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TNP-470
promotes initial vascular sprouting in xenograft tumors
Huang J, Frischer JS, New T, Kim ES, Serur A, Lee A,
Kadenhe-Chiwishe A, Pollyea DA, Yokoi A, Holash J, Yancopoulos GD,
Kandel JJ, Yamashiro DJ
Division
of Pediatric Surgery, College of Physicians and Surgeons of
Columbia University, New York, NY, USA.
TNP-470 (AGM-1470), an analogue of fumagillin, was one of the
first molecules proposed to have antiangiogenic properties.
This concept was based on its ability to inhibit both endothelial
proliferation in vitro and tumor growth in vivo in a number of
xenograft models.
Yet, subsequent investigations indicated that the biochemical
activities associated with TNP-470 are not selective for
endothelial cells.
Moreover, recent evidence suggests that this agent inhibits tumor
growth in vivo, but without a corresponding decrease in
angiogenesis.
Therefore, we performed a detailed comparison of TNP-470 to a
validated antiangiogenic agent, a VEGF inhibitor termed VEGF-Trap,
using a xenograft model of Wilms tumor.
Treatment with TNP-470 for 5 weeks significantly suppressed
xenograft growth (83%).
Surprisingly, this inhibition was not associated with a decrease
in angiogenesis, but instead with an increase in tiny
neovessels.
To determine whether this was a direct effect of TNP-470 on tumor
vessels, we examined its effect in a short-term assay using large
tumors with established vasculature.
In contrast to treatment with VEGF-Trap, which led to rapid vessel
regression and tumor hypoxia, tumors exposed to TNP-470 for 1 day
displayed increased capillary sprouting, with significantly
increased microvessel density, vessel length, and branch
points.
TNP-470 did not induce tumor hypoxia as demonstrated by minimal
pimonidazole staining and VEGF expression.
TNP-470 did, however, cause a marked increase in apoptosis of
tumor cells.
Our results indicate that the antitumor effects of TNP-470 cannot
be attributed to prevention of neoangiogenesis, but instead to its
direct action on tumor cells.
PMID: 15026554
[PubMed - indexed for MEDLINE]
Source:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15026554
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