Nitrosoureas like 1,3-bis (2-chloroethyl)-1-nitrosourea (BCNU) have been used extensively to treat a variety of human haematologic and solid cancers and due to their property of crossing the blood-brain barrier, are of potential use in treating tumors of the CNS. Our recent studies demonstrated that nitrosoureas like BCNU cure a high percentage (greater than 90%) of mice bearing primary, syngeneic tumors and 100% of these 'cured' mice resisted subsequent challenge with the same tumor. Earlier studies hypothesized that BCNU treatment may make the tumor cells more susceptible to lysis by cytotoxic T lymphocytes (CTL) or macrophages (M0). Based on our studies, however, we hypothesized that in addition to the direct tumoricidal action, BCNU may selectively act on tumor-specific suppressor T cells (Ts) and this may represent a single major effect of BCNU which provides protection on subsequent tumor challenge. The present investigation is aimed at delineating the modulating effect of nitrosoureas on anti-tumor immunity and can be divided into: (1) Does BCNU-treatment abolish tumor-specific Ts thereby rendering the BCNU-cured mice resistant to secondary challenge with the same tumor? (2) Does tumor rejection require the participation of CTL or T helper cells (Th)? (3) Comparative efficacy of different nitrosoureas in the treatment of syngeneic tumors and its relation to Ts. The action of BCNU on Ts will be screened using both in vitro cell-mixing experiments and in vivo adoptive transfer experiments. The mechanism by which BCNU-cured mice reject secondary tumor challenge will be investigated to determine the relative roles played by LYT 1+ 2- Th and Lyt 1- 2+ CTL. The last series of experiments will evaluate other nitrosoureas such as 1-neopentyl-3(2-chloroethyl)-3 nitrosourea (NPCNU), its isomer (iso-NPCNU), streptozotocin (STZN), chlorozotocin (CLZ) etc. for their capacity to cure mice of the syngeneic tumor and induce tumor-resistance and investigate whether their efficacy is related to their capacity to act selectively on Ts. The studies proposed above, will not only help to understand the basic mechanism by which nitrosoureas like BCNU act on tumor cells and tumor-secific immunity of the host, but also may provide valuable information for those engaged in clinical trials of nitrosoureas against malignant diseases.
