MECHANISM OF MELPHALAN-MEDIATED TUMOR ERADICATION

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In general, the proposed research is aimed at obtaining information that should make it possible to delineate some of the characteristics of a tumor system in which a low dose of melphalan is curative at an advanced stage of tumor growth. We know already that the curative effectiveness of a low dose of melphalan for mice bearing a large MOPC-315 plasmacytoma depends on the contribution of antitumor immunity in tumor eradication. We will determine whether a low dose of melphalan is curative also for mice bearing a large tumor of selected plasmacytomas that differ in their immunogenicity, thus eliciting varying degrees of antitumor immunity that can contribute to tumor eradication. For each of these tumors, we will establish a dose-response curve to determine the lowest dose of melphalan that is curative for mice at an advanced stage of tumor growth. In tumor models for which a low dose of melphalan is curative at an advanced stage of tumor growth, we will determine whether the curative effectiveness of the low dose of drug is due solely to the drug's tumoricidal activity or whether T-cell-dependent antitumor immunity also aids in tumor eradication. In tumor models for which a low dose of melphalan is not curative at an advanced stage of tumor growth, we will determine whether the failure of the low-dose chemotherapy to cure such mice is due to relative resistance of the tumor cells (as compared with the MOPC-315 cells) to the direct toxic effects of the drug and/or due to the development of an insufficient level of antitumor immunity to control the tumor burden that remains after clearance of the drug from the circulation. The information gathered from the proposed studies should make it possible to delineate some of the characteristics of a tumor system in which it might be possible to exploit host antitumor immunity therapeutically. (HF)