Sensitivity of K562 human chronic myelogenous leukemia blast cells transfected with a human multidrug resistance cDNA to cytotoxic drugs and differentiating agents.
The blast crisis of chronic myelogenous leukemia (CML) is refractory to most forms of cancer chemotherapy, but may be amenable to drugs that differentiate rather than kill leukemic cells. One mechanism implicated in resistance to cytodestructive drugs is overexpression of P-glycoprotein, the MDR1 gene product. While several classes of drugs sensitize multidrug-resistant (MDR) cells by interfering with the function of P-glycoprotein in vitro, few sensitizers have been effective in vivo. We have developed a preclinical model of MDR/CML uncomplicated by other mechanisms of drug resistance to evaluate the effects of MDR1 overexpression on cytodestructive and differentiation therapy and the ability of sensitizers to restore chemosensitivity in this disease. The CML-derived cell line K562 was transfected with a human MDR1 cDNA from the pHaMDR1/A expression vector and selected with vinblastine. Resistant K562 clones were 20-30-fold resistant to vinblastine, were cross-resistant to doxorubicin and etoposide, and remained sensitive to cytosine arabinoside, 6-thioguanine, hydroxyurea, and mechlorethamine. Resistance was associated with decreased cellular accumulation of cytotoxic drug and was reversed by cyclosporin A and trans-flupenthixol. The MDR phenotype did not adversely affect the ability of K562 cells to produce fetal hemoglobin in response to hemin, and was associated with increased responsiveness of cells to differentiate with cytosine arabinoside. Upon differentiation, the resistant clones increased MDR1 mRNA and P-glycoprotein. These studies suggest that the overexpression of the MDR1 gene in CML may not adversely affect the ability to undergo erythroid differentiation and that these resistant K562 cell lines are good models for studying drug resistance mediated by P-glycoprotein in CML.
Hait
W N
WN
Yale University School of Medicine, Department of Medicine, New Haven, Connecticut 06510.
Choudhury
S
S
Srimatkandada
S
S
Murren
J R
JR
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015139:Blotting, Southern; D002454:Cell Differentiation / Q000187:drug effects; D016572:Cyclosporine / Q000494:pharmacology*; D003561:Cytarabine / Q000494:pharmacology; D004247:DNA / Q000235:genetics / Q000302:isolation & purification; D004351:Drug Resistance / Q000235:genetics*; D005475:Flupenthixol / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D006427:Hemin / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive; D008562:Membrane Glycoproteins / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured; D014747:Vinblastine / Q000494:pharmacology*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D003561:Cytarabine; D014747:Vinblastine; D006427:Hemin; D016572:Cyclosporine; D004247:DNA; D005475:Flupenthixol