Budman Daniel R, Calabro Anthony
Section of Experimental Therapeutics, Don Monti Division of Oncology, North Shore University Hospital, New York University, Manhasset, 11030, USA.
Oncology. 2006;70(2):147-53. doi: 10.1159/000093006. Epub 2006 Apr 26.
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.
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.
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.
Combinations of zoledronic acid with either gemcitabine or fluvastatin may have a therapeutic role in treatment of bone metastasis of selected malignancies.
通过中位效应等效线图分析和体外凋亡试验，确定临床上可用的药物与唑来膦酸的协同组合，以增强抗肿瘤活性。
在一个72小时的体外系统中，使用处于指数生长期的单层培养的特定人类癌细胞系，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作为双联药物的相互作用。通过标准的MTT试验测量药物对生长的影响。将中位效应等效线图分析应用于结果，以确定药物组合是否存在协同作用、相加作用或拮抗作用。还通过细胞质组蛋白相关DNA片段化凋亡试验对协同组合进行检测，以验证其作用不是细胞抑制性的。
唑来膦酸与吉西他滨在8个细胞系中的7个中表现出全面的细胞毒性协同作用。临床上可达到的氟伐他汀与唑来膦酸浓度在8个细胞系中的7个中也表现出协同作用。所有乳腺癌细胞系均敏感。唑来膦酸和表柔比星在所有4个研究的乳腺癌细胞系中均表现为拮抗作用。
唑来膦酸与吉西他滨或氟伐他汀的组合可能在某些恶性肿瘤骨转移的治疗中具有治疗作用。
