Summary
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 30μM 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 30μM, 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.
Similar content being viewed by others
References
Bessho F, Kinumaki H, Kobayashi M (1985) Treatment of child ren with refractory acute lymphocytic leukemia with vincristine and diltiazem. Med Pediatr Oncol 13: 199–202
Bonanou-Tzedaki SA, Sohl MK, Arnstein HR (1987) The role of cAMP and calcium in the stimulation of proliferation of immature erythroblasts by erythropoietin. Exp Cell Res 170: 276–289
Cairo MS, Siegel S, Anas H (1989) Clinical trial of continuous-in-fusion verapamil, bolus vinblastine and continuous-infusion VP-16 in drug-resistant pediatric tumors. Cancer Res 49: 1063–1066
Campos L, Guyotat D, Archimbaud E, Calmard-Oriol P, Tsuruo T, Troncy J, Treille D, Fiere D (1992) Clinical significance of multidrug-resistance P-glycoprotein expression on acute nonlymphoblastic leukemia cells at diagnosis. Blood 79: 473–476
Chaudhary PM, Roninson IB (1991) Expression and activity of P-glycoprotein, a multidrug efflux pump, in human hematopoietic stem cells. Cell 66: 85–94
Dalton WS, Durie BGM, Alberts DS, Gerlach JH, Cress AE (1986) Characterization of a new drug-resistant myeloma cell line which express p-glycoprotein. Cancer Res 46: 5125–5130
Delwel R, Salem M, Pellens C, Dorssers L, Wagemaker G, Clark S, Lowenberg B (1988) Growth regulation of human acute myeloid leukemia: effects of five recombinant growth factors in a serum-free culture system. Blood 72: 1944–1949
Durie BGM, Dalton WS (1988) Reversal of drug resistance in multiple myeloma with verapamil. Br J Haematol 68: 203–206
Haussermann K, Wolf MF, Schumacher K (1989) Potentiation of cytotoxicity of vincristine (VCR) by the enantiomers of verapamil and norverapamil in sensitive and resistant human lymphoma cells. Arch Pharmacol 339 [Suppl]: R116
Hu XF, De Luise M, Martin TJ, Zalcberg JR (1990) Effect of cyclosporin and verapamil on the cellular kinetics of daunorubicin. Eur J Cancer 26: 814–817
Keilhauer G, Emling F, Raschack M, Gries J, Schlick E (1989) The use of R-Verapamil (VPM) is superior to racemic VPM in breaking multidrug resistance of malignant cells. Proc Am Assoc Cancer Res 30: 503
Marie JP, Zittoun R, Sikic B (1991) Multidrug resistance (MDR 1) gene expression in adult acute leukemias: correlations with treatment outcome and in vitro drug sensitivity. Blood 78: 586–592
Nakarai T, Koizumi S (1990) Effects of calcium antagonists on anti-cancer drug toxicity to hematopoietic progenitor cells in normal human bone marrow. Leuk Res 14: 401–405
Presant CA, Kennedy PS, Wiseman C, Gala K, Bouzaglou A, Wyres M, Naessig W (1986) Verapamil reversal of clinical doxorubicin resistance in human cancer. A Wilshire Oncology Medical Group pilot phase I–II study. Am J Clin Oncol 9: 355–357
Salmon SE, Dalton WS, Grogan TM, Plezia P, Lehnert M, Roe DJ, Miller TP (1991) Multidrug-resistant multiple myeloma: laboratory and clinical effects of verapamil as a chemiosensitizer. Blood 78: 44–50
Slater LM, Murray SL, Wetzel MW, Sweet P, Stupecki M (1986) Verapamil potentiation of VP-16-213 in acute lymphatic leukemia and reversal of pleiotropic drug resistance. Cancer Chemother Pharmacol 16: 50–54
Tidefelt U, Sundman-Engberg B, Paul C (1988) Effects of verapamil on uptake and in vivo toxicity of anthracyclines in human leukemic blast cells. Eur J Haematol 40: 385–395
Tsuruo T, Iida H, Norjiri M, Tsukagoshi S, Sakurai W (1983) Cir-cumvention of vincristine and doxorubicin resistance in vitro and in vivo by calcium influx blockers. Cancer Res 434: 2905–2910
Visani G, Rizzi S, Tosi P, Cenacchi A, Gamberi B, Lemoli RM, Papadopulu P, Tura S (1990) In vitro effects of bisantrene on fresh clonogenic leukemia cells: a preliminary study on 15 cases. Haematologica (Pavia) 75: 527–531
Yalowich JC, Zucali JR, Gross M, Ross WE (1985) Effects of verapamil on etoposide, vincristine and adriamycin activity in normal human bone marrow granulocyte-macrophage progenitors and in human K562 leukemia cells in vitro. Cancer Res 45: 4921–4924
Author information
Authors and Affiliations
Additional information
This work was supported in part by MURST 40%–60%
Rights and permissions
About this article
Cite this article
Visani, G., Fogli, M., Tosi, P. et al. Comparative effects of racemic verapamil vs R-verapamil on normal and leukemic progenitors. Ann Hematol 66, 273–276 (1993). https://doi.org/10.1007/BF01695968
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF01695968