ENHANCED EFFICACY OF COMBINATIONS OF RETINOIC ACID AND RETINOID-X RECEPTOR-SELECTIVE RETINOIDS AND ALPHA-INTERFERON IN INHIBITION OF CERVICAL-CARCINOMA CELL-PROLIFERATION

Retinoic acid receptors and retinoid X receptors form heterodimers, bi nd to retinoic acid response elements, and transactivate the transcrip tion of retinoid-responsive genes. Two synthetic retinoids trahydro-5, 5,8,8-tetramethyl-2-anthracenyl)benzoic acid (TTAB) and ramethyl-2-nap hthalenyl)-2-naphthalen-escarboxylic acid (TTNN)], which preferentiall y bind retinoic acid receptors, inhibited the proliferation of cervica l carcinoma ME180 cells by 50% at 0.2 nM and 0.2 mu M, respectively. I n contrast, two other retinoids o-5,5,8,8-tetramethyl-2-naphthalenyl)- 1,3-dithiane (SR11203) and ,5,8,8-tetramethyl-2-naphthalenyl)propenyl) benzoic acid (SR11217)], which preferentially bind retinoic X receptor s, inhibited growth by only 12 and 18% at 1 mu M, respectively. The co mbination of suboptimal concentrations of TTAB (0.1 nM) or TTNN (10 nM ) with each of the retinoic X receptor-selective retinoids at 1 mu M s howed more than additive effects on cell proliferation, especially wit h SR11217. Further increases in proliferation inhibition were observed when IFN-alpha (100 units/ml) was added to these retinoid combination s. Activation of transcription of a reporter gene linked 3' to the ret inoic acid receptor beta retinoic acid response element in transiently transfected cells also exhibited additive effects when. the cells wer e treated with combinations of TTAB or TTNN with SR11217. This additiv e activation of transcription may be the reason why the combination of retinoids is more effective than each retinoid alone. The results als o suggest that the use of combinations of retinoids and IFN-alpha may lead to enhanced antitumor effects.