Identification of a distinctive multiple drug resistance phenotype in tumour cells following in vitro exposure to X-irradiation

Abstract

The clinical observation that reduced response rates to chemotherapy appear characteristic of certain subsets of patients whose tumours have been previously irradiated, prompted our investigations aimed at determining whether we could identify a biological basis for this phenomenon [1]. Using Chinese hamster ovary (CHO) cells as an in vitro model system, we showed that their exposure to fractionated X-irradiation resulted in the expression of drug resistance [2]. Our investigations of the cause of this resistance revealed that these irradiated cells had increased levels of P-glycoprotein (Pgp), the « classic » multidrug-resistance (MDR)-associated membrane glycoprotein. These irradiated cells exhibited resistance to multiple drugs, including the Vinca alkaloids and epipodophyllotoxins, as well as sensitivity to reversal of Vincristine resistance by Verapamil. However, unlike « classic » MDR cells, they showed no change in their sensitivity to anthracyclines. Furthermore, Pgp overexpression occurred in these irradiated cells despite a lack of Pgp gene amplification or of significant alteration in Pgp messenger RNA (mRNA) levels. These initial studies, therefore, suggested that the multiple drug resistance phenotype expressed by these tumour cells following their exposure to fractionated X-irradiation, appeared distinctive from the « classic » MDR phenotype identified in drug resistant tumour cells selected for resistance after exposure to drugs.