Evidence of post-translational regulation of P-glycoprotein associated with the expression of a distinctive multiple drug-resistant phenotype in Chinese hamster ovary cells.

Chinese hamster ovary (CHO) cells following exposure to fractionated X-irradiation in vitro dominantly expressed a distinctive multiple drug-resistant phenotype, characterised by resistance to vinca alkaloids, epipodophyllotoxins and colchicine, but not to anthracyclines, together with overexpression of P-glycoprotein (Pgp), but without any concomitant elevation in Pgp mRNA (J Natl Cancer Inst 1990, 82, 607-612; 1992, 85, 48-53). To investigate the mechanism of this Pgp overexpression, Pgp stability ws examined in an X-irradiation pretreated subline and compared with that of two colchicine-selected drug-resistant CHO sublines. These studies revealed a slower turnover of Pgp in the X-irradiated cells (T1/2 > or = 40 h) relative to the drug-selected sublines (T1/2 = 17 h), indicating that Pgp overexpression appears to be differently regulated in these independently-derived resistant sublines. These data add support to our proposal that the development of drug resistance following X-irradiation may arise by a mechanism distinct from that operating after drug selection.