Abstract
Multidrug resistance (MDR) contributes to treatment failure in several hematologic malignancies, including acute myeloid leukemia (AML), multiple myeloma (MM) and non-Hodgkin’s lymphoma (NHL). This is particularly relevant with the anthracyclines (doxorubicin, daunorubicin, epirubicin), vinca alkaloids (vincristine, vinblastine), epipodophyllins (etoposide, teniposide), taxanes (paclitaxel, docetaxel), topotecan and amsacrine. The MDR phenotype of cells results in a pleiotropic drug resistance that leads to development of refractory disease. Classic mechanisms of MDR include drug efflux pumps, glutathione-transferase upregulation, topoisomerase II-associated MDR and, as recently observed, extracellular matrix-mediated MDR [1]. Principally, MDR is associated with overexpression of P-glycoprotein (Pgp or MDR1), an integral membrane protein, that belongs to a superfamily of ATP-binding cassette (ABC) transporters, encoded by the mdr1 gene located on chromosome 7 and acting on a wide range of substrates that are large hydrophobic and amphipatic molecules [2]. Substrates of Pgp are compounds such as rhodamine 123 and calcein-acetoxymethyl ester (calcein-AM) commonly used with monoclonal antibodies, for functional and expression analysis. Overexpression of this 170 kDa protein, often developed after exposure to cytotoxic agents, is associated with cross-resistance to a wide range of compounds and consequently with a resistant disease. Besides its role in cancer resistance, Pgp seems to have multiple physiological functions, since it is also expressed in many non-tumoral tissues including epithelial cells of gastrointestinal tract, adrenal gland, biliary canaliculi [3,4] and brain capillaries [5]. It is possible that tumors derived from these tissues present higher levels of Pgp expression and a stronger resistance to chemotherapeutic agents.
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