INDUCTION OF PGP3 EXPRESSION AND REVERSION OF THE MULTIDRUG-RESISTANCE PHENOTYPE IN 9-OH-ELLIPTICINE-RESISTANT CHINESE-HAMSTER LUNG FIBROBLASTS TRANSFECTED WITH THE MYC ONCOGENE

Chinese hamster lung cells resistant to the DNA topoisomerase II inhib itor 9-OH-ellipticine (DC-3F/9-OH-E) are cross resistant to various dr ugs through the expression of the MDR phenotype. The myc oncogene was approximately 10-fold amplified and 20-fold overexpressed in parental DC-3F cells as compared with DC-3F/9-HO-E cells. Transfection of the r esistant cells with a mouse c-myc gene did not alter the resistance to topoisomerase II inhibitors and, in cells with a low multidrug (MDR) expression, reversed this phenotype. Northern and Western blot analyse s revealed an increased expression of pgp1 in the DC-3F/9-OH-F cells, which was not modified in the myc-transfected clones. However, myc exp ression in these clones resulted in an increased expression of pgp3, r oughly in proportion to the level of myc expression. Transfection of t he DC-3F/9-OH-E cells with the human MDR3 gene, homologous to pgp3, al so resulted in the reversion of the MDR phenotype. These results show that (1) expression of the transfected myc gene positively regulates p gp3 expression but has no effect on pgp1; (2) when observed, reversion of the MDR phenotype is proportional to the levels of myc and pgp3 ex pression; and (3) this reversion, resulting from pgp3 expression, is a ssociated with a decreased functional activity of the pgp1 protein and might require an appropriate balance of pgp1 and pgp3 expression. Cop yright (C) 1996 Elsevier Science Inc.