CHAPTER 18 – SOLVING THE PROBLEM OF MULTIDRUG RESISTANCE: ABC TRANSPORTERS IN CLINICAL ONCOLOGY

摘要: Acquired drug resistance was first observed in a laboratory model 1950, mouse leukemic cells passaged mice treated with 4-amino- N 10 -methyl-pteroylglutamic acid. Daunorubicin-selected resistant tumor were found to have energy-dependent transport of daunorubicin that could be inhibited by vinblastine, vincristine, and other anthracyclines. Further, selection for vinblastine resulted the same phenotype. Tumor cell lines selected doxorubicin or vincristine became cross-resistant structurally unrelated anticancer agents, displayed active outward efflux, characterized increased expression 170 kDa membrane glycoprotein known as P170 P-glycoprotein. As critical this discovery human ATP-binding cassette (ABC) transporter was, it observation reversed vitro several different compounds, including verapamil brought Pgp into prominence potential target improving cancer therapy. This chapter begins reviewing mammalian ABC transporters linked multidrug resistance. It also reviews progress has been made developing clinical targets