A NOVEL RETINOIC ACID RECEPTOR-SELECTIVE RETINOID, ALRT1550, HAS POTENT ANTITUMOR-ACTIVITY AGAINST HUMAN ORAL SQUAMOUS CARCINOMA XENOGRAFTSIN NUDE-MICE

We have identified a novel retinoid, ALRT1550, that potently and selec tively activates retinoic acid receptors (RARs), ALRT1550 binds RARs w ith K-d values of congruent to 1-4 nM, and retinoid X receptors with l ow affinities (K-d congruent to 270-556 nM). We studied the effects of ALRT1550 on cellular proliferation in squamous carcinoma cells. ALRT1 550 inhibited in vitro proliferation of UMSCC-22B cells in a concentra tion-dependent manner with an IC50 value of 0.22 +/- 0.1 (SE) nM, 9-ci s 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 administrati on (daily, 5 days/week) of ALRT1550, begun 3 days after implanting tum or cells, inhibited tumor growth by UP to 89% ill a dose-dependent man ner over the range of 3-75 mu g/kg. ALRT1550 (30 mu g/kg) also inhibit ed 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 therape utic index of congruent to 17 in this model, indicating 3 separation b etween doses that inhibited tumor growth and that induced symptoms of hypervitaminosis A, In summary, ALRT1550 potently inhibits cellular pr oliferation in vitro and irt vivo in this squamous cell carcinoma tumo r model, These data support additional study of ALRT1550 for its Poten tial for improving anticancer therapy in human clinical trials.