Immunomodulating anticancer alkylating drugs: targets and mechanisms of activity

Abstract

CY and L-PAM potentiated specific anti-tumor response in addition to their killing effect. The immunomodulating effect of a low dose of either CY or L-PAM was expressed in mice bearing large s.c. MOPC-315 plasmacytoma tumors. Cured mice were resistant to a challenge dose of the syngeneic tumor and their spleens contained specific cytotoxic T cells. Induction of specific anti-tumor response by a low dose of alkylating drugs was due to expression of "latent anti-tumor" capability. This fitted with the conception that "suppressed concomitant immunity" occurring in tumor-bearing animals can be activated. The immunomodulating activity of alkylating drugs was related to enhancement of T-cell functions:impairment of suppressor T-cell activity,enhancement of effector T-cell activity and increase in production of cytokines at the tumor site. The target tumor killing activity of a low dose alkylating drug was dissociated from its immunomodulating activity by treating mice bearing a tumor resistant to an alkylating drug. A low dose of CY had an immunomodulating effect in human cancer such as reduction of ConA-induced suppressor cell activity in melanoma, some improvement in addition to use of melanoma vaccine, and potentiation of DTH in cancer patients. The immunomodulating effect of alkylating drugs suggest that their use might be beneficial not only for killing tumor cells but also for promoting specific anti-tumor immune response.