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Suppression of Secondary Cellular Immunity to a Tumor Allograft by Cyclophosphamide and 1,3-Bis(2-chloroethyl)-1-nitrosourea¹

Division of Oncology, Department of Medicine, University of Washington School of Medicine, Seattle, Washington 98195

C57BL/6 mice (H-2^b) were immunized with lethally x-irradiated Moloney virus-induced lymphoma cells of BALB/c origin (H-2^d) on Days 0 and 10 and received drug on Days 11 and 14. Their spleen cells were then tested for reactivity against Moloney virus-induced lymphoma of BALB/c origin by the ⁵¹Cr-release cytotoxicity assay. In non-drug-treated mice the secondary cytotoxic response was maximal on Days 14 to 15, declined rapidly, and recurred after Day 21. The cytotoxic effector cells were shown to be -bearing T-lymphocytes.

Cyclophosphamide (CY), 180 mg/kg, given on Day 11, totally prevented the development of a cytotoxic response and, when given on Day 14, abolished the response already established. CY, 48 mg/kg, as well as 1,3-bis(2-chloroethyl)-1-nitrosourea. 33 mg/kg, were almost as suppressive. Immune mice given CY on Day 14 and reimmunized on Day 36 exhibited a normal tertiary response.

Mice similarly immunized on Days 1 and 10 and given drugs on Day 14 were challenged on Day 15 with up to 3.5 x 10⁸ viable Moloney virus-induced lymphoma cells of BALB/c origin. Despite H-2 incompatibility, all nonimmune control mice developed ascites and died, whereas all mice immunized but not given drug failed to develop ascites. By contrast, 17 of 34 immunized mice given CY, 180 mg/kg, and 7 of 34 given 1,3-bis(2-chloroethyl)-1-nitrosourea developed ascites. The ascites eventually regressed. The results show that CY and 1,3-bis(2-chloroethyl)-1-nitrosourea can suppress a secondary cellular immune response as measured by the T-cell-mediated ⁵¹Cr-release cytotoxicity assay in vitro and by viable tumor challenge in vivo.

¹ Presented in part at the 65th Annual Meeting of the American Association for Cancer Research, Houston, Texas, March 27 to 30, 1974. This work was supported by Grants CA 10777 and CA 05231 from the National Cancer Institute, NIH, and USPHS.

² American Cancer Society Junior Clinical Faculty Fellow.

³ Scholar of the Leukemia Society of America.

Received 9/23/74. Accepted 11/ 8/74.