Showing papers by "David A. Gewirtz published in 2003"

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 Mice

Abstract: Purpose: The purpose of this research was to evaluate theinfluence of the combination of the vitamin D 3 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 mm 3 , 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 × 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.

Effect of the vitamin D3 analog ILX 23-7553 on apoptosis and sensitivity to fractionated radiation in breast tumor cells and normal human fibroblasts

Abstract: Previous work from this laboratory has demonstrated that the vitamin D3 analogs EB 1089 and ILX 23-7553 enhance the response of breast tumor cells to ionizing radiation and promote radiation-induced apoptotic cell death. The current studies were designed to more closely simulate clinical radiotherapy in the treatment of breast cancer by examining the utility of ILX 23-7553 as an adjunct to fractionated ionizing radiation. The potential toxicity to normal tissue of the combination of ILX 23-7553 and fractionated radiation was assessed in a model of BJ human fibroblasts in culture. MCF-7 cells and human fibroblasts were treated with fractionated radiation alone (5×2 Gy over 3 days), ILX 23-7553 alone (50 nM) or ILX 23-7553 followed by 5×2 Gy. Viable cell numbers were determined by trypan blue exclusion and apoptosis by the TUNEL assay. A statistical model of additivity was utilized to assess the nature of the interaction between ILX 23-7553 and fractionated radiation. Radiation and ILX 23-7553 each alone reduced viable cell numbers by 72±3.1% and 62±4.8%, respectively. Pretreatment with ILX 23-7553 followed by 5×2 Gy reduced viable cell numbers by 93.2±0.7%. The interaction between ILX 23-7553 and fractionated radiation appeared to be additive despite the fact that the combination of ILX 23-7553 and fractionated radiation also promoted a twofold increase in apoptotic cell death. ILX 23-7553 failed to enhance the response to radiation or to promote apoptosis in BJ human foreskin fibroblasts. ILX 23-7553 enhanced the antiproliferative and apoptotic effects of fractionated ionizing radiation in MCF-7 breast cancer cells. These effects appeared to be selective in that similar responses were not observed in a model of normal human fibroblasts. Vitamin D3 analogs such as ILX 23-7553 may prove to have utility in combination with conventional radiotherapy of breast cancer as well as other malignancies which are sensitive to vitamin D3.