Inhibition of angiogenesis by non-toxic doses of temozolomide

Abstract

It is well established that certain chemotherapeutic agents have potent antiangiogenic properties which may be part of their antitumor activity. Temozolomide (TMZ) is a lipophilic methylating agent used in the therapy of malignant melanoma and other tumors. We sought to determine whether TMZ is capable of inhibiting angiogenesis or influencing endothelial function. We used the in vivo chorioallantoic membrane (CAM) assay, and HUVEC-based in vitro Matrigel, adhesion and proliferation assays to determine the antiangiogenic effects of different doses of TMZ. In the CAM assay, angiogenesis was significantly inhibited by 5 microM TMZ, a concentration also found to be effective in interfering with in vitro angiogenesis as measured by the Matrigel assay. For the inhibition of basic fibroblast growth factor (bFGF)-, vascular endothelial growth factor (VEGF)- or beta-phorbol 12-myristate-13-acetate (PMA)-induced endothelial cell proliferation or endothelial cell adhesion to fibronectin, TMZ concentrations of at least 25 microM were necessary, indicating that bFGF-, VEGF- or protein kinase C-mediated pathways may not primarily be involved in the observed antiangiogenic effect. Thus, we could demonstrate that TMZ inhibits angiogenesis at low, non-toxic doses that correspond to the plasma concentrations achieved by an oral application of 20 mg/m2 every 8 h. This 'metronomic' scheduling has already been used in phase I studies and has produced antitumor effects. Therefore, the antitumor activity of TMZ may, at least in part, be due to its antiangiogenic properties. The precise mechanism of its antiangiogenic action remains to be elucidated.

Improved tumor oxygenation and survival in glioblastoma patients who show increased blood perfusion after cediranib and chemoradiation

“…Temozolomide may have mild antiangiogenic properties when given at a low daily dose (i.e., a "metronomic" schedule), which might explain the elevated perfusion in this one patient (24). However, the higher prevalence of increased perfusion in patients treated with cediranib suggests that antiangiogenic therapy with cediranib contributed to the elevated blood perfusion.…”

Synergistic inhibition of angiogenesis and glioma cell-induced angiogenesis by the combination of temozolomide and enediyne antibiotic lidamycin

“…It has been addressed that the antitumor activity of TMZ may, 45 at least in part, be due to its anti-angiogenic properties. Some in vivo animal experiments also indicated that the anti-glioma effects of TMZ alone or in combination therapies are associated with anti-angiogenesis.…”

Canadian Recommendations for the Treatment of Recurrent or Progressive Glioblastoma Multiforme

“…In vitro studies have indicated that low-dose temozolomide, at a concentration equivalent to 20 mg/ m 2 every 8 hours, inhibits angiogenesis 79 . Preliminary studies have reported that continuous low-dose temozolomide plus a cyclooxygenase 2 inhibitor has anti-angiogenic effects and is well tolerated 80,81 .…”