MULTIFACTORIAL DRUG-RESISTANCE PHENOMENON IN ACUTE LEUKEMIAS - IMPACTOF 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 a ctivated different resistance phenomena. Four phenomena were studied a t the time of diagnosis in a series of 35 lymphoblastic and 25 myelobl astic acute (de novo) leukemias, by an immunocytochemical method. Two energetic drug transport processes were investigated: the classical MD R/P170 and the P110/LRP56 proteins, and two physiological detoxifying activities such as the glutathione transferases (GST alpha, mu, pi) an d the metallothioneins (Mts). The results demonstrate that these pheno mena are independent but their synergic activity can increase their im pact on the outcome. P110/LRP56 positive cases demonstrated 48.8% comp lete remission (CR) rate compared to 71.4% for negative tests. When P1 70 and P110 were both positive or negative, the CR rates were 27.3% an d 81.8% respectively (p = 0.0120), and survival curves were also diffe rent (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 reac tions. Survival curves for these two groups were different. The CR rat e 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 po sitive and Mts negative compared to 100% for P170 negative and Mts pos itive (p = 0.038) patients. Survival curves were also different (p = 0 .0510). We conclude that these four mechanisms induce an independent d rug 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.