Chou T C, Otter G M, Sirotnak F M
Molecular Pharmacology and Therapeutics Program, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
Cancer Chemother Pharmacol. 1996;37(3):222-8. doi: 10.1007/BF00688320.
A new dihydrofolate reductase inhibitor, edatrexate (EDX), and the microtubule polymerization promotor, taxol (TXL) or taxotere (TXT), each have significant therapeutic activity against human breast cancer in clinical trials. Since they also have distinctly different mechanisms of actions and have mainly non-overlapping toxicities, they may be effective in combination in the treatment of this disorder. Schedule-dependent interactions between these taxanes and EDX against human breast adenocarcinoma cells (SK-Br-3) were quantitatively assessed in vitro to determine whether these interactions are synergistic or antagonistic. SK-Br-3 cells were grown as a monolayer in 96-well microplates. The dose-effect relationships of the drugs, singly and in combination, in inhibiting the growth over a 7-day period were determined by the SRB protein staining assays. Cell cultures were exposed to drug as a 3-h pulse at either 0-3 h or 24-27 h. Synergism or antagonism at different concentrations and at different effect levels were assessed with the median effect principle and the combination index-isobologram method using computer software. These methods were selected because they take into account both the potencies and the shape of the dose-effect curves. Exposure of cells to an equimolar combination of EDX + TXL (0-3 h) resulted in synergism at high effect levels. Pretreatment of cells with EDX (0-3 h) followed by TXL (24-27 h) showed even greater synergism in inhibiting cell growth. Moderate antagonism was observed with the reverse schedule. EDX + TXT (0-3 h) was additive, but pretreatment with EDX (0-3 hr) followed by TXT (24-27 h) showed synergism. However, the reverse order showed antagonism. Studies on another breast tumor cell line, ZR-57-1, also showed the schedule of EDX (0-3 h) + TXT or TXL (24-27 h) to be more synergistic than, the other two schedules examined. These results show potent schedule-dependent synergism of the combinations of TXL or TXT with EDX, and should form a rationale for designing clinical protocols utilizing these agents particularly for the treatment of breast cancer patients.
一种新型二氢叶酸还原酶抑制剂依达曲沙（EDX）以及微管聚合促进剂紫杉醇（TXL）或多西他赛（TXT），在临床试验中对人类乳腺癌均具有显著的治疗活性。由于它们还具有明显不同的作用机制且主要毒性不重叠，因此联合使用可能对治疗这种疾病有效。在体外对这些紫杉烷类药物与依达曲沙针对人乳腺腺癌细胞（SK-Br-3）的时间依赖性相互作用进行了定量评估，以确定这些相互作用是协同还是拮抗。SK-Br-3细胞在96孔微孔板中单层生长。通过SRB蛋白质染色测定法确定药物单独及联合使用在7天内抑制生长的剂量-效应关系。细胞培养物在0至3小时或24至27小时接受3小时的药物脉冲处理。使用计算机软件，采用中位效应原理和联合指数-等效线图法评估不同浓度和不同效应水平下的协同或拮抗作用。选择这些方法是因为它们兼顾了剂量-效应曲线的强度和形状。细胞暴露于依达曲沙+紫杉醇的等摩尔组合（0至3小时）在高效应水平下产生协同作用。先用依达曲沙（0至3小时）预处理细胞，然后用紫杉醇（24至27小时）处理，在抑制细胞生长方面显示出更大的协同作用。采用相反顺序观察到中度拮抗作用。依达曲沙+多西他赛（0至3小时）是相加作用，但先用依达曲沙（0至3小时）预处理，然后用多西他赛（24至27小时）处理则显示出协同作用。然而，相反顺序显示出拮抗作用。对另一种乳腺肿瘤细胞系ZR-57-1的研究也表明，依达曲沙（0至3小时）+多西他赛或紫杉醇（24至27小时）的顺序比所研究的其他两种顺序更具协同作用。这些结果表明紫杉醇或多西他赛与依达曲沙的组合具有显著的时间依赖性协同作用，应为设计使用这些药物的临床方案提供理论依据，特别是用于治疗乳腺癌患者。
