Molecular basis for thymidine modulation of the efficacy and toxicity of alkylating agents

Pharmacology & Therapeutics
W J Hwu, D E Mozdziesz

Abstract

The antitumor activity of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) in mice previously was shown to be markedly enhanced by co-administration of thymidine. We have examined the cellular mechanisms underlying the augmentation effect of thymidine. It was found that thymidine did not increase the cytotoxicity of BCNU for B16/F10 melanoma or L1210 leukemia cells in vitro. Instead, thymidine appeared to augment the activity of tumor-specific cytotoxic T-cells in tumor-bearing mice, which specifically rejected a secondary challenge with the B16/F10 tumor. Thus, development of an antitumor immune response is facilitated by thymidine in BCNU-induced immunosuppressed mice. These preclinical studies suggested that combination therapy with alkylating agents and thymidine may be a more efficacious and less toxic anticancer therapy. The potential efficacy of the sequential administration of dacarbazine (DTIC), BCNU, and thymidine in patients with advanced malignant melanoma was investigated. As predicted from animal studies, sequential administration of DTIC, BCNU, and thymidine is a relatively nontoxic therapy for metastatic melanoma. This treatment induced durable responses in up to 35% of patients, and hence is superior to many commonl...Continue Reading

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