Durmaz R, Deliorman S, Uyar R, Işiksoy S, Erol K, Tel E
Department of Neurosurgery, Medical Faculty, Osmangazi University, Eskişehir, Turkey.
Clin Neurol Neurosurg. 1999 Dec;101(4):238-44. doi: 10.1016/s0303-8467(99)00061-x.
The presence of the cellular multidrug resistance (MDR1) gene and its product, P-glycoprotein (Pgp), is thought to be a mechanism for the failure of chemotherapy in cancer patients. Calcium channel blockers have been shown to sensitise cancer cells to anticancer drugs by reversing Pgp expression in cell lines. The interactions between anticancer drugs such as carmustine (BCNU), vincristine (VCR) and procarbazine (PCB) and calcium channel blockers such as nimodipine and verapamil on cultured cells of glioblastoma from eight patients were therefore tested. Pgp expression was examined immunohistochemically using C219 monoclonal antibody in cytospin preparation. The cytotoxicity of the drugs was screened using microculture tetrazolium assay. The cells from five patients showed positive immunoreaction for Pgp. Nimodipine showed growth-inhibitory activity against glioblastoma cells at a rate of 16.55-26.88% (P < 0.05), but a similar effect was not observed with verapamil. While antiproliferative effects of BCNU were around 20.91-45.09% (P < 0.05) on the cells from seven patients, VCR was the most effective agent in inhibition of cell growth at a rate of 26.43-48.47% (P < 0.05). The response of the cells from five patients to PCB was from 11.98 to 16.32% (P < 0.05). When used together, nimodipine further enriched cytotoxicity of the anticancer drugs up to 11.14-40.85% (P < 0.05) without relation to Pgp expression. In conclusion, the enhancement of cytotoxicity of anticancer drugs by nimodipine suggests that there might be a synergy between anticancer drugs and nimodipine in the inhibition of glioma cell growth.
细胞多药耐药（MDR1）基因及其产物P-糖蛋白（Pgp）的存在被认为是癌症患者化疗失败的一种机制。钙通道阻滞剂已被证明可通过逆转细胞系中的Pgp表达，使癌细胞对抗癌药物敏感。因此，测试了卡莫司汀（BCNU）、长春新碱（VCR）和丙卡巴肼（PCB）等抗癌药物与尼莫地平和维拉帕米等钙通道阻滞剂对8例患者的胶质母细胞瘤培养细胞的相互作用。在细胞涂片制备中使用C219单克隆抗体通过免疫组织化学检查Pgp表达。使用微量培养四氮唑蓝法筛选药物的细胞毒性。来自5例患者的细胞对Pgp呈阳性免疫反应。尼莫地平对胶质母细胞瘤细胞显示出16.55 - 26.88%的生长抑制活性（P < 0.05），但维拉帕米未观察到类似效果。BCNU对7例患者的细胞的抗增殖作用约为20.91 - 45.09%（P < 0.05），VCR是抑制细胞生长最有效的药物，抑制率为26.43 - 48.47%（P < 0.05）。5例患者的细胞对PCB的反应为11.98%至16.32%（P < 0.05）。当联合使用时，尼莫地平进一步增强了抗癌药物的细胞毒性，高达11.14 - 40.85%（P < 0.05），且与Pgp表达无关。总之，尼莫地平增强抗癌药物的细胞毒性表明，在抑制胶质瘤细胞生长方面，抗癌药物与尼莫地平之间可能存在协同作用。
