Stimulatory Effects of Vitamin A Analogs on Induction of Cell-mediated Cytotoxicity in Vivo¹

Previously, we observed that pretreatment of mice with low doses (25 to 300 μg/mouse/day) of the antineoplastic agent, β-all-trans-retinoic acid (β-RA), for 5 days before challenge with allogeneic tumor cells resulted in stimulated induction of cell-mediated cytotoxicity (CMC) but that higher doses (≥500 μg/mouse/day) suppressed CMC. The present study examined the ability of three other less toxic retinoids to stimulate CMC. Administration of 25-, 100-, 300-, or 800-μg/mouse/day i.p. doses of β-RA, trimethylmethoxyphenyl analog of β-RA, 13-cis-retinoic acid, or retinyl palmitate daily for 5 days into C57BL/6 mice stimulated CMC to 8- to 10-fold after challenge with suboptimal immunogen inoculum (10⁶ S194 myeloma cells/mouse). When retinoid-treated mice were challenged with a higher number of tumor cells (3 × 10⁶ or 10⁷/mouse), CMC was also enhanced; however, it was to a low degree (2- to 4-fold). Optimal stimulation of CMC by β-RA occurred at 100 μg/mouse/day, while at 800 μg/mouse/day CMC was somewhat inhibited. In contrast, the three other retinoids did not suppress but rather stimulated CMC even better at the highest dose tested. The trimethylmethoxyphenyl analog exhibited a higher stimulatory effect on CMC than did the other retinoids, especially in mice challenged with optimal immunogen doses. These results demonstrate that, in addition to β-RA, other retinoids are capable of enhancing CMC. This property may in part mediate their reported antineoplastic activity.