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Blood, Vol. 94 No. 3 (August 1), 1999:
pp. 1046-1056
Simultaneous Activity of MRP1 and Pgp Is Correlated With In Vitro
Resistance to Daunorubicin and With In Vivo Resistance in Adult Acute
Myeloid Leukemia
Ollivier Legrand,
Ghislaine Simonin,
Anne Beauchamp-Nicoud,
Robert Zittoun, and
Jean-Pierre Marie
From Université Paris 6, Formation de Recherche Claude Bernard,
E 9912 INSERM, and Service d'Hématologie, Hôpital
Hôtel-Dieu, Paris, France.
In adult acute myeloid leukemia (AML), the weight of the
contribution of the combined activity of Pgp and MRP1 to drug
resistance is not known. To address this question, we compared the
activity of these proteins to the in vitro resistance to daunorubicin
(DNR), etoposide, and cytosine arabinoside (Ara-C), using the
calcein-AM uptake and the 3-[4, 5-di-methyl-thiazol-2, 5-diphenyl]
tetrazolium bromide (MTT) assay in 80 adult AML patients. We found no
correlation or only a weak correlation between the in vitro drug
resistance to DNR and etoposide and MRP1 or Pgp expression or function
when tested separately. However, a strong correlation was observed between the simultaneous activity of MRP1 and Pgp (quantified as the
modulation of calcein-AM uptake by cyclosporin A and probenecid) and
the LC50 of DNR (r = .77, P < .0001). This
emphasized the role of these two proteins, not separately, but together
in the resistance to DNR. In contrast, Mvp/LRP expression did not
correlate with the LC50 of DNR. A high level of simultaneous activity
of Pgp and MRP1 was predictive of a poor treatment outcome (for
achievement of CR [P = .008], duration of relapse-free
survival [RFS; P = .01], and duration of
overall survival [OS; P = .02]). In addition, high LC50 of DNR and high LC50 of etoposide together were also predictive of a poor treatment outcome (for duration of RFS [P = .02] and duration of OS [P = .02]). The
unfavorable cytogenetic category was more closely associated with the
combined activity of both MRP1 and Pgp (P = .002) than with
the activity of Pgp or MRP1 separately. This could explain the poor
prognosis and the in vitro resistance to daunorubicin in this group of
patients. These data suggest that treatment outcome may be improved
when cellular DNR and etoposide resistance can be circumvented or
modulated. Modulation of not only Pgp but also MRP1 could be essential
to attain this aim in adult AML.
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