Experimental Study on the Effect of Combination Therapy of Interferon Alpha and Retinoic Acid in Renal Cell Carcinoma

Ko, Young Tae; Moon, Woo Chul

Abstract

Experimental study was done to investigate the effect of combination therapy of recombinant interferon alpha-2a (IFN-alpha) and 13-cis-retinoic acid(13cRA) or all-transretinoic acid(TRA) on the in vitro and in vivo proliferation of human renal carcinoma cell line(CURC-2). 13cRA inhibited the in vitro proliferation of CURC-2 significantly at tolerable serum concentration in human(0.000001mole) and IC50 of 13cRA was found to be about 0.000003 mole. TRA did not inhibit the in vitro proliferation of CURC-2 significantly at tolerable serum concentration and IC50 of TRA was found to be too high(0.00003mole) to be administered in vivo. IFN-alpha inhibited in vitro proliferation of CURC-2 significantly with IC50 of about 500 unit/ml. Combined administration of low concentration of IFN-alpha(300 unit/ml) and 13cRA (0.000001mole) showed significant synergistic antiproliferative effect (79%, p<0.01 ) compared to single administration of IFN-alpha(29%) and 13cRA(29%). Combined administration of IFN-alpha and TRA showed underadditive effect. Combined administration of IFN-alpha(50,000 unit s.c./mouse/day) and 13cRA (0.5 mg p.o./mouse/day) to nude mouse significantly decreased the incidence(p<0.05) and tumor weight(p<0.001) of subcutaneously implanted CURC-2 cells and showed significant synergistic effect(p<0.05) compared to 13cRA or IFN-alpha single administration. 13cRA-administered animals did not show toxic sign of hypervitaminosis A. These results suggest that IFN-alpha and 13cRA show significant synergistic antiproliferative effect both in vitro and in vivo on human renal carcinoma cells and that combination therapy of IFN-alpha and 13cRA may become effective and safe adjuvant therapy for renal cell carcinoma. Based on the results of this study, clinical trials of combination therapy of IFN-alpha and 13cRA are ongoing in patients with renal cell carcinoma.