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 hair, 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.