Farinelle S, Malonne H, Chaboteaux C, Decaestecker C, Dedecker R, Gras T, Darro F, Fontaine J, Atassi G, Kiss R
Laboratory of Histopathology, Faculty of Medicine, Université Libre de Bruxelles, 808 route de Lennik, 1070 Brussels, Belgium.
J Pharmacol Toxicol Methods. 2000 Jan-Feb;43(1):15-24. doi: 10.1016/s1056-8719(00)00080-0.
The aim of the present work is to characterize (both in vitro and in vivo) the influence of TNP-470 on different cell functions involved in angiogenesis and, more particularly, on endothelial cell growth, cell migration and vessel formation. In addition, a possible direct anti-tumor activity was investigated. To this end, we made use in vitro of human umbilical cord endothelial vein (HUVEC) cells and two human cancer cell lines. The TNP-470 effects on the growth of cancer cell lines were compared to those of Taxol (an inhibitor of microtubule depolymerization), a cytotoxic reference which also displays strong antiogenic activity at low (non-toxic) doses. The in vitro effects were characterized on the mouse mammary MXT adenocarcinoma, on which we also characterized the influence of three clinically active anti-tumor compounds (as cytotoxic references). The purpose of this part of the study was to determine the actual TNP-470-related anti-tumor activity and to evaluate the possible toxic side-effects at the doses at which this compound induces tumor growth inhibition. These investigations were completed by analyzing the TNP-470 effects on HUVEC cell motility and in vitro and in vivo vessel formation. The results show that in vitro, TNP-470 inhibited the growth not only of HUVEC, but also of neoplastic cells. Furthermore, TNP-470 clearly inhibited in vitro endothelial cell motility (p<10(-5)). However, it had only a minor effect (p=0.02) on the formation of HUVEC cell networks on Matrigel(R). In vivo, TNP-470 was able to inhibit tumor growth (on the MXT model) at a dose (50 mg/kg) associated with toxic side-effects. Histological examination showed a significant inhibition of vessel formation (p<0.001) at high (toxic) and intermediary (non-toxic) doses (50 and 20 mg/kg). However, we also observed that TNP-470 stimulated lymphocyte proliferation. Thus, care must be taken with the TNP-470 compound in combination with other anti-tumoral agents in order to avoid certain unfortunate clinical complications.
本研究的目的是（在体外和体内）表征TNP - 470对血管生成中涉及的不同细胞功能的影响，更具体地说，是对内皮细胞生长、细胞迁移和血管形成的影响。此外，还研究了其可能的直接抗肿瘤活性。为此，我们在体外使用了人脐静脉内皮细胞（HUVEC）和两种人类癌细胞系。将TNP - 470对癌细胞系生长的影响与紫杉醇（一种微管解聚抑制剂）进行了比较，紫杉醇是一种细胞毒性对照物，在低（无毒）剂量下也显示出强大的抗血管生成活性。在小鼠乳腺MXT腺癌上表征了体外效应，我们还表征了三种临床活性抗肿瘤化合物（作为细胞毒性对照物）的影响。本研究这一部分的目的是确定与TNP - 470相关的实际抗肿瘤活性，并评估该化合物在诱导肿瘤生长抑制的剂量下可能产生的毒副作用。通过分析TNP - 470对HUVEC细胞运动性以及体外和体内血管形成的影响，完成了这些研究。结果表明，在体外，TNP - 470不仅抑制了HUVEC的生长，还抑制了肿瘤细胞的生长。此外，TNP - 470在体外明显抑制了内皮细胞的运动性（p<10(-5)）。然而它对基质胶上HUVEC细胞网络的形成仅有轻微影响（p = 0.02）。在体内，TNP - 470在与毒副作用相关的剂量（50 mg/kg）下能够抑制肿瘤生长（在MXT模型上）。组织学检查显示，在高（有毒）和中（无毒）剂量（50和20 mg/kg）下，血管形成受到显著抑制（p<0.001）。然而，我们还观察到TNP - 470刺激淋巴细胞增殖。因此，在将TNP - 470化合物与其他抗肿瘤药物联合使用时必须谨慎，以避免某些不良的临床并发症。
