Retinoic acid receptors and retinoid X receptors form heterodimers, bind to retinoic acid response elements, and transactivate the transcription of retinoid-responsive genes. Two synthetic retinoids [4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-anthracenyl)benzoic acid (TTAB) and 6-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-2-naphthalenecarboxylic acid (TTNN)], which preferentially bind retinoic acid receptors, inhibited the proliferation of cervical carcinoma ME180 cells by 50% at 0.2 nm and 0.2 µm, respectively. In contrast, two other retinoids [2-(4-carboxyphenyl)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1,3-dithiane (SR11203) and 4-(2-methyl-1-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)propenyl)benzoic acid (SR11217)], which preferentially bind retinoic X receptors, inhibited growth by only 12 and 18% at 1 µm, respectively. The combination of suboptimal concentrations of TTAB (0.1 nm) or TTNN (10 nm) with each of the retinoic X receptor-selective retinoids at 1 µm showed more than additive effects on cell proliferation, especially with SR11217. Further increases in proliferation inhibition were observed when IFN-α (100 units/ml) was added to these retinoid combinations. Activation of transcription of a reporter gene linked 3′ to the retinoic acid receptor β retinoic acid response element in transiently transfected cells also exhibited additive effects when the cells were treated with combinations of TTAB or TTNN with SR11217. This additive activation of transcription may be the reason why the combination of retinoids is more effective than each retinoid alone. The results also suggest that the use of combinations of retinoids and IFN-α may lead to enhanced antitumor effects.

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Supported by USPHS Grants P30 CA16672-18 [R. L.] and P01 CA51993 [M. I. D.] from the National Cancer Institute and by the Abell-Hanger Foundation Professorship [R. L.].

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