studies suggest that the combination of 5-fluorouracil (FUra) and 3′-azido-3′-deoxythymidine (AZT) is more cytotoxic than either agent alone. Therefore, a biochemical therapeutic evaluation this was initiated. Quantitation cytotoxicity FUra plus AZT against growth HCT-8 cells revealed 1 µm (∼10% inhibitory concentration) increased decreased its 50% concentration by 60%. Similarly, incubating 5 over 50%. Biochemical analysis indicated did not affect FUra-induced inhibition thymidylate synthase or [3H]-FUra incorporation into nucleic acids. In contrast, incubation [3H]-AZT (5 µm) acid fraction these 52% ( P < 0.05). Therapeutic athymic (nude) mice bearing xenographs that, while weekly (85 mg/kg) (600 exerts minimal antineoplastic activity (after 4 courses, treatment/control = 0.81 0.70, respectively), their combination, at same doses, inhibited tumor nearly 70% 0.01 versus alone). Fura-related host toxicity addition AZT. Higher doses alone were effective vivo , various murine tissues, including xenografts. FUra, however, acids tissue-specific manner. presence spleen, liver, gut 40, 21, 4%, respectively, xenografts 2-fold. Analysis activities selected enzymes involved pyrimidine metabolism suggests effect may be related to salvage capacity tissues. These findings are described light potential impact on human colon cancer chemotherapy.