Itraconazole and multidrug resistance: Possible effects on remission rate and disease-free survival in acute leukemia

Abstract

Itraconazole, a triazole antifungal agent, has been reported to reverse drug resistance against daunorubicin in acute leukemia. In a subanalysis from a double-blind, placebo-controlled trial examining the effects of itraconazole on the prevention of fungal infections in neutropenic patients, we studied the effects of itraconazole on remission rate and disease-free survival in patients with acute lymphoblastic (ALL) and acute myelogenous leukemia (AML) receiving remission induction treatment schedules containing daunorubicin (DNR). Eleven ALL and 17 AML patients received itraconazole and 12 ALL and 25 AML patients were given placebo. Among AML patients the remission rate was slightly higher in the itraconazole group, whereas the disease-free survival was higher among ALL patients given itraconazole. In AML patients DFS was comparable in both groups but the number of high-risk patients in the itraconazole group was higher. These preliminary results may suggest a role for itraconazole in reversing multidrug resistance. Larger trials, however, are required to substantiate these findings and to correlate them with its in vitro effects on multidrug resistance.

High-Throughput Screening for Daunorubicin-Mediated Drug Resistance Identifies Mometasone Furoate as a Novel ABCB1-Reversal Agent

“…After High-Throughput Screening Identifies ABCB1-Reversal Agents excluding 7 drugs that had no record for safe internal use in humans, and through additional preclinical testing, 4 additional candidates appearing to have unfavorable in vitro therapeutic indices were also removed from consideration, allowing us to further constrain our list of lead candidates to 7 compounds. Because ketoconazole, 16 bepridil, 17 nicardipine, 18 and cyclosporine A 6,19 have been used as ABCB1-reversal agents in the clinical setting for cancer control, we further constrained our list of lead compounds to 3 agents. Interestingly, of the remaining 3 compounds, only mometasone furoate appears to be a novel ABCB1-reversal agent to DNR-mediated drug resistance.…”

Repurposing itraconazole as an anticancer agent

“…Based on preclinical data detailing the reversal of daunorubicin resistance by itraconazole (34), a sub-analysis of itraconazole anticancer activity was conducted in 27 patients with acute lymphoblastic leukemia (35), and itraconazole treatment was likely to be associated with improved disease-free survival (Table II) ) and carboplatin (4 mg/min/ml) in combination with itraconazole (400 mg), following which a median OS of 11.4 months was observed. In addition, 28 patients with biliary tract cancer received itraconazole, and subsequently experienced a median OS of 12 months (40).…”

Repurposing itraconazole for the treatment of cancer

“…Resistance to the cytotoxic agent daunorubicin has been reversed by itraconazole (63). It has been demonstrated that the addition of itraconazole (100 mg twice daily) improves remission rates in acute myelogenous leukaemia and disease-free survival in acute lymphoblastic leukaemia (33). This supports itraconazole's action of reversing drug resistance and is considered to be associated with its involvement with cytochrome P-450 and P-glycoprotein.…”

“…Drug resistance is a major obstacle in the desire to cure malignancies (33). Combination therapy is believed to reduce the development of drug resistance when compared with treatment with one drug alone (40,41).…”

“…As previously stated, itraconazole is used for fungal infection prophylaxis in immunosuppressive conditions (9). In patients with acute leukaemia it is often administered for prophylactic purposes in those receiving chemotherapy (33,62). Resistance to the cytotoxic agent daunorubicin has been reversed by itraconazole (63).…”