Five putative drug resistance parameters (MDR1/P-glycoprotein, MDR-associated protein, glutathione-S-transferase, bcl-2 and topoisomerase IIalpha) in 57 newly diagnosed acute myeloid leukaemias. Swiss Group for Clinical Cancer Research (SAKK).
Using a modified quantitative reverse transcriptase (RT) PCR assay in 57 patients with acute myeloid leukaemia (AML) from a Swiss Phase III multicentre study (SAKK 30/85), we measured the m-RNA expression of the genes from the multidrug resistance gene 1 (MDR1), the multidrug resistance associated protein (MRP), glutathione-S-transferase (GST) pi, bcl-2 and topoisomerase (topo) IIalpha. P-glycoprotein (p-gp) was measured by Western blot, and GST activity by functional assays. To analyse progression-free (PFS) and overall survival (OS), parameters were prospectively divided into "low" and "high" groups, according to their median values (exceptions: MDR1 and p-gp). Median follow-up was 60 months.


RESULTS
MDR1- and MRP mRNA levels correlated with each other (r=0.54, Spearman), FABM4/M5 and extramedullary disease. "Low" bcl-2-mRNA predicted longer PFS: 22 months vs. 7 months (median,p=0.02, log rank), and longer OS: 64 months vs. 14 months (p=0.06). "Low" topo IIalpha predicted poorer outcome: median PFS 9 vs. 19 months (p=0.03); median survival 12 months vs. "not reached" (p=0.03). An improved outcome tendency, albeit nonsignificant, was seen in p-gp-negative patients. In a Cox model adjusted for age, performance status, presence of Auer rods, FAB type and clinical response, bcl-2 and topo IIalpha mRNA levels retained their predictive values.
Lohri
A
A
Department of Research, University Clinic, Basel, Switzerland.
van Hille
B
B
Bacchi
M
M
Fopp
M
M
Joncourt
F
F
Reuter
J
J
Cerny
T
T
Fey
M F
MF
Herrmann
R
R
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D000208:Acute Disease; D000328:Adult; D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; D004250:DNA Topoisomerases, Type II / Q000235:genetics*; D004268:DNA-Binding Proteins; D018432:Drug Resistance, Multiple / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D019450:Genes, MDR; D005982:Glutathione Transferase / Q000235:genetics*; D006801:Humans; D007527:Isoenzymes / Q000235:genetics*; D007951:Leukemia, Myeloid / Q000188:drug therapy / Q000235:genetics* / Q000503:physiopathology; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics; D011237:Predictive Value of Tests; D011379:Prognosis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; D007527:Isoenzymes; D009363:Neoplasm Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D005982:Glutathione Transferase; D004250:DNA Topoisomerases, Type II