Visani G, Fogli M, Tosi P, Ottaviani E, Gamberi B, Cenacchi A, Manfroi S, Tura S
Institute of Hematology L e A. Seragnoli, University of Bologna, Italy.
Ann Hematol. 1993 Jun;66(6):273-6. doi: 10.1007/BF01695968.
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.
R-维拉帕米（R-VPM）是消旋维拉帕米（VPM）的一种对映体，最近有报道称其在体外逆转耐药性方面具有与VPM相当的活性，在动物模型中未表现出明显的心血管毒性，即使剂量比VPM高三倍。在本研究中，我们评估了R-VPM在体外对15例急性非淋巴细胞白血病（ANLL）患者诊断时的克隆性白血病细胞（CFU-L）以及15名健康志愿者的骨髓红系祖细胞（BFU-E）和髓系祖细胞（CFU-GM）的影响。对于CFU-L，单独持续暴露于VPM或R-VPM显示出轻微的抑制活性；与柔红霉素（DNR）联合使用时，R-VPM被证明更有效（DNR的平均IC50：单独使用 = 24.53 ng/ml ± 6.2 SE， + VPM = 18.8 ng/ml ± 4.6 SE， + R-VPM = 17.9 ng/ml ± 4.8 SE）。对于CFU-GM，在使用的最低浓度下，VPM和R-VPM的毒性都最小，但在相同剂量下，30 μM的VPM比R-VPM毒性显著更大（残余生长 = 39.2% ± 6.5%，而R-VPM为71.8% ± 9.3%，p = 0.005）。对于BFU-E，VPM和R-VPM都导致更一致的生长抑制；在高剂量时，VPM的毒性再次比R-VPM更大（30 μM时残余生长为33.4% ± 12.8% 对 53.4% ± 10.4%，p = 0.03）。VPM比R-VPM更能增强DNR对骨髓的毒性，并且这种差异在红系祖细胞集落生长方面具有统计学意义（p = 0.04）。总之，与VPM相比，R-VPM在白血病克隆细胞上似乎至少同样有效，而对正常骨髓前体细胞毒性较小，因此表明即使在因VPM毒性作用而无法达到的浓度下，R-VPM在体内也可能安全使用。
