A Novel Retinoic Acid Receptor-Selective Retinoid, Alrt1550, Has Potent Antitumor Activity Against Human Oral Squamous Carcinoma Xenografts In Nude Mice

We have identified a novel retinoid, ALRT1550, that potently and selectively activates retinoic acid receptors (RARs), ALRT1550 binds RARs with K-d values of congruent to 1-4 nM, and retinoid X receptors with low affinities (K-d congruent to 270-556 nM). We studied the effects of ALRT1550 on cellular proliferation in squamous carcinoma cells. ALRT1550 inhibited in vitro proliferation of UMSCC-22B cells in a concentration-dependent manner with an IC50 value of 0.22 +/- 0.1 (SE) nM, 9-cis Retinoic acid (ALRT1057), a pan agonist retinoid that activates RARs and retinoid X receptors, inhibited proliferation with an IC50 value of 81 +/- 29 nM. fil vivo, as tumor xenografts in nude mice, UMSCC-22B formed well-differentiated squamous carcinomas, and oral administration (daily, 5 days/week) of ALRT1550, begun 3 days after implanting tumor cells, inhibited tumor growth by UP to 89% ill a dose-dependent manner over the range of 3-75 mu g/kg. ALRT1550 (30 mu g/kg) also inhibited growth of established tumors by 72 +/- 3% when tumors were allowed to grow to congruent to 100 mm(3) before dosing began. In comparison, 9-cis retinoic acid st 30 mg/kg inhibited growth of established tumors by 73 +/- 5%. Interestingly, retinoids did not appear to alter tumor morphologies in UMSCC-22B tumors, Notably, ALRT1550 produced a therapeutic index of congruent to 17 in this model, indicating 3 separation between doses that inhibited tumor growth and that induced symptoms of hypervitaminosis A, In summary, ALRT1550 potently inhibits cellular proliferation in vitro and irt vivo in this squamous cell carcinoma tumor model, These data support additional study of ALRT1550 for its Potential for improving anticancer therapy in human clinical trials.