Effects of novel and conventional anti-cancer agents on human endothelial permeability: influence of tumour secreted factors.

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.