Abstract. L1210 leukemia was transplanted serially in CDF, mice treated with 5-(3,3-dimethyl-1-triazeno)imidazole4-carboxamide (DIC, NSC 45388). After four different lines (C lines) had been treated for several generations, a marked increase in survival time of untreated mice was observed. In contrast, mice treated with DIC or immunosuppressed with cyclophosphamide succumbed earlier with generalized leukemia. Furthermore, a C line showed unusually high sensitivity to chemotherapeutic treatment with 1,3 bis(2-chloroethyl)-1-nitrosourea. The data suggest that C lines acquired strong antigenicity for CDF, and DBA/2 hosts. DIC treatment may have selected highly antigenic variants or induced somatic mutations resulting in the appearance of strong new transplantation antigen(s).Introduction. The influence exerted by cytotoxic drugs on cell antigens has bcen studied in vitro' and in Vivo.2 Urethan' as well as thalidomide3 seemed to produce antigenic simplification of normal tissue transplantation antigens in vitro. On the other hand, specific changes of tumor transplantation antigens were observed after treatment with 5-fluorouracil in vivo. 2 These observations suggested the possibility that chemoresistant tumor lines4 obtained after long-term treatment with antineoplastic agents might show altered antigenic properties as compared with the original sensitive line. Preliminary experiments with long-transplanted L1210 leukemic lines resistant to 5-(3,3-dimethyl-1-triazeno)imidazole4-carboxamide (DIC, NSC 45388) and also to methotrexate indicated that both were antigenically different from the original sensitive leukemia. Thus, a number of L1210 lines resistant to these drugs has been developed de novo in order to characterize them with respect to tumor transplantation immunity.The present paper describes the growth properties of four distinct DIC-treated lines under various experimental conditions in vivo. The data suggest that leukemic cells acquired rather strong transplantation antigens, foreign to the original host, after a few transplant generations in DIC-treated mice.

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Generalized leukemia was observed on day 3 following intra‐peritoneal inoculation of leukemic (L1210) ascites cells in CDF1 mice. On day 3 after tumor implantation, residual viable leukemic cells were detected in the peritoneal cavities and spleens of leukemic mice 6 h following treatment with 180 mg/kg of cyclophosphamide. Mice receiving weekly intraperitoneal injections of X‐irradiated leukemic (L1210) cells for 6 weeks were resistant to a challenge of tumor cells. When incubated in vitro, spleen and bone marrow cells of immune mice were able to inactivate viable leukemic cells, as evidenced by failure of tumor growth in mice inoculated with these cells. Leukemic mice injected with immune spleen or bone‐marrow cells from isogeneic mice following treatment with cyclophosphamide survived a 60‐day observation period. In one such experiment 90‐day survivors were able to resist re‐inoculation of tumor cells. Leukemic (DBA/2) mice inoculated with allogeneic spleen cells following cyclophosphamide treatment survived for longer periods than mice injected with isogeneic spleen cells.

L‐asparaginase was effective in increasing the life span of leukemic (L5178Y) mice. However, the therapeutic effect of the drug was reduced when this treatment was preceded by a series of pretreatments (relative to tumor implantation) with the drug. The data from in vitro and in vivo studies revealed the involvement of humoral antibodies to L‐asparaginase in reducing therapeutic activity of the drug in leukemic mice. Similarly, the antileukemic activity of the drug was neutralized when L‐asparaginase was pre‐incubated with immune sera obtained from rabbits or mice. The therapeutic activity of the drug was retained when the pretreatment with L‐asparaginase in mice was accompanied by a single injection of cyclophosphamide, an immunosuppressant drug. Sera from these mice did not contain precipitin antibody to L‐asparaginase.

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