P-glycoprotein and Multidrug Resistance Protein Activities in Relation to Treatment Outcome in Acute Myeloid Leukemia
2000
Despite treatment with intensive chemotherapy, a considerable number of
patients with acute myeloid leukemia (AML) die from their disease due
to the occurrence of resistance. Overexpression of the transporter
proteins P-glycoprotein (P-gp) and multidrug resistance protein (MRP) 1
has been identified as a major cause of cross-resistance to
functionally and structurally unrelated drugs. In the present study,
the functional activity of P-gp and MRP was determined in 104 de
novo AML patients with a flow cytometric assay using rhodamine
123 (Rh123) in combination with PSC833 and carboxyfluorescein (CF) in
combination with MK-571. The results were compared with clinical
outcome and with known prognostic factors. The functional activity of
P-gp and MRP, expressed as Rh123 efflux blocking by PSC833 and CF
efflux blocking by MK-571, demonstrated a great variability in the AML
patients. A strong negative correlation was observed between Rh123
efflux blocking by PSC833 and Rh123 accumulation (r s =−
0.69, P < 0.001) and between CF efflux blocking
by MK-571 and CF accumulation (r s = −0.59,
P < 0.001). A low Rh123 accumulation and a high
Rh123 efflux blocking by PSC833 were associated with a low complete
remission (CR) rate after the first cycle of chemotherapy
( P = 0.008 and P = 0.01,
respectively). Patients with both low Rh123 and CF accumulation
( n = 16) had the lowest CR rate (6%), whereas
patients with both high Rh123 and CF accumulation
( n = 11) had a CR rate of 73%. AML patients with
French-American-British classification M1 or M2 showed a lower Rh123
accumulation than patients with French-American-British classification
M4 or M5 ( P = 0.02). No association was observed
between the multidrug resistance parameters and overall survival of the
AML patients. Risk group was the only predictive parameter for overall
survival ( P = 0.003).
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