Multidrug resistance of acute leukemia and a strategy to overcome it

A representative cause of multidrug resistance (MDR) is expression of the M DR gene (mdr1) and its product P-glycoprotein (P-gp). The function of P-gp is thought to be the extrusion of anticancer drugs from the cell against a concentration gradient. In acute myelogenous leukemia (AML), P-gp expressio n in leukemic blast cells at initial presentation has been reported to be 2 0% to 40%. The remission rate of acute leukemia patients is significantly l ower in P-gp(+) patients than in P-gp(-) patients. A significantly shorter survival and relapse free survival in P-gp(+) AML patients compared with P- gp- patients has been reported. Intracellular daunorubicin/Rhodamine 123 co ntent in P-gp(+) leukemic blast cells is significantly lower than in P-gp(- ) leukemic blast cells. By using a leukemic blast colony assay, lowered sen sitivity to the anticancer drug was revealed not only in leukemic blast cel ls but also in leukemic progenitors. One method to overcome MDR with a poss ibility of clinical application is to use drugs that interfere with the fun ction of P-gp. The addition of MS-209 in vitro as an MDR-reversing agent si gnificantly enhanced the intracellular daunorubicin/Rhodamine 123 accumulat ion and the retention of P-gp(+) leukemic blast cells to a level similar to that of P-gp(+) blast cells. Recent clinical trials using MDR-reversing ag ents have demonstrated some encouraging results in P-gp(+) patients but not in P-gp(-) patients. Int J Hematol. 2000;72:413-424. (C)2000 The Japanese Society of Hematology.