STI571 enhances the therapeutic index of epothilone B by a tumor-selective increase of drug uptake.
STI571 enhances the therapeutic index of epothilone B by a tumor-selective increase of drug uptake.
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发表时间：
2003-09
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通讯作者：
K. Pietras;M. Stumm;M. Hubert;E. Buchdunger;K. Rubin;C. Heldin;P. Mcsheehy;M. Wartmann;A. Ostman
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作者：
K. Pietras;M. Stumm;M. Hubert;E. Buchdunger;K. Rubin;C. Heldin;P. Mcsheehy;M. Wartmann;A. Ostman
目的探讨STI571是否通过血小板源性生长因子受体抑制，增强化疗药物epothilone B （EPO906）的治疗反应，如果是，分析其作用机制。实验设计采用不同剂量的EPO906单独或与STI571联合给药以及不同时间给药的方法治疗患有s.c.人间变甲状腺癌的SCID小鼠。监测肿瘤生长、肿瘤间质液压力（IFP）和肿瘤及正常器官中EPO906的摄取情况。结果STI571能增强EPO906的治疗效果。联合治疗的肿瘤比单药治疗的肿瘤小约40%。改善的疗效与肿瘤IFP降低和肿瘤EPO906水平增加3倍相匹配。肝脏、肾脏和肠道中EPO906水平未见明显升高。通过在整个治疗过程中测量体重来确定，共处理不会降低EPO906的耐受性。STI571诱导的肿瘤IFP降低和肿瘤摄取增加至少需要每日三次的STI571剂量，并且在最后一次使用STI571治疗后3天未观察到。仅当STI571与降低肿瘤IFP和增加肿瘤对EPO906的摄取相关时，才观察到EPO906治疗效果的增强。结论：STI571通过选择性增加肿瘤对EPO906的摄取，提高了EPO906的治疗指数。STI571对肿瘤IFP的影响与肿瘤对EPO906的药物摄取之间的相关性提示两者之间存在因果关系。因此，该研究验证了STI571用于联合治疗，特别是提高EPO906的治疗指数，并可能提高一般化疗药物的治疗指数。
PURPOSE The purpose is to investigate whether STI571, through platelet-derived growth factor receptor inhibition, enhances the therapeutic response to the chemotherapeutic drug epothilone B (EPO906) and, if so, to analyze the mechanism(s) underlying the effect. EXPERIMENTAL DESIGN SCID mice with s.c. human anaplastic thyroid carcinomas were treated with different doses of EPO906 alone or in combination with STI571 and with different timing of STI571 and EPO906 administration. Tumor growth, tumor interstitial fluid pressure (IFP), and uptake of EPO906 in tumors and normal organs were monitored. RESULTS STI571 potentiated the therapeutic effect of EPO906. Tumors subjected to combination treatment were >40% smaller than those subjected to monotreatment with EPO906. The improved efficacy was matched by reduced tumor IFP and a 3-fold increase in the tumor levels of EPO906. No significant increase of EPO906 levels was seen in liver, kidney, or the intestinal tract. Cotreatment did not reduce the tolerability of EPO906, as determined by measuring body weight throughout treatment. STI571-induced reduction in tumor IFP and increase in tumor uptake required a minimum of three daily doses of STI571 and was not observed 3 days after last treatment with STI571. The enhancement of EPO906 therapeutic efficacy was only observed when STI571 was scheduled in a manner associated with reduced tumor IFP and increased tumor uptake of EPO906. CONCLUSIONS We conclude that STI571 increases the therapeutic index of EPO906 by selectively increasing the EPO906 uptake in tumors. The correlations between STI571 effects on tumor IFP and tumor drug uptake of EPO906 suggest a causal relationship between these phenomena. The study thus validates STI571 for combination treatment to enhance the therapeutic index of EPO906 in particular and, possibly, of chemotherapeutics in general.