Mechanism of synergistic action of all-trans- or 9-cis-retinoic acid and interferons in breast cancer cells.

Combination of all-trans-retinoic acid (RA) with either interferon-alpha or -gamma resulted in a synergistic amplification of the anti-proliferative effect on cultured breast cancer cells. RA could be replaced by other biologically active retinoids. The synergism was also observed for the induction of 2'-5'-oligoadenylate synthetase, an enzyme which is involved in anti-viral activity of interferons and possibly in growth regulation of tumor cells. Combination of RA with interferon-gamma increased the down-regulation of specific binding sites for [125I]interferon-gamma. On the other hand interferons had no effect on the cytoplasmic binding protein for RA. Comparing all-trans- with 9-cis-RA, the latter was more effective in inhibiting tumor cell growth and in inducing synergism with interferon-gamma. This would indicate that retinoic X receptors are more important in mediating these effects than the RA receptors (RARs). This assumption is also supported by the failure of Ro-415253, a specific RAR-alpha antagonist, to reduce the synergistic interaction of RA with interferon with respect to growth inhibition.