Concentration- and schedule-dependent effects of chemotherapy on the angiogenic potential and drug sensitivity of vascular endothelial cells

Abstract

The anti-angiogenic activity of chemotherapy is both dose- and schedule-dependent. While conventional maximum tolerated dose (MTD) chemotherapy exerts only mild and reversible anti-angiogenic effects, low-dose metronomic (LDM) chemotherapy was developed to specifically target tumour angiogenesis. However, the long-term effects of either MTD or LDM chemotherapy on vascular endothelial cells have never been investigated. Here, we demonstrated that repeated exposure to MTD and LDM chemotherapy differentially impact on the angiogenic potential and chemosensitivity of immortalized endothelial cells. Repeated MTD vinblastine treatment of vascular endothelial cells led to an increased proliferation rate and resistance to paclitaxel. In contrast, repeated LDM treatment with vinblastine or etoposide impaired the angiogenic potential of endothelial cells and increased their chemosensitivity. This effect was associated with a significant decrease in βII- and βIII-tubulin expression. Functional analysis using siRNA showed that silencing the expression of βIII-tubulin in endothelial cells significantly decreased their capacity to form vascular structures and increased their sensitivity to the anti-angiogenic and vascular-disrupting effects of chemotherapy, whereas silencing βII-tubulin expression had no effect. Collectively our results show that LDM chemotherapy impairs the angiogenic potential of endothelial cells while increasing their chemosensitivity—an effect at least in part mediated by the down-regulation of βIII-tubulin expression. Furthermore, our study suggests that βIII-tubulin represents an attractive therapeutic target to increase the anti-angiogenic effects of chemotherapy and overall anti-tumour efficacy.Electronic supplementary materialThe online version of this article (doi:10.1007/s10456-012-9321-x) contains supplementary material, which is available to authorized users.

Cisplatin, Etoposide, and Bevacizumab Regimen Followed by Oral Etoposide and Bevacizumab Maintenance Treatment in Patients With Extensive-Stage Small Cell Lung Cancer: A Single-Institution Experience

“…29 Indeed, it has been suggested that the repeated exposure to low-dose metronomic treatment with oral E might impair the angiogenic potential of endothelial cells and increase their chemosensitivity. 30 These preclinical data might further support the rationale for the current study in which, indeed, the combination of the antiangiogenic agent Bev with low-dose metronomic oral E was used as maintenance treatment after induction chemotherapy in patients with ED-SCLC who responded to treatment. We acknowledge that our findings, even if promising, are derived from a small single-institution experience.…”

Role of vascular normalization in benefit from metronomic chemotherapy

“…The antiangiogenic effect of metronomic chemotherapy on the tumor vasculature may be mediated via increased levels of the endogenous angiogenesis inhibitor thrombospondin-1 (TSP-1) (6). TSP-1 is produced not only by stromal cells, but also by cancer cells (7), and induces apoptosis in circulating endothelial cells (8)(9)(10)(11). Other negative regulators of angiogenesis (e.g., endostatin, soluble VEGF receptors) also can affect vascular function (6).…”

Effects of Neoadjuvant Chemotherapy and Radiotherapy on Flap Perfusion in a Novel Mouse Model Using Standard Clinical Assessment and Near-Infrared Fluorescence Angiography

“…Chemotherapy hampers the infl ammatory response, reducing oxygen delivery to the wound and increasing the likelihood of infection [15]. Lawrence et al, found that these delays in wound healing were especially pronounced in cases where chemotherapeutic agents were administered pre-operatively or within 3 weeks post-operatively [7].…”