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ST1926 is a novel atypical retinoid endowed with strong and selective apoptotic and anti-proliferative activities against numerous leukemia and solid cancer cell lines. The apoptotic activity of ST1926 translates into in vivo therapeutic efficacy, as demonstrated in a number of different animal experimental models. Currently the compound is under clinical development and is scheduled for phase I clinical trials. ST1926 is a ligand for nuclear retinoic acid receptors and shows relative selectivity for RARgamma. However, in certain cell lines, the in vitro apoptotic activity of the retinoid is unrelated to its ability to interact with RARgamma. To evaluate the significance of RARgamma expression in the in vitro and in vivo pharmacological activity of ST1926 directly, we used the the mouse F9 teratocarcinoma cell line (F9/WT) and its variant, F9-RARgamma-/- (F9/RG-), in which the gene coding for RARgamma was ablated by homologous recombination. F9/WT cells express RARgamma and RARalpha constitutively and are competent for retinoic-acid-induced differentiation. F9/RG- do not express RARgamma and do not respond to the differentiating action of retinoic acid. In this model, we observe that ST1926 is equally effective in inducing apoptosis of the F9/WT and the F9/RG- cell lines. By contrast, following intraperitoneal transplantation into singenic 129/Sv mice, F9/WT cells are significantly more responsive to oral administration of ST1926 (20 mg/kg) than the F9/RG- counterpart (% increased life span: F9/WT, 38%; F9/RG-, 12%). Our results indicate that RARgamma expression plays a significant role in the in vivo overall therapeutic effect of ST1926, perhaps through indirect effects on the host-tumor interactions. Moreover, the data suggest that selection of target human tumors for clinical trials involving ST1926 should take into account expression of RARgamma in the neoplastic cell. In light of the results obtained in vitro and in vivo, the F9/WT and F9/RG- cell lines were used to identify genes over- or under-expressed by ST1926 in a RARgamma-dependent and independent-fashion using gene microarrays consisting of approximately 21,000 elements. Many genes were identified with this methodology and some of them genes are in the process of being tested for their functional involvement in the process of growth inhibition and apoptosis set in motion by ST1926 in F9/WT and F9/RG- cells.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]