The clinical outcome of interferon-γ treatment of metastatic renal cell carcinoma remains unsatisfactory. To overcome this, a reagent that has a different action on cancer cells is desired. One such candidate may be 13-cRA (cis retinoic acid), a vitamin A derivative known to markedly regulate the differentiation and proliferation of normal and neoplastic cells. Moreover, 13-cRA demonstrates a remarkable synergistic effect with IFN-γ in certain types of cancer. We investigated the efficacy of concomitant administration of 13-cRA and IFN-γ. The in vivo anti-tumor effects were evaluated in a lung metastasis model using a mouse renal cell carcinoma cell line (RenCa). The in vitro anti-tumor effects were also assessed by MTT assay. The presence of retinoic acid receptors (RAR)-α, -β and -γ was examined by PCR analysis. The influence of IFN-γ on these retinoic acid receptors was evaluated by Northern blotting. IFN-γ showed anti-tumor effects both in vivo and in vitro. This effect was enhanced synergistically with concomitant 13-cRA treatment. RenCa cells expressed RAR-α, and -γ, but not -β according to PCR analysis. IFN-γ treatment increased the expression level of RAR-α and RAR-γ according to Northern blot analysis. Combination therapy using IFN-γ and 13-cRA showed synergistic anti-tumor effects, which exceeded those of each therapy alone. Moreover, IFN-γ treatment increased RAR-α and RAR-γ expression. Thus, the augmented anti-tumor effects of IFN-γ and 13-cRA may be attributable to enhanced expression of RAR-α and RAR-γ by IFN-γ treatment.

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