Aschele C, Baldo C, Sobrero A F, Debernardis D, Bornmann W G, Bertino J R
Department of Medical Oncology, Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy.
Clin Cancer Res. 1998 May;4(5):1323-30.
The quinazoline folate analogue raltitrexed (ZD1694; Tomudex) and the camptothecin derivative irinotecan are two new agents showing clinical activity against colorectal cancer. To identify the optimal conditions to achieve synergistic cytotoxicity before the clinical development of their combination, we explored the interactions between ZD1694 and the active metabolite of irinotecan, 7-ethyl-10-hydroxycamptothecin (SN-38), in vitro. Cytotoxicity was evaluated with a clonogenic assay using the human colon cancer cell line HCT-8. Different schedules of administration and different dose ratios of the two agents were compared and evaluated for synergism, additivity, or antagonism with a quantitative method based on the median-effect principle of Chou and Talalay (T. C. Chou and P. Talalay, Adv. Enzyme Regul., 22: 27-55, 1984). Sequential short-term (1 and 4-h) exposures to SN-38 followed by ZD1694 resulted in synergistic cytotoxicity at broad dose-effect ranges. At a high level of cell kill, the synergism was greater when either equiactive doses of the two agents or higher relative doses of ZD1694 were used. A 24-h interval between exposure to SN-38 and ZD1694 significantly enhanced the magnitude of the synergy (P = 0.001). The opposite sequence or simultaneous exposures produced significantly less potentiation or nearly additive interactions (P = 0.0006 and P < 0.0001). The synergism was completely lost under conditions of more prolonged drug exposure (24-h continuous exposure). In conclusion, in this in vitro model of human colon cancer, ZD1694 and SN-38 produced synergistic cytotoxicity. Our findings support the clinical use of this combination and provide a rationale for a clinical trial using sequential short-term exposures to equiactive doses of SN-38 and ZD1694 administered sequentially with a 24-h interval.
喹唑啉叶酸类似物雷替曲塞（ZD1694；拓优得）和喜树碱衍生物伊立替康是两种对结直肠癌具有临床活性的新型药物。为了在其联合应用的临床开发之前确定实现协同细胞毒性的最佳条件，我们在体外研究了ZD1694与伊立替康的活性代谢产物7-乙基-10-羟基喜树碱（SN-38）之间的相互作用。使用人结肠癌细胞系HCT-8通过克隆形成试验评估细胞毒性。比较并评估了两种药物不同的给药方案和不同剂量比，采用基于Chou和Talalay中位效应原理的定量方法（T.C.Chou和P.Talalay，《酶调节进展》，22：27 - 55，1984）来判断协同、相加或拮抗作用。先短期（1小时和4小时）暴露于SN-38后再给予ZD1694，在较宽的剂量效应范围内产生了协同细胞毒性。在高细胞杀伤水平下，当使用两种药物的等效活性剂量或更高相对剂量的ZD1694时，协同作用更强。在暴露于SN-38和ZD1694之间间隔24小时可显著增强协同作用的强度（P = 0.001）。相反的给药顺序或同时暴露产生的增强作用明显较小或几乎为相加作用（P = 0.0006和P < 0.0001）。在更长时间的药物暴露（24小时持续暴露）条件下，协同作用完全消失。总之，在这个人结肠癌体外模型中，ZD1694和SN-38产生了协同细胞毒性。我们的研究结果支持这种联合用药的临床应用，并为一项临床试验提供了理论依据，该试验采用依次短期暴露于等效活性剂量的SN-38和ZD1694，且给药间隔为24小时。
