ABSTRACT
A series of dimethyl aryl-triazene derivatives and related monomethyl compounds were studied for their efficacy in mediating a strong increase in immunogenicity (i.e., chemical xenogenization, CX) of murine leukemic cells following in vitro treatment. It was found that all compounds under investigation were able to induce CX. The dimethyl derivatives were able to induce CX only after metabolic activation, whereas related monomethyl compounds were active per se. The antigenicity acquired by triazene-treated leukemic cells was very marked; intact hosts histocompatible with the parental line were able to reject up to 10(7) cells. Antigenic tumor cells retained their immunogenic properties even after a large number of transplant generations in the absence of the drug. This means that marked immunogenicity of triazene-treated cells is a stable and heritable characteristic.
Subject(s)
Antigens, Neoplasm , Dacarbazine/pharmacology , Leukemia L1210/immunology , Triazenes/pharmacology , Animals , Histocompatibility , Male , Mice , Neoplasm TransplantationABSTRACT
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 MIP, 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 vitro 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 CCl4. 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.
Subject(s)
Dacarbazine/pharmacology , Leukemia L1210/immunology , Animals , Antigens, Neoplasm/immunology , Carmustine/therapeutic use , Cell Line , Cytological Techniques , Dacarbazine/metabolism , Leukemia L1210/drug therapy , Leukemia L1210/pathology , Mice , Mice, Inbred C57BL , Microsomes, Liver/metabolism , Neoplasm Transplantation , Prognosis , Transplantation ImmunologyABSTRACT
Administration of BCG and Corynebacterium parvum is known to cause depression of the hepatic microsomal enzyme system (HMES) in mice. In the present study we explored the effects on HMES of two chemical immunoadjuvants, one of which (pyran copolymer) with peculiarly long-lasting biological activities. The two synthetic immunoadjuvants proved to be potent HMES inhibitors and, for pyran copolymer, peak levels of inhibition concurred with maximal macrophage activation. The inhibition was largely dose-dependent and could not be prevented by immunopharmacologic maneuvers that are known to block the C. parvum effect on HMES. The possibility is discussed that common mechanism(s) underlie the depression of HMES by immunoactive substances of both bacterial and chemical origin.
Subject(s)
Adjuvants, Immunologic/pharmacology , Microsomes, Liver/drug effects , Aminopyrine N-Demethylase/antagonists & inhibitors , Aniline Hydroxylase/antagonists & inhibitors , Animals , BCG Vaccine/pharmacology , Biotransformation/drug effects , Mice , Microsomes, Liver/metabolism , Poly I-C/pharmacology , Propionibacterium acnes/immunology , Pyran Copolymer/pharmacologyABSTRACT
The liberation of cyanide from succinonitrile has been studied to obtain information on the cellular systems responsible for the release of this metabolite. 1) Using isolated endoplasmic reticulum preparations a complex between succinonitrile and cyt. P 450 has been detected. This finding together with the inhibition of cyanide liberation by SKF-525A in liver slices indicates that the endoplasmic reticulum is involved in the early stages of succinonitrile metabolism. 2) The decreased metabolism of succinonitrile which was observed after addition of inhibitors of oxidative phosphorylation indicates that an energy-dependent mitochondrial step might be involved in the subsequent steps. 3) It is concluded that cyanide liberation from succinonitrile is a multistep process in which the mitochondrial membrane and the endoplasmic reticulum are involved. The requirement for cellular integrity in order to accomplish the process of succinonitrile metabolism suggests other components or equilibria that are difficult to reproduce in in vitro experiments.
