Multidrug resistance of acute leukemia and a strategy to overcome it.

Abstract

A representative cause of multidrug resistance (MDR) is expression of the MDR gene (mdr1) and its product P-glycoprotein (P-gp). The function of P-gp is thought to be the extrusion of anticancer drugs from the cell against a concentration gradient. In acute myelogenous leukemia (AML), P-gp expression in leukemic blast cells at initial presentation has been reported to be 20% to 40%. The remission rate of acute leukemia patients is significantly lower in P-gp+ patients than in P-gp- patients. A significantly shorter survival and relapse-free survival in P-gp+ AML patients compared with P-gp- patients has been reported. Intracellular daunorubicin/Rhodamine123 content in P-gp+ leukemic blast cells is significantly lower than in P-gp- leukemic blast cells. By using a leukemic blast colony assay, lowered sensitivity to the anticancer drug was revealed not only in leukemic blast cells but also in leukemic progenitors. One method to overcome MDR with a possibility of clinical application is to use drugs that interfere with the function of P-gp. The addition of MS-209 in vitro as an MDR-reversing agent significantly enhanced the intracellular daunorubicin/Rhodamine 123 accumulation and the retention of P-gp+ leukemic blast cells to a level similar to that of P-gp- blast cells. Recent clinical trials using MDR-reversing agents have demonstrated some encouraging results in P-gp+ patients but not in P-gp- patients.

• Authors: T Motoji, S Motomura, Y H Wang
• Journal: International journal of hematology (Int J Hematol) Vol. 72 Issue 4 Pg. 418-24 (Dec 2000) ISSN: 0925-5710 [Print] Japan
• PMID: 11197207 (Publication Type: Journal Article, Review)

Chemical References

• ATP Binding Cassette Transporter, Subfamily B, Member 1

Topics

• ATP Binding Cassette Transporter, Subfamily B, Member 1 (antagonists & inhibitors, genetics, metabolism)
• Clinical Trials as Topic
• Drug Resistance, Multiple (genetics)
• Drug Resistance, Neoplasm (genetics)
• Genetic Therapy
• Humans
• Leukemia, Myeloid, Acute (drug therapy, therapy)