Modulation of Multidrug Resistance in Acute Myeloid Leukemia

Abstract

Over the past decade, delineation of the prognostic relevance of P-Glycoprotein (Pgp) provided convincing evidence that expression of this multidrug transporter contributes to anthracycline resistance in AML. Trials testing competitive inhibitors of the export protein showed that such clinical strategies possess sufficient activity to eliminate MDRI expressing clones, and fostered phase III trials and the development of modulators with greater potency and Pgp affinity. Randomized trials in adult and pediatric AML have shown major improvement in treatment outcome with cyclosporin-A (CsA), whereas similar studies using the second generation cyclosporin-D analogue, PSC-833, are negative. Two randomized trials tested the benefit of CsA inhibition of Pgp in adult patients with highrisk AML. The Medical Research Council (MRC) trial evaluated the addition of CsA to standard- and timed-sequential ADE induction (araC, daunorubicin [DNR], and etoposide), however, patients received a modulator dosage (5 mg/kg/day) insufficient for Pgp blockade. In the Southwest Oncology Group (SWOG) 9126 trial, participants assigned to treatment with CsA received 16mg/kg/day, yielding blood concentrations sufficient for reversal of anthracycline resistance in a biological assay. Patients received sequential treatment with high dose ara-C and infusional DNR, with or without CsA during induction and consolidation. Addition of CsA significantly reduced the frequency of induction resistance (47% vs. 31%; p=0.0077) and improved the rate of CR (33% vs. 40%; p=0.14), without altering induction mortality. Two-year relapse-free (RFS 37% vs 5%; p=0.035) and overall survival (OS 22% vs 12% p=0.046) was significantly improved in CsA-treated patients. Importantly, median survival in patients with Pgp⁺ leukemia increased in 3-fold with CsA treatment (12 months vs. 4 months). CsA delayed excretion of bilirubin and increased the steady state blood concentrations of DNR and DNR-ol. Althou>gh CR rate increased and induction resistance decreased with increasing steady state (SS) DNR serum concentration in the CsA cohort, a similar relationship was not apparent in the control group. An analogous relationship was observed between SS-DNR concentration and RFS and OS, supporting a targeted interaction by CsA to enhance anthracycline sensitivity. The SWOG study has important implications for anthracycline pharmaco-therapy in AML. SS DNR concentration may be a critical determinant of treatment outcome when administered with a cell defense inhibitor such as CsA, whereas in its absence, greater systemic DNR exposure may increase non-hematologic toxicities. The success of CsA and failure of the more specific Pgp antagonist, PSC 833, suggests that CsA targets biological targets in addition to Pgp that are essential to cell defense. Recognition that the phenomenon of multidrug resistance (MDR) arises from the interaction of numerous cellular events, indicates that successful MDR modulation requires interruption of redundant mechanisms of leukemia cell defense.

Over the past two decades a great deal of information has emerged as to how malignant cells survive toxic insults and become resistant to antineoplastics. Anthracycline resistance in particular, may arise from the actions of one or more membrane transport proteins that promote the transmembrane export of xenobiotics, reduce intracellular drug accumulation, and thereby limit nuclear drug exposure. The best characterized of these proteins is P-glycoprotein (Pgp), a 170kd adenosine triphosphate (ATP)-dependent multispecific drug transporter (List 1996). The MDR-1 gene, which encodes Pgp, is a member of a family of over 70 genes, termed the ATP-Binding Cassette transporter gene superfamily. These genes share a signature DNA coding sequence, which encodes an ATP-binding domain necessary for the transport function of these proteins. Recent investigations have shown that the substrate specificity of Pgp is more sophisticated than previously realized, and that this transporter contributes to cellular resistance to cancer therappy in at least two ways;

• 1. active drug extrusion, and

• 2. increased apoptotic threshold.

From the Blood and Marrow Transplant Program; Section of Hematology/Oncology, Department of Internal Medicine