Synergistic antitumor activity of cisplatin, paclitaxel, and gemcitabine with tumor vasculature-targeted tumor necrosis factor-α
Synergistic antitumor activity of cisplatin, paclitaxel, and gemcitabine with tumor vasculature-targeted tumor necrosis factor-α
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DOI：
10.1158/1078-0432.ccr-05-1147
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发表时间：
2006-01-01
影响因子：
11.5
通讯作者：
Corti, A
中科院分区：
文献类型：
--
作者：
Sacchi, A;Gasparri, A;Corti, A
目的：亚纳克剂量的肿瘤坏死因子(NGR)-肿瘤坏死因子(TNF-α)可增强阿霉素和马法兰在小鼠模型中的抗肿瘤活性。除了阿霉素和马法兰、顺铂、紫杉醇和吉西他滨外，我们还检测了NGR-TNF与不同机制的化疗药物联合使用的抗肿瘤活性。实验设计：在小鼠淋巴瘤、纤维肉瘤和乳腺癌模型中，单独测试化疗药物以及联合使用NGR-TNF(0.1 ng)。研究了不同给药方案对肿瘤生长、动物体重、肿瘤灌注量和细胞毒性的影响。结果：NGR-肿瘤坏死因子对所有药物均有不同程度的增强作用。药效的提高并没有伴随着毒性的增加，至少从动物体重的减少来看是这样。协同作用是短暂的，在所有模型和所有受试药物中，NGR-TNF与给药之间的最大协同作用存在2小时的延迟。结论：小剂量NGR-TNF靶向肿瘤血管内靶向给药，可通过不同的作用机制提高化疗药物的疗效。最佳给药方案要求在不考虑药物细胞毒性机制的情况下，用NGR-肿瘤坏死因子预处理2小时。本工作可为设计NGR-肿瘤坏死因子联合化疗药物的临床研究提供重要信息。
Purpose: Subnanogram doses of NGR-tumor necrosis factor (TNF), aTNF-alpha derivative able to target tumor neovessels, can enhance the antitumor activity of doxorubicin and melphalan in murine models. We have examined the antitumor activity of NGR-TNF in combination with various chemotherapeutic drugs acting via different mechanisms, including, besides doxorubicin and melphalan, cisplatin, paclitaxel, and gemcitabine.Experimental Design: Chemotherapeutic drugs were tested alone and in combination with NGR-TNF (0.1 ng) in murine lymphoma, fibrosarcoma, and mammary adenocarcinoma models. Different administration schedules have been tested and the effects on tumor growth, animal weight, tumor perfusion, and cell cytotoxicity have been investigated.Results: Pretreatment with NGR-TNF enhanced the response to all these drugs although to a different extent. The increased efficacy was not accompanied by increased toxicity at least as judged from the loss of animal weight. The synergistic effect was transient, maximal synergism being observed with a 2-hour delay between NGR-TNF and drug administrations in all models and with all drugs tested. NGR-TNF did not increase the in vitro cytotoxicity of chemotherapeutic drugs against tumor cells, suggesting that the in vivo synergism depends on NGR-TNF effects on host cells rather than on tumor cells.Conclusions: Targeted delivery of low doses of NGR-TNF to the tumor vasculature can increase the efficacy of various drugs acting via different mechanisms. Optimal administration schedule requires 2 hours of pretreatment with NGR-TNF independently from the mechanism of drug cytotoxicity. This work could provide important information for designing clinical studies with NGR-TNF in combination with chemotherapeutic drugs.