Effect of cyclosporine on 3-methylcholanthrene-induced carcinogenesis and immune responses in the rat.

Cyclosporine A (CsA) was used to immunosuppress male Sprague-Dawley rats treated with the chemical carcinogen 3-methylcholanthrene (3MC). Rats treated with low doses of CsA (2.5 or 5 mg/kg) given 2 days prior to an injection of 3MC, and then daily for 2 weeks or twice weekly for 10 weeks did not develop tumors. Rats treated with 2.5 mg/kg CsA for 2 weeks beginning 5 days after a single 3MC injection had tumor incidence similar to rats treated with 3MC only. To further examine the effects of CsA on immune function, groups of rats were then treated with 2.5, 5, 10 or 20 mg/kg CsA daily for 14 days and immune function assessed by measuring delayed-type hypersensitivity (DTH), natural killer cell (NK) activity, and production of interleukin 2 (IL-2), interferon (IFN), prostaglandin E2 (PGE2) and specific IgG antibody. Natural killer cell cytotoxicity was enhanced and antibody production was suppressed in rats treated with all doses of CsA tested. Interleukin 2 production was elevated at the two lower doses, but antibody production, DTH reactions and synthesis of IL-2 and IFN were suppressed with the higher dose treatments (10, 20 mg/kg CsA). The enhanced NK activity seen in rats treated with the lower doses of CsA may be due to the increase in IL-2 production, while enhancement of NK activity at higher doses may be due to other mechanisms. The tumor data suggest that CsA does not prevent tumor formation in our chemical-induced model due to an increase in NK activity, since this enhancement was seen even when tumors did develop normally.