Multidrug Resistance-Associated Protein Gene Mediated Drug Resistance In Acute Leukemias

Multidrug resistance (MDR) is one of the major problems resulting in chemotherapy failure in leukemias. There are three distinct forms of MDR: 1. Classical MDR, characterized by P-glycoprotein (Pgp) overexpression, showing resistance to anthracyclines, anthracendiones, vinca alkaloids, epipodophyllotoxins, homoharringtonine, taxol, and so on. 2. Atypical MDR, resulting from quantitative or qualitative alterations of DNA topoisomerase Ⅱ, and showing a drug resistance spectrum similar to classical MDR except for vinca alkaloids. 3. Non-Pgpmediated MDR, showing the same drug resistance features as classical MDR but no overexpression of Pgp. It has been proved that overexpression of multidrug resistance-associated protein (MRP) gene is responsible for parts of this form of MDR. We investigated MRP gene expression in 54 patients with acute leukemias by semi-quantitative reverse transcription polymerase chain reaction (RT-PCR), and at the same time Pgp expression was also detected in 34 of the 54 patients.The results are as follows:1. Pgp overexpression (Pgp~+ ) was defined as JSB - 1 positive cells≥10%, and MRP overexpression (MRP~+ ) was defined as the ratio of MRP/β2 - microglobulin (β2M)≥1.2. MRP gene expression in acute lymphocytic leukemia (ALL) patients was slightly higher than that in acute nonlymphocytic leukemia (ANLL) patients, the MRP/β2M ratios were 0.047 ~ 2.694, with a median of 0.577 for ALL (n= 11) and 0~4.08,0.337 for ANLL (n = 43), respectively. 32.56% of ANLL and 36.36% of ALL were MRP~+ .3. MRP gene expression showed no difference between previously treated (n = 20, range 0.023~4. 08, median 0.505) and non-treated (n = 34, range 0~ 3.107, median 0.358) leukemia patients, and MRP~+ accounted for 35% and 32.4% in these two groups, respectively.4. Level of MRP in clinical resistant group (n= 12, range 0.036~4.08, median 1.182) was higher than that in complete remission (CR) group (n = 20, range 0. ~ 2. 065, median 0. 217) (P = 0. 0659), MRP~+ accounted for 66.67% and 20%, respectively (P =0.0213).5. None of samples in control group showed MRP~+ (n = 8, range 0 ~ 0.47, median 0).6. MRP gene expression had no relation to FAB subgroups.7. MRP gene expression was significantly different between CD13~+ group and CD13~- group (P = 0. 0029).8. In clinical resistant group, overexpression of Pgp was found in 45.45% of the patients, while in non-resistant group, only in 5.56% (P = 0.0185). There was no correlation between expression of MRP and Pgp(P = 0.6328).9. The criterion for MDR was defined as Pgp~+/MRP~+, and its positive predictive value, negative predictive value, accuracy, sensitivity and specificity were 100%, 88.2%, 90%, 60% and 100%, respectively.