Reversal effect of itraconazole on adriamycin and etoposide resistance in human leukemia cells.
Itraconazole is a triazole antifungal agent that inhibits cell membrane serol biosynthesis. Currently, itraconazole is a potent candidate for in vivo use to revert multidrug resistance in acute leukemias, with the added benefit of its antifungal effect. As previously reported, itraconazole, as well as verapamil, reversed adriamycin-resistant K562 cells (K562/ADR) and HL60 cells (HL60/ADR) in dosages compatible to the plasma levels achieved by the therapeutic dosages used for the treatment of fungal infections. By RT-PCR analysis of mdr1, mdr3, and mrp mRNA, these adriamycin-resistant cells showed a higher expression of the transcript of these genes than those of the parent cells. By FACS analysis, both the adriamycin-resistant cells showed a higher expression of P-glycoprotein on their cell surfaces. These results suggested the involvement of itraconazole in the mdr gene and/or mrp gene product-associated resistance. Furthermore, itraconazole partially reversed etoposide resistance in both the K562 and K562/ADR cells. The present study suggests that itraconazole may reverse multidrug resistance, at least in part, via a classical MDR-associated mechanism.
Kurosawa
M
M
Third Department of Internal Medicine, Hokkaido University School of Medicine, Sapporo, Japan.
Okabe
M
M
Hara
N
N
Kawamura
K
K
Suzuki
S
S
Sakurada
K
K
Asaka
M
M
D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D000935:Antifungal Agents / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D004317:Doxorubicin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005047:Etoposide / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D017964:Itraconazole / Q000494:pharmacology*; D007938:Leukemia / Q000235:genetics* / Q000378:metabolism; D014407:Tumor Cells, Cultured
D000903:Antibiotics, Antineoplastic; D000935:Antifungal Agents; D000972:Antineoplastic Agents, Phytogenic; D017964:Itraconazole; D005047:Etoposide; D004317:Doxorubicin