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

Purpose: Overexpression of the ErbB family of growth factor receptors is pr esent in a,vide variety of human tumors and is correlated with poor prognos is. The purpose of this study was to determine the effects of a novel small molecule ErbB tyrosine kinase inhibitor, CI-1033, in combination with ioni zing radiation on breast cancer cell growth and survival. Materials & Methods: Growth assays were performed on ErbB-overexpressing hu man breast cancer cells developed in our laboratory in the presence of 0.1- 1.0 muM CI-1033 (Parke Davis). Clonogenic survival assays were performed in the presence of ionizing radiation with or without CI-1033, For some exper iments, clonogen numbers, defined as the product of surviving fraction and total number of cells, were calculated at each time point during a course o f multifraction radiation. Results: CI-1033 potently inhibited the growth of ErbB-overexpressing breas t cancer cells. A single 48-h exposure of 1 muM CI-1033 resulted in growth inhibition for 7 days, whereas three times weekly administration resulted i n sustained growth inhibition. Clonogenic survival was modestly decreased a fter 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 radiatio n 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 cytotoxi city of ErbB-overexpressing breast cancer cells, and has synergistic effect s when combined with ionizing radiation. These data suggest that CI-1033 ma y have excellent clinical potential both alone and in combination with radi ation therapy. (C) 2000 Elsevier Science Inc.