Combined Therapy with Direct and Indirect Angiogenesis Inhibition Results in Enhanced Antiangiogenic and Antitumor Effects

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Author list: Sckell A
Publisher: American Association for Cancer Research
Publication year: 2003
Volume number: 63
Issue number: 24
Start page: 8890
End page: 8898
Number of pages: 9
ISSN: 0008-5472
Languages: English-Great Britain (EN-GB)


The multifaceted nature of the angiogenic process in malignant neoplasms
suggests that protocols that combine antiangiogenic agents may be more
effective than single-agent therapies. However it is unclear which
combination of agents would be most efficacious and will have the
highest degree of synergistic activity while maintaining low overall
toxicity. Here we investigate the concept of combining a "direct"
angiogenesis inhibitor (endostatin) with an "indirect" antiangiogenic
compound [SU5416, a vascular endothelial growth factor receptor 2
(VEGFR2) receptor tyrosine kinase (RTK) inhibitor]. These angiogenic
agents were more effective in combination than when used alone in vitro
(endothelial cell proliferation, survival, migration/invasion, and tube
formation tests) and in vivo. The combination of SU5416 and low-dose
endostatin further reduced tumor growth versus monotherapy in human
prostate (PC3), lung (A459), and glioma (U87) xenograft models, and
reduced functional microvessel density, tumor microcirculation, and
blood perfusion as detected by intravital microscopy and
contrast-enhanced Doppler ultrasound. One plausible explanation for the
efficacious combination could be that, whereas SU5416 specifically
inhibits vascular endothelial growth factor signaling, low-dose
endostatin is able to inhibit a broader spectrum of diverse angiogenic
pathways directly in the endothelium. The direct antiangiogenic agent
might be able to suppress alternative angiogenic pathways up-regulated
by the tumor in response to the indirect, specific pathway inhibition.
For future clinical evaluation of the concept, a variety of agents with
similar mechanistic properties could be tested.


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Last updated on 2019-10-08 at 00:30