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Gemini Vitamin D Analogues Inhibit Estrogen Receptor–Positive and Estrogen Receptor–Negative Mammary Tumorigenesis without Hypercalcemic Toxicity

Authors' Affiliations: ¹ Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey and ² Environmental and Occupational Health Sciences Institute, Piscataway, New Jersey; ³ The Cancer Institute of New Jersey, New Brunswick, New Jersey; and ⁴ BioXell, Inc., Nutley, New Jersey

Requests for reprints: Nanjoo Suh, Department of Chemical Biology, Ernest Mario School of Pharmacy, 164 Frelinghuysen Road, Rutgers, The State University of New Jersey, Piscataway, NJ 08854. Phone: 732-445-3400, ext. 226; Fax: 732-445-0687; E-mail: nsuh{at}rci.rutgers.edu.

Numerous preclinical, epidemiologic, and clinical studies have suggested the benefits of vitamin D and its analogues for the prevention and treatment of cancer. However, the hypercalcemic effects have limited the use of 1,25(OH)₂D₃, the hormonally active form of vitamin D. To identify vitamin D analogues with better efficacy and low toxicity, we have tested >60 novel Gemini vitamin D analogues with a unique structure of two side chains for growth inhibition of breast cancer cells. Our initial studies found that some Gemini analogues are 5–15 times more active than 1,25(OH)₂D₃ in growth inhibition assay. In vivo experiments were designed to study the inhibitory effect of selected Gemini vitamin D analogues against mammary carcinogenesis by using (a) an N-methyl-N-nitrosourea–induced estrogen receptor (ER)-positive mammary tumor model and (b) an MCF10DCIS.com xenograft model of ER-negative mammary tumors. Among vitamin D analogues we tested, Gemini 0072 [1,25-dihydroxy-20S-21(3-trideuteromethyl-3-hydroxy-4,4,4-trideuterobutyl)-23-yne-26,27-hexafluoro-19-nor-cholecalciferol] and Gemini 0097 [1,25-dihydroxy-20R-21(3-trideuteromethyl-3-hydroxy-4,4,4-trideuterobutyl)-23-yne-26,27-hexafluoro-19-nor-cholecalciferol] administration inhibited by 60% the NMU-induced mammary tumor burden compared with the NMU-treated control group, but these compounds were devoid of hypercalcemia toxicity. In an ER-negative xenograft model, Gemini 0097 significantly suppressed tumor growth without hypercalcemia toxicity. We found that the inhibitory effect of Gemini 0097 was associated with an increased level of cyclin-dependent kinase inhibitor p21 and the insulin-like growth factor binding protein 3 in both ER-positive and ER-negative mammary tumors. Our results suggest that Gemini vitamin D analogues may be potent agents for the prevention and treatment of both ER-positive and ER-negative breast cancer without hypercalcemia toxicity.

Key Words: Gemini vitamin D • estrogen receptor • mammary tumorigenesis • IGFBP-3 • Smad

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