Comparison of the therapeutic effects of a new arotinoid, Ro 40-8757, and all-trans- and 13-cis-retinoic acids on rat breast cancer.
A novel arotinoid, 4-((2-(p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl- 2-naphthyl)propenyl]phenoxy))ethyl))-morpholine, was tested in rats bearing established chemically induced mammary tumors. At a dose of 0.35 mmol/kg/day of 4-((2-(p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2- naphthyl)propenyl]phenoxy)ethyl))-morpholine, decreased tumor growth was seen after 2 weeks. By weeks 4 and 5, tumor burdens were decreased to 10-30% of initial values and 50-70% of the animals became free of palpable tumors. Stabilization 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 this compound were dose-dependent weight loss during the first 1-3 weeks, attributed to poor palatability of the food admix as well as flaking of the skin and alopecia at later times. Bone toxicity, a characteristic side effect of retinoids in rodents, was rare with this arotinoid, mainly confined to young rats treated for more than 12 weeks with high doses. In a comparative study, neither all-trans-retinoic acid nor 13-cis-retinoic acid had significant antitumor effects at doses that were tolerated by the animals. When all-trans-retinoic acid was administered 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 toxicity and general deterioration in all the animals. Such marked toxicity was not evident with the arotinoid at doses having high antitumor activity. The high efficacy and relatively low toxicity of 4-((2-(p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2- naphthyl)propenyl]phenoxy)ethyl))-morpholine suggest that it may be a promising new anticancer agent.
Teelmann
K
K
Pharmaceutical Research Department Dermatology, F. Hoffman-La Roche, Ltd, Basel, Switzerland.
Tsukaguchi
T
T
Klaus
M
M
Eliason
J F
JF
D015127:9,10-Dimethyl-1,2-benzanthracene; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D004195:Disease Models, Animal; D004435:Eating / Q000187:drug effects; D005260:Female; D008325:Mammary Neoplasms, Experimental / Q000139:chemically induced / Q000188:drug therapy*; D009025:Morpholines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012176:Retinoids / Q000494:pharmacology*; D014212:Tretinoin / Q000494:pharmacology*
D000970:Antineoplastic Agents; D009025:Morpholines; D012176:Retinoids; D014212:Tretinoin; D015127:9,10-Dimethyl-1,2-benzanthracene; C081137:mofarotene