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

Department of Immunology, Naval Medical Research Institute, Bethesda, Maryland 20014 [J. H., G. S., T. S.]; National Foundation for Cancer Research, Medical University, Debrecen, Hungary [G. S., T. S.]; Department of Immunology, Merck Institute for Therapeutic Research, Rahway, New Jersey 07065 [A. A.]; and the National Institute of Arthritis, Metabolism, and Digestive Diseases, NIH, Bethesda, Maryland 20205 [T. S., K. L.]

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 N,N'-bis(chloroethyl)-N-nitrosourea decreased significantly when the tumor cells were first incubated with fibrinogen and transglutaminase. Based on these results and other published 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 preventing 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 DNA of the tumor cells.

¹ This work was supported by the Naval Medical Research and Development Command (Work Unit No. M F 51.542.015.0040) and by the National Foundation for Cancer Research.

² On leave from the Department of Dermatology, University School of Medicine, P. O. Box 480, H6701, Szeged, Hungary.

³ Permanent address: Department of Pulmonary Diseases (Division of Medicine), University Medical School of Debrecen, Hungary.

⁴ Permanent address: Department of Clinical Chemistry, University Medical School of Debrecen, P. O. Box 40, H-4012 Debrecen, Hungary.

⁵ To whom requests for reprints should be addressed: at Department of Immunology, Merck Institute for Therapeutic Research, P. O. Box 2000, Rahway, N. J. 07065.

Received 10/20/80. Accepted 1/20/81.