Yu D S, Sun G H, Ma C P, Chang S Y
Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, Republic of China.
Urology. 1999 Aug;54(2):377-81. doi: 10.1016/s0090-4295(99)00126-0.
To determine the effect of various modulators on intracellular drug accumulation in renal cell carcinoma (RCC) tumor cells and the modulation of cytotoxicity of various chemotherapeutic drugs on the native RCC cell line and acquired intrinsic multidrug resistance (MDR) sublines because MDR is a major obstacle to effective chemotherapy of RCC.
The cytotoxicity of adriamycin to RCC 8701 and its MDR subline was analyzed. Fourteen MDR modulators, including calcium antagonists, protein kinase C inhibitor, glutathione transferase inhibitor, protein/peptide synthesis inhibitors, respiratory chain inhibitors, uncoupling reagent, adenosine triphosphate synthesis inhibitor, and ionophores, were examined for their MDR-reverse activity using the microplate tetrazolium test.
The intracellular adriamycin concentration significantly increased and reached maximum 4 hours after simultaneous treatment with calcium antagonists, tamoxifen, and oligomycin. The result demonstrated that verapamil, quinidine, tamoxifen, and oligomycin had an additive effect on the cytotoxicity of adriamycin and vinblastine against RCC8701 and RCC8701/ADR800 tumor cells. RCC8701/ADR800 tumor cells were more sensitive to modulator enhancement than native cells. The enhancement was related to the dosage and treatment duration of the modulators. Further trials on simultaneous additions to cocktail mixtures of the above four modulators showed no additive or synergistic effect on cytotoxicity against RCC8701/ADR800 tumor cells.
Calcium antagonists and tamoxifen and oligomycin can individually be an effective chemotherapy adjunct for overcoming the native drug resistance or acquired MDR in RCC. Combination regimens, however, need more study regarding timing of administration, dosage, and frequency of modulators.
确定各种调节剂对肾细胞癌（RCC）肿瘤细胞内药物蓄积的影响，以及各种化疗药物对天然RCC细胞系和获得性内在多药耐药（MDR）亚系细胞毒性的调节作用，因为多药耐药是RCC有效化疗的主要障碍。
分析阿霉素对RCC 8701及其MDR亚系的细胞毒性。使用微孔板四氮唑试验检测了14种MDR调节剂，包括钙拮抗剂、蛋白激酶C抑制剂、谷胱甘肽转移酶抑制剂、蛋白质/肽合成抑制剂、呼吸链抑制剂、解偶联剂、三磷酸腺苷合成抑制剂和离子载体，以观察它们的MDR逆转活性。
同时使用钙拮抗剂、他莫昔芬和寡霉素处理后，细胞内阿霉素浓度显著增加，并在4小时后达到最大值。结果表明，维拉帕米、奎尼丁、他莫昔芬和寡霉素对阿霉素和长春碱对RCC8701和RCC8701/ADR800肿瘤细胞的细胞毒性具有相加作用。RCC8701/ADR800肿瘤细胞比天然细胞对调节剂增强作用更敏感。增强作用与调节剂的剂量和处理持续时间有关。对上述四种调节剂同时添加到鸡尾酒混合物中的进一步试验表明，对RCC8701/ADR800肿瘤细胞的细胞毒性没有相加或协同作用。
钙拮抗剂、他莫昔芬和寡霉素可分别作为克服RCC天然耐药或获得性MDR的有效化疗辅助药物。然而，联合用药方案在给药时间、剂量和调节剂频率方面需要更多研究。
