Retinyl ethers as cancer chemopreventive agents. Suppression of mammary cancer

• Published in: Anti-cancer drug design Vol. 12; no. 1; p. 15
• Main Authors: Shealy, Y F, Frye, J L, Riordan, J M, Hill, D L, McPhillips, M, Wille, J J, Sani, B P, Kalin, J R, Eto, I, Grubbs, C J
• Format: Journal Article
• Language: English
• Published: United States 01-01-1997
• Subjects: Animals; Anticarcinogenic Agents - chemical synthesis; Anticarcinogenic Agents - therapeutic use; Carcinogens; Drug Screening Assays, Antitumor; Female; Mammary Neoplasms, Experimental - chemically induced; Mammary Neoplasms, Experimental - prevention & control; Methylnitrosourea; Rats; Rats, Sprague-Dawley; Vitamin A - analogs & derivatives; Vitamin A - chemical synthesis; Vitamin A - therapeutic use
• ISSN: 0266-9536

It had been demonstrated previously that retinyl methyl ether (RME) can suppress carcinogen-induced mammary cancers in vivo. It had also been shown that RME is demethylated enzymatically to retinol and produces the toxic effects of retinol; however, a rationale was developed for further investigations of retinyl ethers and was the basis for the synthesis and biological evaluations of new retinyl ethers for the chemoprevention of mammary cancer, reported herein. Two of the new retinyl ethers, retinyl 3-methyl-2-butenyl ether (RMBE) and retinyl 2-propynyl ether (RPE), were evaluated for the suppression of mammary cancers in vivo. RMBE, RPE, RME, the 2,3,6-trimethyl-4-methoxyphenyl analogue of RME, and retinyl acetate (a positive control) were incorporated individually into the feed of rats that had been injected with N-methyl-N-nitrosourea to induce mammary cancers. Ninety-day tests of these compounds for suppression of mammary cancer showed that RPE has significant cancer chemopreventive activity, comparable to that of retinyl acetate in simultaneous tests. RMBE demonstrated borderline activity. Both RPE and RMBE were less toxic than retinyl acetate or RME and, in contrast to the other retinoids, did not cause accumulation of large amounts of retinyl palmitate in the liver. Further investigations of RPE showed that it accumulated in mammary tissue after a single oral dose was administered to female rats, reached maximum concentrations within 24 h, and was still present at 75-80% of maximum concentrations after 72 h. In ethanol at 25 degrees C, RPE slowly underwent intramolecular cyclization; small amounts of the cyclized product also appeared in mammary tissue of rats dosed with RPE. During the mammary cancer bioassay, however, RPE was essentially stable in the feed. Some of the new retinyl ethers, as well as RME, bind to cellular retinol-binding protein.