Watts M E, Woodcock M, Arnold S, Chaplin D J
Gray Laboratory Cancer Research Trust, Mount Vernon Hospital, Northwood, Middlesex, U.K.
Anticancer Res. 1997 Jan-Feb;17(1A):71-5.
A number of anti-cancer agents have been implicated in vascular toxicity. The effects have been attributed to direct drug toxicity towards endothelium. Little attention has been focussed on the interaction between anticancer drugs, endothelial cells and tumour secreted factors. It is well known that tumours can secrete factors such as vascular permeability factor which do affect endothelial cells and could alter their response to the vascular effects of anticancer drugs. In the present study, we have examined, in vitro, the direct effects of vinblastine (VBL), 5-fluorouracil (5-FU), melphalan (L-PAM) and the novel tubulin inhibitor combretastatin A-1 (CBS) on endothelial permeability under normal and tumour simulated conditions. Monolayers of human umbilical vein endothelial cells (HUVEC) grown on membrane filters were incubated in drug in normal growth medium or medium conditioned by the human melanoma cell line, RPMI-7951 (TCM). VBL caused a rapid increase in permeability during the first 20 minutes, which was maintained for the duration of the experiment (120 minutes). The effect was not altered by TCM or restored to control levels when VBL was replaced by drug-free medium. Similarly, CBS caused a rapid increase in permeability; however, in contrast to VBL, this increase was enhanced by TCM. The changes induced by VBL and CBS were accompanied by contraction of the endothelial F-actin cytoskeleton. Neither L-PAM nor 5-FU altered the permeability of HUVEC monolayers. This study demonstrates that certain anti-cancer agents have a direct effect on endothelial cells, leading to an increase in the permeability of endothelial monolayers. Both VBL and CBS have vascular components in their mode of action which may lead to vascular collapse and tumour necrosis.
许多抗癌药物都与血管毒性有关。这些影响被归因于药物对内皮细胞的直接毒性。人们很少关注抗癌药物、内皮细胞和肿瘤分泌因子之间的相互作用。众所周知，肿瘤可以分泌诸如血管通透性因子等因子，这些因子确实会影响内皮细胞，并可能改变它们对抗癌药物血管效应的反应。在本研究中，我们在体外研究了长春碱（VBL）、5-氟尿嘧啶（5-FU）、美法仑（L-PAM）和新型微管蛋白抑制剂康普瑞汀A-1（CBS）在正常和肿瘤模拟条件下对内皮通透性的直接影响。将生长在膜滤器上的人脐静脉内皮细胞（HUVEC）单层培养物在正常生长培养基或由人黑色素瘤细胞系RPMI-7951（TCM）条件培养的培养基中与药物一起孵育。VBL在最初20分钟内导致通透性迅速增加，并在实验持续时间（120分钟）内保持。TCM不会改变这种效应，当用无药物培养基替换VBL时，通透性也不会恢复到对照水平。同样，CBS也导致通透性迅速增加；然而，与VBL不同的是，TCM增强了这种增加。VBL和CBS诱导的变化伴随着内皮F-肌动蛋白细胞骨架的收缩。L-PAM和5-FU均未改变HUVEC单层的通透性。本研究表明，某些抗癌药物对内皮细胞有直接作用，导致内皮单层通透性增加。VBL和CBS的作用方式都有血管成分，这可能导致血管塌陷和肿瘤坏死。
