title: 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: 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).
authors.affiliation: Department of Pharmacology/Toxicology, Medical College of Virginia, Virginia Commonwealth University, P.O. Box 980230, Richmond, VA, USA.
authors.forename: Mark K
authors.initials: MK
authors.lastname: Polar
authors.forename: Chris
authors.initials: C
authors.lastname: Gennings
authors.forename: Misook
authors.initials: M
authors.lastname: Park
authors.forename: Mona S
authors.initials: MS
authors.lastname: Gupta
authors.forename: David A
authors.initials: DA
authors.lastname: Gewirtz
mesh_terms: 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
chemical_list: C428283:ILX237553; D011838:Radiation-Sensitizing Agents; D002762:Cholecalciferol