CHROMOSOME MEDIATED GENE-TRANSFER OF DRUG-RESISTANCE TO MITOXANTRONE

The anthracenedione, mitoxantrone, frequently selects for a unique dru g resistance phenotype that is not mediated by either MDR 1, MRP, or a ltered DNA topoisomerase II. In this study, we demonstrate that mitoxa ntrone resistance is likely to be multifactorial with at least one res istance mechanism being the result of a dominant genetic event. This f inding was demonstrated by conducting chromosome transfer experiments from human breast cancer cell lines that were either sensitive (MCF7/S ) or resistant to mitoxanthrone (MCF7/Mitox). Chromosomes transferred from MCF7/Mitox cells into CHO-K1 cells resulted in the isolation of m ultiple clones resistant to mitoxantrone. In contrast, chromosomes tra nsferred from the drug sensitive MCF7/S, parent cell line did not conf er drug resistance in the rodent CHO-K1 recipient cell line. Both Alu- PCR analysis and Southern blot analysis demonstrated human DNA in the CHO-KI cells receiving chromosomes from the MCF7/Mitox cells. Unlike t he MCF7/Mitox cell line, the drug resistant, CHO-K1 chromosome transfe rrent clones did not have a decrease in total drug accumulation. We co nclude that chromosome transfer from the MCF7/Mitox cell line into CHO -K1 cells, confers a non-transport mediated mechanism of drug resistan ce that is a dominant genetic event. These studies provide evidence of the genetic multifactorial nature of multidrug resistance in cells se lected with mitoxantrone in vitro.