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

Abstract

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. 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. 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. 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.