COMPARISON OF THE THERAPEUTIC EFFECTS OF A NEW AROTINOID, RO-40-8757,AND ALL-TRANS-RETINOIC AND 13-CIS-RETINOIC ACIDS ON RAT BREAST-CANCER

A novel arotinoid, yl-2-naphthyl)propenyl]phenoxy}ethyl}}-morpholine, was tested in rats bearing established chemically induced mammary tumo rs. At a dose of 0.35 mmol/kg/day of yl-2-naphthyl)propenyl]phenoxy}et hyl}}-morpholine, decreased tumor growth was seen after 2 weeks. By we eks 4 and 5, tumor burdens were decreased to 10-30% of initial values and 50-70% of the animals became free of palpable tumors. Stabilizatio n of tumor size through 15 weeks of treatment was seen in rats given 0 .23 mmol/kg/day of the arotinoid. The predominate adverse effects of t his compound were dose-dependent weight loss during the first 1-3 week s, attributed to poor palatability of the food admix as well as flakin g of the skin and alopecia at later times. Bone toxicity, a characteri stic side effect of retinoids in rodents, was rare with this arotinoid , mainly confined to young rats treated for more than 12 weeks with hi gh doses. In a comparative study, neither all-trans-retinoic acid nor 13-cis-retinoic acid had significant antitumor effects at doses that w ere tolerated by the animals. When all-trans-retinoic acid was adminis tered at 0.08 mmol/kg/day, tumor reduction was seen during weeks 4-6, but treatment was terminated after week 6 due to severe skeletal toxic ity and general deterioration in all the animals. Such marked toxicity was not evident with the arotinoid at doses having high antitumor act ivity. The high efficacy and relatively low toxicity of hyl-2-naphthyl )propenyl]phenoxy}ethyl}}-morpholine suggest that it may be a promisin g new anticancer agent.