Inhibition of angiogenesis by non-toxic doses of temozolomide
作者:
Hjalmar Kurzen,
Stefan Schmitt,
Helmut Näher,
Thomas Möhler,
期刊:
Anti-Cancer Drugs
(OVID Available online 2003)
卷期:
Volume 14,
issue 7
页码: 515-522
ISSN:0959-4973
年代: 2003
出版商: OVID
关键词: endothelium;cancer;metronomic therapy;triazene
数据来源: OVID
摘要:
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 thein vivochorioallantoic membrane (CAM) assay, and HUVEC-basedin vitroMatrigel, adhesion and proliferation assays to determine the antiangiogenic effects of different doses of TMZ. In the CAM assay, angiogenesis was significantly inhibited by 5 μM TMZ, a concentration also found to be effective in interfering within vitroangiogenesis as measured by the Matrigel assay. For the inhibition of basic fibroblast growth factor (bFGF)-, vascular endothelial growth factor (VEGF)- or &bgr;-phorbol 12-myristate-13-acetate (PMA)-induced endothelial cell proliferation or endothelial cell adhesion to fibronectin, TMZ concentrations of at least 25 μM 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/m2every 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.
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