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In Vitro Generation of a Highly Immunogenic Subline of L1210 Leukemia following Exposure to 5-(3,3'-Dimethyl-1-triazeno)imidazole-4-carboxamide¹

Institute of Pharmacology, University of Perugia, Via del Giochetto, Perugia 06100 Italy [A. R. C., A. B., A. G., A. C., M. C. F.], and National Cancer Institute, NIH, Bethesda, Maryland 20205 [A. G.]

Strong and heritable increase of immunogenicity of L1210 Ha leukemia has been obtained in vitro following multiple treatments with 5-(3,3'-dimethyl-1-triazeno)imidazole-4-carboxamide (DTIC), metabolically activated by mouse liver preparations (MLP) containing liver microsomes. The DTIC-treated leukemia (L1210D line) or the control line treated with MLP alone (L1210N line) showed comparable growth kinetics in vitro. However, progressive increase of immunogenicity occurred in leukemic cells in the course of in vitro treatments with DTIC plus MLP, but not with MLP alone, as evidenced by comparative studies on transplantation immunity elicited in BALB/c x DBA/2 F₁ mice by graded inocula of L1210D or L1210N leukemia cells. In vivo experiments confirmed that metabolic transformation of DTIC is required for increasing tumor immunogenicity. In fact, L1210Ha cells became highly immunogenic when treated with DTIC in intact mice but not in animals metabolically depressed by CCI₄. Immunochemotherapy experiments based on the antigenic cross-reactivity between the L1210D line and the original L1210Ha leukemia showed that i.p. administration of L1210D cells followed by 1,3-bis(2-chloroethyl)-1-nitrosourea treatment afforded marked protection in mice inoculated intracerebrally with the parental lymphoma.

The present findings could provide an adequate in vitro technique for developing further studies on DTIC-mediated immunogenic changes of tumors, including human cancer cells growing in tissue culture.

¹ This work was supported by a C.N.R. (Rome, Italy) contract: Progetto Finalizzato Controllo della Crescita Neoplastica, Sottoprogetto: Controllo Çhemioterapico N.80.01521.96.

² To whom requests for reprints should be addressed.

Received 4/ 1/80. Accepted 2/ 5/81.

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