title: TNP-470 promotes initial vascular sprouting in xenograft tumors.
abstract: 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.
authors.affiliation: Division of Pediatric Surgery, College of Physicians and Surgeons of Columbia University, New York, NY, USA.
authors.forename: Jianzhong
authors.initials: J
authors.lastname: Huang
authors.forename: Jason S
authors.initials: JS
authors.lastname: Frischer
authors.forename: Tamara
authors.initials: T
authors.lastname: New
authors.forename: Eugene S
authors.initials: ES
authors.lastname: Kim
authors.forename: Anna
authors.initials: A
authors.lastname: Serur
authors.forename: Alice
authors.initials: A
authors.lastname: Lee
authors.forename: Angela
authors.initials: A
authors.lastname: Kadenhe-Chiwishe
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Pollyea
authors.forename: Akiko
authors.initials: A
authors.lastname: Yokoi
authors.forename: Jocelyn
authors.initials: J
authors.lastname: Holash
authors.forename: George D
authors.initials: GD
authors.lastname: Yancopoulos
authors.forename: Jessica J
authors.initials: JJ
authors.lastname: Kandel
authors.forename: Darrell J
authors.initials: DJ
authors.lastname: Yamashiro
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000792:Angiography; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis; D002196:Capillaries / Q000473:pathology; D045744:Cell Line, Tumor; D003510:Cyclohexanes; D019793:Fluorescein / Q000494:pharmacology; D006801:Humans; D000860:Hypoxia; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D020287:In Situ Nick-End Labeling; D037102:Lectins / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D008833:Microcirculation; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000473:pathology; D009389:Neovascularization, Pathologic; D009593:Nitroimidazoles / Q000494:pharmacology; D000077609:O-(Chloroacetylcarbamoyl)fumagillol; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology; D012717:Sesquiterpenes / Q000494:pharmacology*; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis / Q000378:metabolism; D009396:Wilms Tumor
chemical_list: D020533:Angiogenesis Inhibitors; D000903:Antibiotics, Antineoplastic; D003510:Cyclohexanes; D037102:Lectins; D009593:Nitroimidazoles; D011838:Radiation-Sensitizing Agents; D012717:Sesquiterpenes; D042461:Vascular Endothelial Growth Factor A; C033815:pimonidazole; D019793:Fluorescein; D000077609:O-(Chloroacetylcarbamoyl)fumagillol