Effects of retinoic acid and interferon-gamma on expression of the retinoic acid receptor in mouse renal cell carcinoma.
The clinical outcome of interferon-gamma 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-gamma in certain types of cancer. We investigated the efficacy of concomitant administration of 13-cRA and IFN-gamma. 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)-alpha, -beta and -gamma was examined by PCR analysis. The influence of IFN-gamma on these retinoic acid receptors was evaluated by Northern blotting. IFN-gamma showed anti-tumor effects both in vivo and in vitro. This effect was enhanced synergistically with concomitant 13-cRA treatment. RenCa cells expressed RAR-alpha, and -gamma, but not -beta according to PCR analysis. IFN-gamma treatment increased the expression level of RAR-alpha and RAR-gamma according to Northern blot analysis. Combination therapy using IFN-gamma and 13-cRA showed synergistic anti-tumor effects, which exceeded those of each therapy alone. Moreover, IFN-gamma treatment increased RAR-alpha and RAR-gamma expression. Thus, the augmented anti-tumor effects of IFN-gamma and 13-cRA may be attributable to enhanced expression of RAR-alpha and RAR-gamma by IFN-gamma treatment.
Hara
I
I
Department of Urology, Kobe University School of Medicine, Kobe 650-0017, Japan. hara@med.kobe-u.ac.jp
Taguchi
I
I
Miyake
H
H
Hara
S
S
Gotoh
A
A
Kamidono
S
S
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000378:metabolism / Q000556:secondary; D017931:DNA Primers / Q000737:chemistry; D004357:Drug Synergism; D005260:Female; D007371:Interferon-gamma / Q000627:therapeutic use*; D015474:Isotretinoin / Q000627:therapeutic use*; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000556:secondary; D051379:Mice; D008807:Mice, Inbred BALB C; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000378:metabolism*; D000072482:Retinoic Acid Receptor alpha; D014407:Tumor Cells, Cultured; D000097768:Retinoic Acid Receptor gamma
D000970:Antineoplastic Agents; D017931:DNA Primers; D007371:Interferon-gamma; D015474:Isotretinoin; D012333:RNA, Messenger; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D000097768:Retinoic Acid Receptor gamma; C000607072:Rara protein, mouse