Synergistic apoptosis and antitumor activity induced by ST1926, an atypical retinoic acid derivative

Abstract

14029 Background: ST1926 is a novel adamantyl retinoid active against a wide panel of human tumor cell lines, including p53-defective cells. Moreover, its cytotoxic activity is not affected by Pgp overexpression or resistance to cisplatin. The drug induces an early G1/S cell cycle arrest associated with a modulation of genes involved in apoptosis and DNA damage. Although the ST1926 molecular targets are still not fully elucidated, some in vitro studies suggest that this drug induces activation of both intrinsic and extrinsic apoptotic pathways. Methods: ST1926 antiproliferative activity was evaluated in vivo by oral route using fractionated daily schedules in CD1 nude mice against different human tumor xenografts, including NSCLC, ovarian carcinoma, H&N, neuroblastoma and melanoma, as well as hematological malignancies. Pharmacokinetic and toxicological studies were conducted in rodents and dogs after single and repeated (5 days and 4 weeks) oral administration. Results: As monotherapy, ST1926, showing a favorable tolerability profile, was effective in inhibiting tumor growth in several tumor models. In particular, ST1926 showed significant tumor inhibition on doxorubicin- and platinum-resistant ovarian carcinomas at 30 mg/kg po given according to different schedules. The most prominent tumor growth inhibitory effects were noted in combination regimens with cisplatin and carboplatin in both sensitive and resistant ovarian carcinoma. The plasma t1/2 was about two hours in all animal species tested. The hemolymphopoietic system and GI tract were identified as the main target organs of toxicity. Toxicology findings indicated the starting dose in humans at 30 mg daily for five consecutive days. Conclusions: ST1926 is a new antitumor proapototic agent acting through particular molecular mechanisms. ST1926 is active by oral administration on both solid tumors, especially ovarian carcinoma, and acute myeloid leukemia. A Phase I clinical program to evaluate safety and tolerability of ST1926 as monotherapy and in combination with platinum compounds is ongoing in women with advanced ovarian cancer. [Table: see text]