A UNIQUE INTERACTION BETWEEN POLYAMINE AND MULTIDRUG-RESISTANCE (BETA-GLYCOPROTEIN) TRANSPORTERS IN CULTURED CHINESE-HAMSTER OVARY CELLS TRANSFECTED WITH MOUSE MDR-1 GENE

We have shown that: a functional link exists between the polyamine tra nsporter and the multi-drug resistance (MDR) efflux transporter (P-gly coprotein, P-gp) in MDR-positive cancer cells: To further explore the nature of this interaction, we have examined the effect of reduced pol yamine transport activity on cellular expression and activity of P-gp acquired by either selection or transection. Chinese hamster ovary (CH O) cells and their polyamine transport-deficient mutants (CHOMGBG) wer e transfected with mouse mdr-1b gene. The activity of P-gp in these ce lls was quantified by measuring cellular accumulation of radiolabeled taxol and etoposide in the presence and absence of the P-gp modulator SDZ PSC-833 (valspodar; a semisynthetic undecapeptide derived from cyc losporin D). The mdr-1b-transfected CHO cells accumulated 2- to 3-fold less taxol and etoposide than.the controls, an accumulation defect re versed by the potent MDR modulator PSC-833. Despite expression of P-gp on the surface of mdr-1b-transfected CHOMGBG cells, this classic MDR phenotype was not observed. Similarly, CHO cells, bur not CHOMGBG cell s, showed MDR activity after selection with doxorubicin as determined by reduced accumulation of radiolabeled taxol. Treatment with 50 mu M of reduced polymer of spermine and glutaraldehyde, a selective blocker of the polyamine transport system, reduced MDR activity in mdr-1-tran sfected CHO cells and restored cellular accumulation of etoposide and taxol to control levels, effects not observed in mdr-1-transfected CHO MGBG cells. Notably, mdr-1-transfected CHO cells were 4- to 16-fold mo re resistant to the cytotoxic effects of the P-gp substrates doxorubic in, taxol, and etoposide than were the mdr-1-transfected CHOMGBG cells . CHO cells transfected with the mdr-1 gene exhibited a 23% reduction in cellular uptake of [C-14]spermidine compared with untransfected con trols; spermidine accumulation in CHOMGBG cells was no different than that in untransfected controls. These data suggest that the existence of a functioning polyamine transport system may be a requirement for M DR transporter activity, while the expression of functioning P-gp appe ars to reduce polyamine transporter activity. (C) 1998 Elsevier Scienc e Inc.