Radiation Resistance in a Melphalan-Resistant Subline of a Rat Mammary Carcinoma

Abstract

A subline of a rat mammary carcinoma (MATB 13762), selected for resistance to melphalan, is cross-resistant to other alkylating drugs, to unrelated drugs and to ionizing radiation. The difference in radioresponse between the sensitive wild-type cell line and the melphalan- and radiation-resistant line (MLNr) is related to the size of the alpha component in the linear-quadratic model. Reduction of dose rate does not affect the response of MLNr cells but does increase survival for wild-type cells. MLNr cells have elevated levels of reduced glutathione (GSH) and overexpress redox enzyme glutathione-S-transferase and glutathione peroxidase. Modest depletion of GSH (to 50% of control) radiosensitizes MLNr cells but not wild-type cells. On the basis of the results of an excision assay, growth delay and tumor control experiments, MATB MLNr tumors are also more radioresistant than wild-type cells when irradiated in situ. However, wild-type cells irradiated shortly after excision of the tumor are much more radioresistant than the same cells irradiated 24 h after excision or maintained in culture, and their response resembles that of MLNr cells irradiated under the same conditions. These results suggest that, in spite of some similarity between in vivo and in vitro observations, intrinsic radioresistance is not the most important factor influencing the response of MLNr cells in vivo.