Radiosensitization of human breast cancer cells by a novel ErbB family receptor tyrosine kinase inhibitor

Int J Radiat Oncol Biol Phys. 2000 Dec 1;48(5):1519-28. doi: 10.1016/s0360-3016(00)01358-4.

Abstract

Purpose: Overexpression of the ErbB family of growth factor receptors is present in a wide variety of human tumors and is correlated with poor prognosis. The purpose of this study was to determine the effects of a novel small molecule ErbB tyrosine kinase inhibitor, CI-1033, in combination with ionizing radiation on breast cancer cell growth and survival.

Materials & methods: Growth assays were performed on ErbB-overexpressing human breast cancer cells developed in our laboratory in the presence of 0.1-1.0 microM CI-1033 (Parke Davis). Clonogenic survival assays were performed in the presence of ionizing radiation with or without CI-1033. For some experiments, clonogen numbers, defined as the product of surviving fraction and total number of cells, were calculated at each time point during a course of multifraction radiation.

Results: CI-1033 potently inhibited the growth of ErbB-overexpressing breast cancer cells. A single 48-h exposure of 1 microM CI-1033 resulted in growth inhibition for 7 days, whereas three times weekly administration resulted in sustained growth inhibition. Clonogenic survival was modestly decreased after a 7-day exposure to CI-1033. Exposure to both CI-1033 and radiation (6 Gy) yielded a 23-fold decrease in clonogenic survival compared to radiation alone. In a multifraction experiment, exposure to CI-1033 and three 5-Gy fractions of gamma radiation decreased the total number of clonogens in the population by 65-fold compared to radiation alone.

Conclusion: CI-1033 results in potent growth inhibition and modest cytotoxicity of ErbB-overexpressing breast cancer cells, and has synergistic effects when combined with ionizing radiation. These data suggest that CI-1033 may have excellent clinical potential both alone and in combination with radiation therapy.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Breast Neoplasms / radiotherapy*
  • Cell Division / drug effects
  • Cell Survival / radiation effects
  • Dose Fractionation, Radiation
  • Enzyme Inhibitors / therapeutic use*
  • ErbB Receptors / metabolism
  • Female
  • Humans
  • Neoplasm Proteins / antagonists & inhibitors*
  • Radiation Tolerance
  • Radiation-Sensitizing Agents / therapeutic use*
  • Receptor, ErbB-2 / antagonists & inhibitors*
  • Tumor Cells, Cultured / drug effects
  • Tumor Cells, Cultured / radiation effects
  • Tumor Stem Cell Assay

Substances

  • Enzyme Inhibitors
  • Neoplasm Proteins
  • Radiation-Sensitizing Agents
  • ErbB Receptors
  • Receptor, ErbB-2