Increased Cytotoxic Sensitivity of YPC-1 Tumor Cells from Mice Treated with Nitrosoureas1

The relative cytotoxic sensitivity of the YPC-1 tumor target cells from untreated mice and from animals treated with nitrosoureas was determined. The amount of 51Cr released from target cells increased significantly when the cells were obtained from treated mice. On the basis of the results of cold-target cytotoxicity inhibition assay, this enhancement was shown to be haplotype specific. The amount of 51Cr released from target cells of mice treated with /V,A/'-bis(chloroethyl)-N-nitrosourea decreased signifi cantly when the tumor cells were first incubated with fibrinogen and transglutaminase. Based on these results and other pub lished data, a model system is suggested. The model is based on the observation that tumors, and thus tumor antigens, at the cell surface are partly or completely covered by fibrinogen or fibrin. The enzyme transglutaminase is involved in the binding of the fibrinogen or fibrin to the cell surface. Accordingly, it is hypothesized that the nitrosoureas have a dual mode of immunotherapeutic activity. The carbamoylating properties inhibit the fibrin-binding activity of transglutaminase, thus preventing fibrin from covering up or coating the tumor cells and prevent ing the ability of sensitized effector cells to recognize the tumor-specific antigens in association with self H-2 antigens. The alkylating property of the nitrosoureas mainly concerns reactivity with the DMA of the tumor cells.