Zoledronic acid (Zometa®) enhances the cytotoxic effect of gemcitabine and fluvastatin:: In vitro isobologram studies with conventional and nonconventional cytotoxic agents
Zoledronic acid (Zometa®) enhances the cytotoxic effect of gemcitabine and fluvastatin:: In vitro isobologram studies with conventional and nonconventional cytotoxic agents
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DOI：
10.1159/000093006
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发表时间：
2006-01-01
期刊：
影响因子：
3.5
通讯作者：
Calabro, A
中科院分区：
文献类型：
--
作者：
Budman, DR;Calabro, A
目的：通过中位效应等线图分析和体外细胞凋亡试验，确定临床可用的药物与唑来膦酸联合使用可增强抗肿瘤活性。方法：在一个72小时的体外系统中研究唑来膦酸与卡铂、顺铂、5'DFUR、多西他赛、表柔比星、氟伐他汀、吉西他滨、伊马替尼、紫杉醇、曲妥珠单抗或长春瑞滨的相互作用，该系统使用指数期单层生长的确定的人类癌细胞系。用标准MTT法测定药物对生长的影响。对结果进行中位效应等线图分析，以确定药物组合是否存在协同作用、加性效应或拮抗作用。协同组合也通过细胞质组蛋白相关DNA片段凋亡测定来验证其不具有细胞抑制作用。结果：唑来膦酸与吉西他滨在8个细胞系中的7个中显示出整体细胞毒性协同作用。氟伐他汀与唑来膦酸的临床可达到的浓度在8个细胞系中的7个中也显示出协同作用。所有的乳腺癌细胞系都是敏感的。唑来膦酸和表柔比星对4种乳腺细胞系均有拮抗作用。结论：唑来膦酸联合吉西他滨或氟伐他汀可能对某些恶性肿瘤的骨转移有治疗作用。版权所有(c) 2006 S. Karger AG，巴塞尔
Objectives: To identify synergistic combinations of clinically available agents with zoledronic acid which would enhance antitumor activity as measured by median effect isobologram analysis and apoptosis assays in vitro. Methods: The interaction of zoledronic acid as a doublet with either carboplatin, cisplatin, 5'DFUR, docetaxel, epirubicin, fluvastatin, gemcitabine, imatinib, paclitaxel, trastuzumab, or vinorelbine was studied in a 72-hour in vitro system using defined human cancer cell lines grown as a monolayer in exponential phase. Drug effect on growth was measured by a standard MTT assay. Median effect isobologram analysis was applied to the results to determine the presence of synergism, additive effects, or antagonism of drug combinations. Synergistic combinations were also assayed by a cytoplasmic histone-associated DNA fragmentation apoptosis assay to verify that the effect was not cytostatic. Results: Zoledronic acid with gemcitabine demonstrated global cytotoxic synergy across 7 of 8 cell lines. Clinically achievable concentrations of fluvastatin with zoledronic acid also demonstrated synergy in 7 of 8 cell lines. All the breast cancer cell lines were sensitive. Zoledronic acid and epirubicin were antagonistic in all 4 breast cell lines studied. Conclusions: Combinations of zoledronic acid with either gemcitabine or fluvastatin may have a therapeutic role in treatment of bone metastasis of selected malignancies. Copyright (c) 2006 S. Karger AG, Basel