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Apoptotic Regression of MCF-7 Xenografts in Nude Mice Treated with the Vitamin D₃ Analog, EB1089¹

W. Alton Jones Cell Science Center (K.V., L.F., M.T., J.W.), Lake Placid, New York 12946; Clarkson University (K.V.), Potsdam, New York 13699 University College Dublin (L.F.), Belfield, Ireland; and Leo Pharmaceutical Products (L.B.), Ballerup, Denmark

Address all correspondence and requests for reprints to: Dr. JoEllen Welsh, W. Alton Jones Cell Science Center, 10 Old Barn Road, Lake Placid, New York 12946. E-mail: jwelsh{at}cell-science.org

1,25-Dihydroxyvitamin D₃ [1,25-(OH)₂D₃] and its synthetic analog EB1089 induce characteristic morphological features of apoptosis in MCF-7 cells in vitro that coincide with up-regulation of clusterin and cathepsin B, proteins associated with apoptosis in the mammary gland, and with down-regulation of Bcl-2, an antiapoptotic protein. To determine whether vitamin D₃ compounds could mediate apoptosis of breast tumors in vivo, we treated nude mice carrying established MCF-7 xenografts with the low calcemic vitamin D₃ analog EB1089 via daily injection or sustained release pellets for up to 5 weeks. The volume of tumors from mice treated with 45 pmol/day EB1089 was 4-fold lower than that of tumors from vehicle-treated control mice after 5 weeks. The reduced growth of tumors from EB1089-treated mice was associated with characteristic apoptotic morphology and a marked reduction in the proportion of epithelial cells to stroma. After 5 weeks of treatment with EB1089, MCF-7 tumors exhibited a 6-fold increase in DNA fragmentation (as measured by in situ end labeling) relative to that in control tumors. The enhanced rate of apoptosis in tumors from EB1089-treated mice was coupled to a 2-fold reduction in proliferation (as measured by expression of proliferating cell nuclear antigen) compared with that in tumors from control mice. The antitumor effects of EB1089 were evident at doses that had minimal effects on serum calcium and body weight. EB1089 treatment did not alter the growth of xenografts derived from a vitamin D₃-resistant variant of MCF-7 cells (MCF-7^D3Res cells), which display resistance to EB1089 in vitro, indicating that resistance to EB1089 is maintained in vivo. Tumors derived from both MCF-7 and MCF-7^D3Res cells underwent apoptotic regression upon estradiol withdrawal, indicating comparable estrogen dependence of tumors with differential sensitivity to vitamin D₃ compounds. These are the first studies to demonstrate apoptotic morphology and regression of human breast tumors in response to treatment with a vitamin D₃ analog in vivo and support the concept that vitamin D₃ compounds can effectively target human breast cancer.

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