Comparative effects of racemic verapamil vs R-verapamil on normal and leukemic progenitors.
R-Verapamil (R-VPM), an enantiomer of racemic verapamil (VPM), has been recently reported to possess an activity equivalent to VPM in reverting drug resistance in vitro, without showing remarkable cardiovascular toxicity in animal models, even in doses three times higher than VPM. In this study, we assessed the effects of R-VPM in vitro, on clonogenic leukemia cells (CFU-L) from 15 patients with acute nonlymphoid leukemia (ANLL) at diagnosis, and on bone marrow erythroid (BFU-E) and myeloid (CFU-GM) progenitors from 15 healthy volunteers. On CFU-L, continuous exposure to VPM or R-VPM alone showed a slight inhibitory activity; in combination with daunorubicin (DNR), R-VPM proved more effective (mean IC50 of DNR: alone = 24.53 ng/ml +/- 6.2 SE, + VPM = 18.8 ng/ml +/- 4.6 SE, +R-VPM = 17.9 ng/ml +/- 4.8 SE). On CFU-GM, both VPM and R-VPM were minimally toxic at the lowest concentration used, but 30 microM VPM were significantly more toxic than R-VPM at the same dose (residual growth = 39.2% +/- 6.5% vs. 71.8% +/- 9.3% with R-VPM, p = 0.005). On BFU-E, both VPM and R-VPM caused more consistent growth inhibition; at high doses, VPM was again more toxic than R-VPM (33.4% +/- 12.8% vs 53.4% +/- 10.4% residual growth at 30 microM, p = 0.03). DNR toxicity on bone marrow was more greatly enhanced by VPM than R-VPM, and this difference was statistically significant on erythroid progenitor colony growth (p = 0.04). In conclusion, in comparison to VPM, R-VPM appeared to be at least equally effective on leukemic clonogenic cells and less toxic on normal bone marrow precursors, thus suggesting a possible safe use in vivo, even in concentrations that cannot be achieved with VPM, owing to its toxic effects.
Visani
G
G
Institute of Hematology L e A. Seragnoli, University of Bologna, Italy.
Fogli
M
M
Tosi
P
P
Ottaviani
E
E
Gamberi
B
B
Cenacchi
A
A
Manfroi
S
S
Tura
S
S
D001854:Bone Marrow Cells; D003114:Colony-Forming Units Assay; D003630:Daunorubicin / Q000494:pharmacology / Q000633:toxicity; D004359:Drug Therapy, Combination; D015672:Erythroid Precursor Cells / Q000187:drug effects; D006801:Humans; D007938:Leukemia / Q000473:pathology*; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy; D013234:Stem Cells / Q000187:drug effects*; D013237:Stereoisomerism; D014410:Tumor Stem Cell Assay; D014700:Verapamil / Q000494:pharmacology* / Q000633:toxicity
D014700:Verapamil; D003630:Daunorubicin