Evidence of differential regulation of P-glycoprotein overexpression in drug-resistant tumour cells selected by exposure to X-irradiation as opposed to antitumour drugs

Clinical resistance to antitumour drugs has been recognised in patients who have received radiotherapy as well as in those treated with chemotherapy. To investigate this phenomenon we developed an experimental model system involving the in vitro exposure of mammalian tumour cells to fractionated X-irradiation and have characterised the resistance phenotype expressed. Following irradiation, tumour cells characteristically proved resistant to the Vinca alkaloids and to the epipodophyllotoxins, but not to the anthracyclines. This pattern was observed in a range of tumour cells of both rodent and human origin. Further examination, using irradiated Chinese hamster ovary cells identified modified accumulation of vincristine and overexpression of a functional P-glycoprotein. Construction of intraspecies hybrids revealed that this resistance phenotype was dominantly expressed. Unexpectedly, however, P-glycoprotein overexpression occurred without any concomitant increase in P-glycoprotein messenger RNA. A comparison of the rate of turnover of P-glycoprotein in these irradiated sublines, with that in the classic multidrug-resistant colchicine-selected CHRC5 cells provided evidence of a significantly prolonged half-life of P-glycoprotein in the tumour cells previously exposed to X-irradiation. Therefore, these data not only provide the first evidence that P-glycoprotein expression can be influenced by exposure to X-rays but also the first detailed example of P-glycoprotein being regulated by a posttranslational increased stability. More recent data have confirmed the existence of this same distinctive multiple drug resistance phenotype in sublines of human ovarian tumour cells similarly exposed in vitro to a series of fractions of X-irradiation. If these results are confirmed, and extended to include other tumour types, they provide a clear rationale for monitoring tumour biopsies for P-glycoprotein associated drug resistance in patients treated with radiotherapy and evaluating protein levels rather than, or as well as, MDR1 messenger RNA expression.