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Participation of T-Lymphocytes in the Curative Effect of a Novel Synthetic Polyamine Analogue, N,N'-Bis[3-(ethylamino)propyl]-1,7-heptanediamine, against L1210 Leukemia in Vivo

Merrell Dow Research Institute, Cincinnati, Ohio 45215

We have recently established that combination therapy with N,N'-bis[3-(ethylamino)propyl]-1,7-heptanediamine (BEPH), a synthetic polyamine analogue, and N,N'-bis-2,3-butadieneyl-putrescine, a polyamine oxidase inhibitor, eradicated L1210 leukemia in mice and induced resistance to a subsequent L1210 challenge. We now demonstrate that BEPH treatment alone, given on a more frequent schedule (5 mg/kg, day 3, 4, 5) or at a higher dose (10 mg/kg, day 3, 4), cures 100% of L1210 leukemic mice. These treated animals were subsequently immune to a second challenge with L1210 tumor cells. However, mice cured with BEPH did not reject P388 leukemic cells, although their mean survival time was slightly prolonged. In an in vivo tumor neutralization assay, splenocytes from cured mice and L1210 cells were injected into naive mice; 80% did not develop L1210 leukemia. Coculturing lymphocytes from cured mice with L1210 cells in vitro generated a potent tumor-specific cytolytic response against L1210 target cells, whereas lymphocytes from naive mice did not generate any significant cytolytic activity. Both the in vitro and in vivo activities were completely eliminated by pretreating the splenic lymphocyte population with anti-Thy-1.2 monoclonal antibodies and complement, indicating T-cells as the effector population. In T-cell-deficient nude mice BEPH treatment was not curative, increasing survival time by approximately 2-fold. We conclude from these studies that T-cell-mediated immunity plays a pivotal role in the mechanism by which synthetic polyamine analogues, such as BEPH, prevent neoplastic growth.

¹ To whom requests for reprints should be addressed, at Merrell Dow Research Institute, 2110 E. Galbraith, Road, Cincinnati, OH 45215.

Received 7/25/90. Accepted 10/ 9/90.