Effect of all-trans retinoic acid on induction, lethality and immunogenicity of murine methylcholanthrene-induced fibrosarcomas.

The effect of 200 micrograms doses of all-trans retinoic acid, given over a long duration (daily for 8 weeks, suspended for 3 weeks, then resumed daily for 4 weeks) or short duration (daily for 30 days), on the induction of fibrosarcomas in C57BL/6J mice by MCA was evaluated. A reduced level of carcinogenesis was observed with both lengths of retinoic acid treatment, since respective incidences of MCA fibrosarcomas were 63 and 61% of those in saline-treated controls. In other studies, the effect of all-trans retinoic acid on syngeneic growth of two experimental fibrosarcomas (B6 25 and B6 27, induced previously in C57BL/6J mice by MCA) was assessed. Retinoic-acid-treated mice were more resistant to higher doses of viable B6 27 (LD50 = 2.85) and especially B6 25 (LD50 = 3.80) than were corresponding saline- or corn-oil-treated controls (LD50 less than 2.0). The strength of resistance conferred by retinoic acid treatment thus varied considerably between these tumors, despite their common strain derivation and histopathological origin. Additional studies explored the effect on B6 27 growth of giving all-trans retinoic acid during either the sensitization or challenge stage of standard syngeneic immunogenicity tests. Mice given all-trans retinoic acid during sensitization displayed a markedly increased resistance to challenge with the immunospecific B6 27 tumor (LD50 = 5.30), compared to challenged controls that received saline (LD50 = 2.60) or corn-oil (LD50 = 2.55) during preimmunization. In contrast, when B6 27-preimmunized mice were treated with all-trans retinoic acid after challenge with homologous tumor, resistance to B6 27 (assessed by tumor growth rate and LD50 dose) was not increased but remained comparable to that of saline-or corn-oil-treated controls. While the mechanism(s) by which all-trans retinoic acid inhibits syngeneic growth of MCA tumors is unknown, our results support an immunostimulatory effect, evidenced by tumor resistance in both non-immune and specifically preimmunized syngeneic hosts.