Effect of the vitamin D3 analog ILX 23-7553 on apoptosis and sensitivity to fractionated radiation in breast tumor cells and normal human fibroblasts.
OBJECTIVE
Previous work from this laboratory has demonstrated that the vitamin D(3) 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.


METHODS
MCF-7 cells and human fibroblasts were treated with fractionated radiation alone (5x2 Gy over 3 days), ILX 23-7553 alone (50 n M) or ILX 23-7553 followed by 5x2 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.


RESULTS
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 5x2 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.


CONCLUSIONS
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 D(3) 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 D(3).
Polar
Mark K
MK
Department of Pharmacology/Toxicology, Medical College of Virginia, Virginia Commonwealth University, P.O. Box 980230, Richmond, VA, USA.
Gennings
Chris
C
Park
Misook
M
Gupta
Mona S
MS
Gewirtz
David A
DA
D017209:Apoptosis / Q000187:drug effects* / Q000528:radiation effects*; D001943:Breast Neoplasms / Q000473:pathology*; D002762:Cholecalciferol / Q000031:analogs & derivatives* / Q000494:pharmacology*; D005260:Female; D005347:Fibroblasts; D006801:Humans; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D011878:Radiotherapy; D014407:Tumor Cells, Cultured
C428283:ILX237553; D011838:Radiation-Sensitizing Agents; D002762:Cholecalciferol