Continuous low-dose therapy with vinblastine and VEGF receptor-2 antibody induces sustained tumor regression without overt toxicity.
Continuous low-dose therapy with vinblastine and VEGF receptor-2 antibody induces sustained tumor regression without overt toxicity.
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DOI：
10.1172/jci8829c1
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发表时间：
2000
期刊：
影响因子：
--
通讯作者：
G. Klement;P. Bőhlen;R. Kerbel
中科院分区：
文献类型：
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作者：
G. Klement;P. Bőhlen;R. Kerbel
各种常规化疗药物可以阻断血管生成或甚至杀死活化的、分裂的内皮细胞。这种作用可能有助于体内化疗的抗肿瘤功效，并可能延迟或防止癌细胞获得耐药性。我们已经实施了一种治疗方案，该方案增强了化疗的潜在抗血管作用，没有明显的毒副作用，并且阻碍了肿瘤细胞耐药性的发展。对2个独立的神经母细胞瘤细胞系的异种移植物进行低剂量长春碱、靶向VEGF的flk-1/KDR（2型）受体的单克隆中和抗体（DC 101）或两种药物一起的连续处理。这种组合的基本原理是，当VEGF介导的存活信号被阻断时，低剂量化疗的任何抗血管作用将在新形成的血管细胞中选择性地增强。DC 101和低剂量长春碱治疗分别导致显著但短暂的异种移植物消退，减少肿瘤血管分布，并直接抑制血管生成。值得注意的是，联合治疗导致大的已建立肿瘤的完全和持续消退，而在持续>6个月的治疗过程中没有宿主毒性的随之增加或获得性耐药性的任何迹象。这篇文章可能在印刷版之前已经在网上发表。公布日期可在JCI网站http://www.jci.org上查阅。
Various conventional chemotherapeutic drugs can block angiogenesis or even kill activated, dividing endothelial cells. Such effects may contribute to the antitumor efficacy of chemotherapy in vivo and may delay or prevent the acquisition of drug-resistance by cancer cells. We have implemented a treatment regimen that augments the potential antivascular effects of chemotherapy, that is devoid of obvious toxic side effects, and that obstructs the development of drug resistance by tumor cells. Xenografts of 2 independent neuroblastoma cell lines were subjected to either continuous treatment with low doses of vinblastine, a monoclonal neutralizing antibody (DC101) targeting the flk-1/KDR (type 2) receptor for VEGF, or both agents together. The rationale for this combination was that any antivascular effects of the low-dose chemotherapy would be selectively enhanced in cells of newly formed vessels when survival signals mediated by VEGF are blocked. Both DC101 and low-dose vinblastine treatment individually resulted in significant but transient xenograft regression, diminished tumor vascularity, and direct inhibition of angiogenesis. Remarkably, the combination therapy resulted in full and sustained regressions of large established tumors, without an ensuing increase in host toxicity or any signs of acquired drug resistance during the course of treatment, which lasted for >6 months. This article may have been published online in advance of the print edition. The date of publication is available from the JCI website, http://www.jci.org.