ENHANCED ANTITUMOR EFFICACY OF CISPLATIN IN COMBINATION WITH ALRT1057(9-CIS RETINOIC ACID) IN HUMAN ORAL SQUAMOUS CARCINOMA XENOGRAFTS IN NUDE-MICE

Cisplatin (DDP) is commonly used to treat head and neck tumors. Therap y frequently fails due to development of DDP resistance or toxicities associated with DDP therapy. In this study, effects of ALRT1057 [9-cis retinoic acid (9-cis RA)] on DDP cytotoxicity were studied in a human oral squamous carcinoma xenograft model. Mice bearing xenografts were dosed p.o. daily 5 days/week with 30 mg/kg 9-cis RA and/or i.p. twice weekly with 0.3-0.9 mg/kg DDP. Maximum tolerated doses of 9-cis RA an d DDP were approximately 60 and greater than or equal to 2.9 mg/kg, re spectively, under their dosing schedules and routes of administration. Control tumors grew rapidly with mean doubling times of 4 +/- 1 days and reached mean volumes of 1982 +/- 199 (SE) mm(3) after 24 days. DDP at doses of 0.3, 0.45, and 0.9 mg/kg inhibited tumor growth by 28, 47 , and 86%, respectively, 24 days after tumor cell implantation. Thirty mg/kg 9-cis RA inhibited tumor growth by 25%. In combination, 0.3 mg/ kg DDP + 30 mg/kg 9-cis RA inhibited tumor growth by 68%; 0.45 mg/kg D DP + 30 mg/kg 9 cis RA inhibited growth by 78%. These decreases were g reater than those that would have been produced by either agent summed separately. Of importance, at doses of 9-cis RA that enhanced DDP cyt otoxicity, no change in dose tolerance was observed as compared to tol erances observed for either agent alone, indicating that 9-cis RA incr eased sensitivity to DDP without altering systemic toxicity. In additi on, 9-cis RA profoundly altered squamous cell carcinoma phenotypes by suppressing squamous cell differentiation, resulting in tumors with in creased numbers of basal cells. In contrast, DDP selectively depleted proliferating basal cells from carcinomas. In combination, morphologic al changes produced by 9-cis RA alone predominated, suggesting a possi ble basis for enhanced DDP sensitivity in tumors exposed to both agent s. These data demonstrate that 9-cis RA enhances tumor sensitivity to DDP, and suggest that this combination should be tested in Phase I-II clinical trials for its potential for improving anticancer therapy of squamous cell cancers.