EXPRESSION OF P-GLYCOPROTEIN-MEDIATED DRUG-RESISTANCE IN CHO CELLS SURVIVING A SINGLE X-RAY DOSE OF 30 GY

We reported previously that Chinese hamster ovary (CHO) cells surviving exposure to repeated doses of 9 Gy of X-irradiation in vitro expressed a multiple drug resistance phenotype characterized by cross-resistance to epipodophyllo-toxins and to Vinca alkaloids, and by P-glycoprotein (Pgp) overexpression (Hill et al. 1990). We have now shown that exposure of these CHO cells to a single 30-Gy X-ray dose similarly resulted in the survivors expressing resistance to vincristine and to etoposide and overexpressing Pgp. In agreement with data obtained on cells which received repeated X-ray exposures, this Pgp overexpression occurred in the absence of any significant elevation of Pgp mRNA. However, the reduced ability to accumulate rhodamine 123 identified in these sublines, and the ability of verapamil to reverse this accumulation defect, implies that the Pgp which was overexpressed was functional. These findings indicate that a series of X-ray exposures is not necessary for expression of this distinctive multiple drug resistance phenotype, suggesting that this results not from a general 'stress-type' response but rather more specifically from the radiation exposure itself, with both single-dose and repeated X-irradiation selecting for similar genetic mutants.