Immunomodulation and enhancement of antitumor activity by co-administration of 1,3-bis(2-chloroethyl)-1-nitrosourea and thymidine

The antitumor activity of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) has been shown previously to be enhanced markedly by the co-administration of pyrimidine deoxyribonucleosides (Lin and Prusoff, Cancer Res 47: 394-397, 1987). In the present study, we examined the cellular mechanisms underlying the augmentation effect of thymidine, one of the pyrimidine deoxyribonucleosides. It was found that thymidine did not increase the cytotoxicity of BCNU for B16/F10 melanoma cells in vitro. Instead, thymidine appeared to produce modulatory actions on the immune system of the tumor-bearing mice. More than 40% of the BCNU/thymidine-cured mice specifically rejected secondary rechallenge with the B16/F10 tumor. Furthermore, these cured mice developed extensive depigmentation of their natural black bair, suggesting immune reactions to normal melanocytes. When spleen cells from normal mice were treated with BCNU alone, their response to T-cell mitogen phytohemagglutinin was suppressed markedly. This suppression was ablated by co-administration of BCNU with thymidine. Such BCNU/thymidine treatment also augmented the activity of tumor-specific cytotoxic T-cells in tumor-bearing mice. Taken together, these results suggest that the enhanced antitumor activity of combined BCNU and thymidine may result from the action of thymidine on the immune effector mechanisms, which facilitate the development of antitumor immune responses in the presence of immunosuppression induced by BCNU.