VOL.: 50 (1990) (p. 77)
Chem. Abstr. Name: R-[R*,R*-(E)]}-L-Cyclic(L-alanyl-D-alanyl-N-methyl-L-leucyl-N-methyl-
Ciclosporin has been used as an immunosuppressive agent since the mid-1980s.
Ciclosporin was tested for carcinogenicity by oral administration in two studies in mice and in one study in rats. In one study in mice, it accelerated the development of leukaemias; tumours were not induced in a chronic bioassay. In rats, negative results were obtained in a study with limited sensitivity.
Ciclosporin enhanced the development of lymphomas induced in two strains of male mice by single whole-body irradiation or N-methyl-N-nitrosourea. In grafted macaques, ciclosporin increased the incidence of lymphomas, a neoplasm that occurs extremely infrequently in this species of monkeys. When given in combination with various other immunosuppressive regimens, ciclosporin induced a substantial increase in the incidence of lymphomas when compared to immunosuppressive regimens excluding ciclosporin. This drug also enhanced the incidence of intestinal adenocarcinomas induced in male rats by N-methyl-N-nitrosourea.
In case reports, both lymphomas and Kaposi's sarcoma have been associated frequently with exposure to ciclosporin. Four cohort studies recorded a high incidence of lymphoma in organ transplant recipients; in two of these, ciclosporin was given without azathioprine or cytotoxic drugs. In several cases, there has been well-documented regression of lymphoma following withdrawal of the drug.
Ciclosporin induced dose-dependent changes in reproductive organ weights in male rats and caused sterility at high doses. Fetal mortality was observed in rats and rabbits when the drug was administered during the second half of gestation at maternally toxic doses. No other sign of embryo- or fetotoxicity was noted.
Ciclosporin is rapidly absorbed and widely distributed in humans and in experimental animals. It is extensively metabolized by the cytochrome P450 system. Adverse effects include nephro- and hepatotoxicity. The compound is immunosuppressive, resulting in tolerance to tissue grafts; its main effect is on the early proliferation of T-cells.
In a single study, ciclosporin was reported to increase the incidence of chromosomal aberrations in the lymphocytes of kidney transplant patients.
Ciclosporin did not induce dominant lethal mutations in mice, chromosomal aberrations in the bone marrow of Chinese hamsters or micronuclei in the bone marrow of Chinese hamsters or mice in vivo. It induced sister chromatid exchange in human peripheral lymphocytes in vitro but did not induce gene mutations in Chinese hamster cells. Ciclosporin did not induce mutations in Salmonella typhimurium.
There is sufficient evidence for the carcinogenicity of ciclosporin in humans.
There is limited evidence for the carcinogenicity of ciclosporin in experimental animals.
Ciclosporin is carcinogenic to humans (Group 1).
For definition of the italicized terms, see Preamble Evaluation.
Last updated: 11 November 1997
See Also: Toxicological Abbreviations