Multifactorial drug-resistance phenomenon in acute leukemias: impact of P170-MDR1, LRP56 protein, glutathione-transferases and metallothionein systems on clinical outcome.

The multidrug resistance phenomenon can be observed in cases which do not express the P170 protein and these cases are suspected as having activated different resistance phenomena. Four phenomena were studied at the time of diagnosis in a series of 35 lymphoblastic and 25 myeloblastic acute (de novo) leukemias, by an immunocytochemical method. Two energetic drug transport processes were investigated: the classical MDR/P170 and the P110/LRP56 proteins, and two physiological detoxifying activities such as the glutathione transferases (GST alpha, mu, pi) and the metallothioneins (Mts). The results demonstrate that these phenomena are independent but their synergic activity can increase their impact on the outcome. P110/LRP56 positive cases demonstrated 48.8% complete remission (CR) rate compared to 71.4% for negative tests. When P170 and P110 were both positive or negative, the CR rates were 27.3% and 81.8% respectively (p = 0.0120), and survival curves were also different (p = 0.030). The CR rate in AML or ALL is weakly affected by GST pi, alpha or mu but relapses are more frequently observed for Positive-GST pi ALL (p = 0.0658). Patients with both P170 and GST pi positive reactions had a 53.3% CR rate compared to 78.9% for both negative reactions. Survival curves for these two groups were different. The CR rate in AMl was 100% for Mts positive and 43.7% for negative cases (p = 0.050), however the median survival was totally different for these two groups (p = 0.046). CR rates were 26.6% for patients who were P170 positive and Mts negative compared to 100% for P170 negative and Mts positive (p = 0.038) patients. Survival curves were also different (p = 0.0510). We conclude that these four mechanisms induce an independent drug resistance but their synergic action increase their impact on the outcome. The metallothioneins seem to have a major impact on the drug resistance phenomenon and its effect should be investigated with high priority, in the light of these results.

Expression of the multidrug resistance-associated P-glycoprotein (P-170) in 59 cases of de novo acute lymphoblastic leukemia: prognostic implications.

Immunocytochemical detection of the multidrug resistance (MDR)-associated membrane protein (P-170) was performed at time of diagnosis in a series of 36 children and 23 adults with acute lymphoblastic leukemia (ALL) using two monoclonal antibodies JSB1 and C219. Immunophenotypes were obtained in all cases and karyotypes were analyzed in 37 cases. Detection with JSB1 or with C219 led to similar results in terms of positive cells and cases, but the intensity of staining was higher with JSB1. In the populations studied, the rate of first complete remission differed between MDR-positive and MDR-negative in adult patients only (56% v 93%, respectively, P = .05). Of the 16 MDR-positive patients who had presented a first complete remission, 13 (81%) relapsed, compared with 13 of 35 (37%) MDR-negative (P = .008) patients. A higher rate of relapse among MDR-positive compared with MDR-negative patients was observed in adults and in children taken separately (adults 100% v 46%; children 73% v 32%, respectively). The survival rates (Kaplan-Meier method) were significantly higher in MDR-negative compared with MDR-positive populations as a whole (P = .002) and among children (P = .05) and adults (P = .03) taken separately. Event-free survival curves followed this trend. The percentage of second complete remission was very low in the MDR-positive group (15%) compared with 38% for the MDR-negative group. These results were shown by multivariate analysis to be independent of age, immunophenotypes, and karyotypes and clearly show the importance of MDR phenotype detection in ALL.