Clinical impact of multidrug resistance in acute leukemia.

The phenomenon of multi-drug resistance is well-described in the experimental literature and can be produced in in vitro cell cultures of leukemic cells. The classic approach to the induction of drug resistance is by the growth of leukemic cells in increasing concentrations of the agent to which resistance develops. The most likely species of drugs to induce resistance is the group known as natural products, those derived from plants and bacteria. Important to the treatment of leukemia is the development of resistance to anthracyclines and to the vinca alkaloids and epipodophyllotoxins, all natural products. P-glycoprotein has been identified as the most ubiquitous mediator of resistance. This protein forms a transmembrane pump which reduces the concentration of natural products within the cell by increasing drug efflux, an active, energy-requiring pumping mechanism [1–3]. P-glycoprotein, Pgp, is also found in the membrane of normal tissues with major excretory functions, such as bowel and kidney [4]. However, its presence in the membrane of leukemic blasts is key to the extrusion of natural products such as the anthracyclines, and this has been studied extensively in in vitro systems [1–5]. In addition, numerous clinical correlative trials have been reported in which expression and function of P-glycoprotein have been evaluated as a possible prognostic factor in terms of remission and survival [6–13]. There appears to be considerable consensus that the demonstration in de novo leukemia of increased Pgp function confers a poorer prognosis in terms of achieving remission, but the degree of independence of this expression as a prognostic factor continues to be debated [6,8–11,14]. This has also led to experimental studies designed to inhibit or reverse the function of the efflux pump. Several agents have been identified which in the laboratory have the capability of inhibiting the effectiveness of the efflux pump and thus promoting increased anthracycline concentration within the cells [15,16]. This has led to clinical trials of Pgp modulating agents, such as cyclosporine and PSC 833, administered with either daunorubicin or mitoxantrone plus other induction agents in poor risk patients in an attempt to overcome drug resistance. Despite some evidence of improved retention of the anthracycline or anthraquinone within the leukemic cells by use of this combination approach with reversal agents [17,18], the clinical outcome has not been improved [18–21]. During efforts to better understand mechanisms of drug resistance, other proteins which mediate resistance have been identified and are being evaluated for their impact on in vitro and in vivo resistance. Three of these being studied in acute leukemia are major vault transporter protein/lung-resistance protein (LRP), MDR-related protein (MRP) and breast cancer resistance protein (BCRP). Of importance to leukemia treatment, all of these proteins reduce the retention of anthracyclines in malignant cells. MRP mediates resistance to numerous natural products [4]. It has also been shown to limit anthracycline accumulation and produce resistance in the absence of Pgp [22]. LRP also appears to evolve in cells which lose their expression of P-glycoprotein, but which maintain their resistance phenotype [4]. BCRP was initially demonstrated in the membrane of cells from solid tumors and mediates resistance to natural products such as mitoxantrone, topotecan and doxorubicin [23,24]. However, Ross et al. have also demonstrated the presence of this protein in the membrane of up to 30% of leukemic blasts [22,25]. The expression of this protein was associated with reduced accumulation of daunorubicin in leukemic blasts [26]. * Corresponding author. Tel.: +1-718-920-1100; fax: +1-718-9201123. E-mail address: jpd4401@aol.com (J.P. Dutcher).