Olson T A, Mohanraj D, Roy S, Ramakrishnan S
Department of Pharmacology, University of Minnesota, Minneapolis 55455, USA.
Int J Cancer. 1997 Dec 10;73(6):865-70. doi: 10.1002/(sici)1097-0215(19971210)73:6<865::aid-ijc17>3.0.co;2-3.
Tumor-derived vascular endothelial growth factor (VEGF)/ vascular permeability factor (VPF) plays an important role in neovascularization and the development of tumor stroma. Furthermore, VEGF receptors are over-expressed in the endothelial cells of tumor vasculature and almost non-detectable in the vascular endothelium of adjoining normal tissues. The differential expression of receptor offers a selective advantage for targeting cytotoxic toxin polypeptides. We have prepared a vascular targeting reagent by chemically linking recombinant VEGF to a truncated form of diphtheria toxin. The VEGF-toxin conjugate was selectively toxic to endothelial cell lines and inhibited experimental neovascularization of the chick chorioallantoic membrane. In the present study, we examined the effects of VEGF-toxin conjugate on solid tumor growth. Athymic nude mice with established subcutaneous tumors were treated with daily intraperitoneal injections of the VEGF-toxin conjugate or free toxin. When compared with control animals treated with the toxin polypeptide alone, the conjugate-treated animals displayed a significant inhibition of tumor growth. Histological analysis of tumors from conjugate-treated animals revealed hemorrhagic necrosis consistent with a vascular-mediated injury. In contrast, highly vascularized normal tissues from conjugate-treated animals demonstrated no evidence of hemorrhage or tissue injury. The conjugate was well tolerated without apparent toxicities. Our results illustrate the anti-tumor activity of a VEGF-toxin conjugate selectively targeting the tumor neovasculature.
肿瘤衍生的血管内皮生长因子（VEGF）/血管通透因子（VPF）在肿瘤新生血管形成和肿瘤基质发展中起重要作用。此外，VEGF受体在肿瘤血管的内皮细胞中过度表达，而在相邻正常组织的血管内皮中几乎检测不到。受体的差异表达为靶向细胞毒素多肽提供了选择性优势。我们通过将重组VEGF化学连接到截短形式的白喉毒素制备了一种血管靶向试剂。VEGF-毒素偶联物对内皮细胞系具有选择性毒性，并抑制鸡胚绒毛尿囊膜的实验性新生血管形成。在本研究中，我们研究了VEGF-毒素偶联物对实体瘤生长的影响。对已建立皮下肿瘤的无胸腺裸鼠每日腹腔注射VEGF-毒素偶联物或游离毒素进行治疗。与单独用毒素多肽治疗的对照动物相比，接受偶联物治疗的动物肿瘤生长受到显著抑制。对接受偶联物治疗动物的肿瘤进行组织学分析，发现出血性坏死，这与血管介导的损伤一致。相比之下，接受偶联物治疗动物的高度血管化正常组织未显示出血或组织损伤的迹象。偶联物耐受性良好，无明显毒性。我们的结果说明了一种选择性靶向肿瘤新生血管的VEGF-毒素偶联物的抗肿瘤活性。
