Resistance to chemotherapy of human cancers has been studied by establishing in vitro and in vivo genetic systems which mimic development of drug resistance. A major mechanism of multidrug resistance in human cancer is expression of the MDR1 gene which we have cloned and sequenced. Expression of the MDR1 gene carried by retroviral vectors can be used to transduce cells to multidrug resistance and has been used to confer resistance to mouse bone marrow cells in vitro and in vivo. Mechanistic studies on P-glycoprotein suggest that it is involved in removing drug directly from the plasma membrane. To study mechanism, we have generated many mutants and initiated biochemical studies including the purification of P-glycoprotein and reconstruction of drug-dependent ATPase activity in artificial liposomes.
