Expression of the mdr-1/P-170 gene in patients with acute lymphoblastic leukemia

Abstract

Increased expression of the multidrug resistance gene (mdr-1/P-170) and the dihydrofolate reductase (DHFR) gene have been implicated in the development of in vitro drug resistance. Overexpression, with or without gene amplification, is seen in the development of drug resistance in culture and it has been postulated that genetic modulation of mdr-1/P-170 and DHFR may also be involved in the development of clinical drug resistance. We screened lymphoblasts from 28 patients with acute lymphoblastic leukemia (ALL) for evidence of overexpression of mdr-1/P-170 using RNAse protection, RNA in situ hybridization and immunohistochemistry. Overexpression of mdr-1/P-170 without gene amplification was detected in samples from four patients (three after multiple relapses, one at presentation). Overexpression of mdr-1/P-170 was heterogeneous within the population of malignant lymphoblasts as demonstrated by RNA in situ hybridization, immunohistochemistry, and drug uptake using daunomycin autofluorescence analysis. There was no evidence of overexpression of DHFR in any of the eight patient samples tested by RNAse protection nor was there any evidence of gene amplification in 11 patient samples on Southern blot analysis. From these observations it appears that overexpression without gene amplification of mdr-1/P-170 may be one mechanism of clinical drug resistance in ALL.

P‐glycoprotein and BCL‐2 levels predict outcome in adult acute lymphoblastic leukaemia

“…Several studies have investigated the expression of the multiple drug resistance 1 (MDR1) gene in leukaemic cells from acute lymphoblastic leukaemia (ALL) patients, either by using different probes (Rothenberg et al , 1989) or by studying the increase in MDR‐1 mRNA and the over‐expression of P‐glycoprotein (PGP) (Marie et al , 1991), in an attempt to demonstrate a correlation with treatment response or patient follow‐up. Although in acute myeloid leukaemia (AML) the prognostic role of PGP has been clearly established (Campos et al , 1992; Del Poeta et al , 1996), the role of PGP in ALL drug resistance is still currently debated (Goasguen et al , 1996; Nussler et al , 1996; Dhooge et al , 1999; Kanerva et al, 2001).…”

Flow cytometric determination of the multidrug‐resistant phenotype in acute leukemia

“…The in vitro systems mentioned above are useful models for understanding how cell lines become drug resistant, but it is logical to ask whether the in vitro models are clinically relevant. Several studies have investigated P-glycoprotein expression in acute leukemia using a number of different methods (6,17,24,25,28,(34)(35)(36)39). The results from these trials have been somewhat variable.…”

Increased intracellular concentrations of doxorubicin in resistant lymphoma cells in vivo by concomitant therapy with verapamil and cyclosporin A

“…High expression of P 170 or mRNA for the mdrl gene, which codes for P 170, has been shown for untreated both solid and hematological tumors (21) and in childhood sarcoma this was strongly correlated to poor prognosis (22). Increased expression of P 170 as the disease progresses from drug responsive to resistant has been shown in a few patients (23,24,25). Clinical trials using verapamil or cyclosporins to improve drug sensitivity are few and inconclusive.…”