Multidrug Resistance in Leukemias and its Reversal

Abstract

Drug resistance often results in failure of anticancer chemotherapy in leukemias. Several mechanisms of drug resistance are known with multidrug resistance (MDR) being the best characterized one. MDR can be due to enhanced expression of certain genes (MDR1, MRP or LRP), alterations in glutathione-S-transferase activity or GSH levels and to reduction of the amount or the activity of topoisomerase II. Here we review the current status of the clinical significance of the various mechanisms of MDR in leukemias and also discuss possibilities for the reversal of MDR. MDR1 gene expression has been seen in many leukemias, notably in acute myeloid leukemia (AML) and blast crisis of chronic myeloid leukemia. Both MDR1 RNA and P-glycoprotein expression of the leukemic cells have been shown to correlate with poor clinical outcome in AML. However, preliminary results indicate that the MRP gene as well as the LRP gene can be expressed in AML. Thus, drug resistance in leukemias appears to be multifactorial. P-glycoprotein-mediated MDR can be reversed by several drugs. These resistance modifiers are currently evaluated with regard to their clinical efficacy. Despite some encouraging results, reversal of drug resistance and subsequent improvement in clinical outcome remains to be shown.

Diallyl trisulfide reverses drug resistance and lowers the ratio of CD133+ cells in conjunction with methotrexate in a human osteosarcoma drug-resistant cell subline

“…Overexpression of P-gp is the most common reason for cross-resistance and MDR. The expression of P-gp has been linked to the development of MDR in human cancer, particularly in leukemia, multiple myeloma, neuroblastoma, soft tissue sarcoma and osteosarcoma (1,2).…”

Anti-leukemic activity of Lintuzumab (SGN-33) in preclinical models of acute myeloid leukemia

“…1,4 MDR may also emerge following unsuccessful chemotherapy in recurrent AML. [6][7][8] CD33, a myeloid lineage-specific antigen, is a sialoadhesin family member normally expressed on precursor myeloid cells and most monocytic cells, 9 and constitutes an important drug target on AML. 10,11 Patients with relapsed disease can be treated with the only approved anti-CD33 drug conjugate, gemtuzumab ozogamicin (Mylotarg ® ), yielding an overall response rate of ~30%.…”

Reversal of anticancer multidrug resistance by the ardeemins

“…Although the etiology of MDR is multifactorial, the overexpression of P-glycoprotein (Pgp), a membrane protein that mediates the transport of MDR drugs, remains the most common alteration underlying MDR in laboratory models (2). Moreover, expression of Pgp has been linked to the development of MDR in human cancer, particularly in the leukemias, lymphomas, multiple myeloma, neuroblastoma, and soft tissue sarcoma (3)(4)(5)(6)(7). Recent studies showed that tumor cells expressing MDR-associated protein (MRP) (8) and lung resistance protein (LRP) (9) and mutation of DNA topoisomerase II (10) also may render MDR.…”