Inhibition of angiogenesis by non-toxic doses of temozolomide.

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Anticancer Drugs. 2003 Aug;14(7):515-22.

Kurzen H, Schmitt S, Näher H, Möhler T.
Department of Dermatology, University of Heidelberg, Germany.

 
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.