Approaches to Overcome Multidrug Resistance: PSC and CdA/ara-C Combination Chemotherapy
Multidrug resistance (MDR) is a potential major problem in acute myeloid leukemia (AML). Approaches to overcome MDR include pharmacological reversal of P-glycoprotein-mediated resistance, and use of effective drugs not affected by MDR, such as nucleoside analogues. Drugs that confer reversal of MDR in vitro include verapamil and cyclosporin A. We have analysed concentrations of anthracyclins and their metabolites within leukemic cells in vivo during continuous infusion of doxorubicin, daunorubicin, and idarubicin, respectively, and documented an elevated steady state level of active metabolites during concomitant treatment with verapamil, and cyclosporina A (CyA).
In a Scandinavian phase I/II study, the CyA analogue PSC833 was given together with daunorubicin and cytosin arabinoside (ara-C) to patients with refractory or relapsing AML to assess a feasible dose level of PSC and daunorubicin. The overall CR rate in 41 patients during the dose finding part of the study was 27%. Patient recruitment into the phase II part continues using a PSC dose of 10 mg/kg/day on days 1–4, and daunorubicin 45 mg/sqm/day on days 1–3, with ara-C 1 g/sqm/2h q 12 h, days 1–4.
2-Chlorodeoxyadenosine (Cladribine, CdA) is a purine analogue with a documented single-drug activity in de novo and relapsed pediatric AML. In analogy with the studies on fludarabine/ara-C combinations, we evaluated ara-CTP concentrations in AML cells during ara-C treatment with or without CdA pretreatment. Priming with CdA gave a 36% median increase in ara-CTP concentrations. Thirty patients (AML n = 21, ALL n = 4, MDS n = 1, MDS-AML n = 4; previously untreated n = 20, previously treated n = 10, 4 of them with relapse following stem cell transplants), aged 20–76 years (median 47 yrs), were given a combination of CdA, ara-C and idarubicin. The overall CR rate from one course was 73%, and among previously untreated patients 85%. Toxicity was limited, and recovery from thrombocytopenia (> 50) and neutropenia (> 0.5) was prompt and occurred on day 21 and 23 from start of treatment (median), respectively. The projected 3-year survival of the 20 previously untreated cases is 70% (with 4 auto-transplants, and 6 allogeneic stem cell transplants during follow-up). CR rate and overall survival in refractory patients were not as encouraging.
KeywordsLymphoma Neutropenia Cyclosporin Alkaloid Erythromycin
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