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The Combination of a Potent Vitamin D₃ Analog, EB 1089, with Ionizing Radiation Reduces Tumor Growth and Induces Apoptosis of MCF-7 Breast Tumor Xenografts in Nude Mice¹

Departments of Surgery [S. S., A. S., S. F., R. S., P. J. H.] and Community and Family Medicine [E. D.], Dartmouth Medical School, Lebanon, New Hampshire 03756; Leo Pharmaceuticals, Ballerup, Denmark [L. B.]; and Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia 23298 [D. A. G.]

Purpose: The purpose of this research was to evaluate theinfluence of the combination of the vitamin D₃ analogue EB 1089 with fractionated radiation on growth and apoptosis of MCF-7 tumor xenografts in athymic mice.

Experimental Design: Four to six-week-old ovariectomized mice were injected s.c. with MCF-7 tumor cells suspended in Matrigel. When tumors reached a size of approximately 150–200 mm³, animals were exposed to EB 1089 (45 pmols/day) for 8 days, whereas mice that were to be irradiated in the absence of EB 1089 received solvent (Solutol HS15). After the termination of EB 1089 and solvent administration, tumors were irradiated (3 x 5 Gy) over a period of 3 days using a 300 KV Pantax Therapax irradiator. Tumor growth was monitored for 25–30 days after the last dose of irradiation in a double-blind manner; tumor cellularity was assessed by H&E and trichrome staining, cell proliferation by Ki-67 staining, and apoptosis by terminal deoxynucleotidyltransferase-mediated nick end labeling assay. Rates of tumor regression were assessed using a mixed effects statistical model.

Results: A significantly higher rate of decline in tumor volume (7.5% per day) was observed in mice exposed to radiation subsequent to EB 1089 compared with animals treated with radiation alone (5.6% per day). Final tumor volumes in animals irradiated after EB 1089 were 50% lower than in the group that received radiation alone. Loss of cellularity, a marked reduction in the fraction of proliferating cells, and the promotion of apoptosis confirmed that the combination of EB 1089 with radiation was significantly more effective than radiation alone in blocking tumor cell growth and promoting tumor cell death.

Conclusions: This work demonstrates that EB 1089 can improve local tumor control by fractionated radiation, in part through the promotion of apoptotic cell death.

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