Effects of verapamil on the cellular accumulation of daunorubicin in blast cells and on the chemosensitivity of leukaemic blast progenitors in acute myelogenous leukaemia.
Verapamil, a calcium channel blocker, was studied for its effects on the cellular daunorubicin (DNR) accumulation in blast cells and on the sensitivity of the blast progenitors to DNR in 30 acute myelogenous leukaemia (AML) patients. Using flow cytometry, verapamil was shown to increase the accumulation of DNR in blast cells. The effect was more prominent in the patients who showed poorer response to chemotherapy including DNR. The per cent increases of DNR content by verapamil were 6.4 +/- 6.3% and 19.5 +/- 23.1% in the 16 responders and the 14 nonresponders, respectively (P less than 0.05). The data suggest the presence of enhanced efflux of DNR in nonresponders. Marked variation in the effects of verapamil among nonresponders suggests the heterogeneity of the mechanisms of drug resistance involved. Verapamil also enhanced the sensitivity of blast progenitors to DNR. The degree of increase of cellular DNR accumulation by verapamil correlated with the degree of increase in chemosensitivity of blast progenitors (nonresponders, P less than 0.005; responders, P less than 0.05). We conclude that enhanced efflux of DNR in blast progenitors may be related to remission induction failure in at least some of resistant AML patients.
Maruyama
Y
Y
First Department of Internal Medicine, Tokyo Medical and Dental University, Japan.
Murohashi
I
I
Nara
N
N
Aoki
N
N
D000328:Adult; D000368:Aged; D002470:Cell Survival / Q000187:drug effects; D003630:Daunorubicin / Q000378:metabolism* / Q000627:therapeutic use; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000097:blood* / Q000188:drug therapy; D007963:Leukocytes, Mononuclear / Q000187:drug effects*; D008297:Male; D008875:Middle Aged; D014700:Verapamil / Q000494:pharmacology* / Q000627:therapeutic use
D014700:Verapamil; D003630:Daunorubicin