Ketoconazole effectively reverses multidrug resistance in highly resistant KB cells.
The antifungal agent ketoconazole was found to overcome resistance to vinblastine and doxorubicin in multidrug resistant KB-V1 cells in vitro. These cells are several hundred-fold more resistant than the parental cell line KB-3-1. Ketoconazole had little or no effect on the parental KB-3-1 cells. The concentrations used to overcome drug resistance in vitro have already been safely used in vivo for treatment of fungal infections and in the monotherapy of hormone independent prostate carcinomas to block adrenal androgen production. Because of a possible beneficial effect of a combination of ketoconazole and a chemotherapeutic drug in multidrug resistant cancers, we examined a panel of 11 prostate carcinoma tissues for the expression of the MDR1 gene by an RNA-PCR assay. MDR1 expression was detectable, albeit at low levels, in 8 of the 11 tumors, suggesting a possible role of this gene in the drug resistance of prostate carcinomas. Our data suggest that ketoconazole might be useful in overcoming multidrug resistance in concentrations that are achievable in humans.
Siegsmund
M J
MJ
Laboratory of Molecular Biology, DCBDC, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892.
Cardarelli
C
C
Aksentijevich
I
I
Sugimoto
Y
Y
Pastan
I
I
Gottesman
M M
MM
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002352:Carrier Proteins / Q000187:drug effects* / Q000235:genetics; D004317:Doxorubicin / Q000494:pharmacology; D004351:Drug Resistance; D004357:Drug Synergism; D006801:Humans; D007624:KB Cells / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology*; D007654:Ketoconazole / Q000494:pharmacology*; D008297:Male; D008562:Membrane Glycoproteins / Q000187:drug effects* / Q000235:genetics; D011471:Prostatic Neoplasms / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis; D012235:Rhodamines / Q000493:pharmacokinetics; D014747:Vinblastine / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002352:Carrier Proteins; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D012235:Rhodamines; D014747:Vinblastine; D004317:Doxorubicin; D007654:Ketoconazole