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1,25-Dihydroxy-16-ene-23-yne-26,27-hexafluorocholecalciferol (Ro24-5531), a New Deltanoid (Vitamin D Analogue) for Prevention of Breast Cancer in the Rat

Mario A. Anzano, Joseph M. Smith, Milan R. Uskokovi, Christopher W. Peer, Larry T. Mullen, John J. Letterio, Marta C. Welsh, Mark W. Shrader, Daniel L. Logsdon, Craig L. Driver, Charles C. Brown, Anita B. Roberts and Michael B. Sporn

Laboratory of Chemoprevention, National Cancer Institute, Bethesda, Maryland 20892 [M. A. A., J. M. S., C. W. P., L. T. M., J. J. L., M. C. W., A. B. R., M. B. S.]; Hoffmann-LaRoche Inc., Nutley, New Jersey 07110 [M. R. U.]; In Vivo Carcinogenesis Program, PRI/Dyn Corp., NCI-Frederick Cancer Research and Development Center, Frederick, Maryland 21702 [M. W. S., D. L. L., C. L. D.]; and Biometry Branch, National Cancer Institute, Bethesda, Maryland 20892 [C. C. B.]

We have used the vitamin D analogue, 1,25-dihydroxy-16-ene-23-yne-26,27-hexafluorocholecalciferol (Ro24-5531), for inhibition of mammary carcinogenesis induced by N-nitroso-N-methylurea (NMU) in Sprague-Dawley rats. Rats were first treated with a single dose of either 15 or 50 mg/kg body weight NMU and then fed Ro24-5531 (2.5 or 1.25 nmol/kg of diet) for 5–7 months. Ro24-5531 significantly extended tumor latency and lessened tumor incidence as well as tumor number in rats treated with the lower dose of NMU. In rats treated with the higher dose of NMU, Ro24-5531 was fed in combination with tamoxifen; in these experiments, Ro24-5531 significantly enhanced the ability of tamoxifen to reduce total tumor burden, as well as to increase the probability that an animal would be tumor free at the end of the experiment. In vitro, Ro24-5531 was 10–100 times more potent than 1,25-dihydroxyvitamin D₃ for inhibition of proliferation of human breast cancer cell lines as well as primary cultures of cells from 2 patients with acute myelogenous leukemia. When fed chronically, Ro24-5531 did not elevate serum calcium in the present studies. We propose the new term, "deltanoids," for the set of molecules composed of vitamin D and its synthetic analogues, in a manner similar to the naming of "retinoids" for the corresponding set of molecules related to vitamin A.

Received 2/ 2/94. Accepted 2/25/94.

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