Potentiation of vincristine and Adriamycin effects in human hemopoietic tumor cell lines by calcium antagonists and calmodulin inhibitors.
Potentiation of vincristine and Adriamycin effects in human hemopoietic tumor cell lines by calcium antagonists and calmodulin inhibitors.
复制标题
钙拮抗剂和钙调蛋白抑制剂增强长春新碱和阿霉素对人造血肿瘤细胞系的作用。
作者：
T. Tsuruo;H. Iida;S. Tsukagoshi;Y. Sakurai
维拉帕米是一种钙内流阻滞剂，在体外可使长春新碱（VCR）在8种由急性淋巴细胞白血病、急性髓细胞性白血病和伯基特淋巴瘤建立的人造血肿瘤细胞系中的细胞毒性增强6- 12倍。VCR对K562白血病耐药细胞株的细胞毒作用明显增强。VCR细胞毒性最多增加约100倍。在这些人肿瘤细胞中，在体外观察到VCR敏感性的异质性（敏感性差异80倍）。B细胞型的BALL和Daudi细胞对VCR更敏感。在6.6或20 μ M的维拉帕米下，各细胞系细胞生长50%抑制所需的药物浓度值落入相当窄的范围内，并且在体外规避了细胞系之间VCR敏感性的异质性。维拉帕米也增强了阿霉素的细胞毒性，尽管增强的程度相当小。其他钙拮抗剂和钙调蛋白抑制剂也可增强VCR的细胞毒性。在这些试剂的最大有效浓度下，K562细胞中VCR细胞毒性增加3- 5倍。在VCR耐药的K562细胞中，观察到这些试剂更显著的增强（20- 45倍）。在体外避免了VCR耐药性。VCR细胞毒作用增强的机制是VCR在K562细胞中蓄积增加，尤其是在耐药细胞中蓄积增加。
verapamil, a calcium-influx blocker, enhanced the cytotoxicity of vincristine (VCR) in vitro 6- to 12-fold in eight human hemopoietic tumor cell lines established from acute lymphatic leukemia, acute myelogenous leukemia, and Burkitt's lymphoma. Great enhancement of VCR cytotoxicity was obtained in a VCR-resistant subline of K562 myelogenous leukemia. A maximum of approximate 100-fold increase in VCR cytotoxicity occurred. Heterogeneity in VCR sensitivity (80-fold difference in sensitivity) was observed in vitro among these human tumor cells. BALL and Daudi cells of B-cell type were more susceptible to VCR. At 6.6 or 20 microM of verapamil, the values for the concentration of drug required for 50% inhibition of cell growth for each cell line fell into a rather narrow range, and heterogeneity in VCR sensitivity among cell lines was circumvented in vitro. Verapamil also enhanced the cytotoxicity of Adriamycin, although the extent of enhancement was considerably small. Enhancement of VCR cytotoxicity also occurred with other calcium antagonists and calmodulin inhibitors. At maximum effective concentration of these reagents, a 3- to 5-fold increase in VCR cytotoxicity occurred in K562 cells. In VCR-resistant K562 cells, a more prominent enhancement (20- to 45-fold) was observed with these reagents. VCR resistance was circumvented in vitro. The mechanism of enhancement of VCR cytotoxicity was explained by the enhanced accumulation of VCR in K562, especially in resistant cells.