TNP-470: The resurrection of the first synthetic angiogenesis inhibitor

Hagit Mann-Steinberg, Ronit Satchi-Fainaro*

*Corresponding author for this work

Research output: Chapter in Book/Report/Conference proceedingChapterpeer-review


TNP-470, an analogue of a naturally secreted antibiotic of Aspergillus fumigatus fresenius-named fumagillin, has been shown to inhibit angiogenesis in vitro and in vivo. TNP-470 was one of the first antiangiogenic compounds to enter clinical trials for cancer, making it a valuable prototype for future trials of angiogenesis inhibitors in oncology. It was halted in clinical Phase II trials following its evaluation in Kaposi's sarcoma, renal cell carcinoma, brain cancer, breast cancer, cervical cancer and prostate cancer. In early clinical reports, TNP-470 was tolerated up to 177 mg/m2 with neurotoxic effects being the principal dose limiting toxicity. To date, there are 500 papers published on TNP-470. They describe the antiangiogenic activity of TNP-470 including its anti-inflammatory, anti-infective and anti-obesity effects. Oxidative stress reduction and hyperpermeabilty decrease by TNP-470 account for yet another anti-cancer effect of this molecule. Mechanistic studies have identified cell cycle mediators and the protein methionine aminopeptidase-2 (MetAP-2) as molecular targets of TNP-470. Cell-cycle inhibition by TNP-470 is mediated at least in part by an activation of p21WAF1/CIP1 because of a p53-dependent mechanism, with reduction of the cyclin DCdk4 and cyclin E-Cdk 2 expression. Furthermore, it has been recently shown that FGFR1/PI3K/AKT signaling pathway is a novel target for the antiangiogenic effects of TNP-470. Coadministration of TNP-470 with chemotherapy increased drug delivery to the tumor followed by increased tumor response to cytotoxic therapy, implicating a potential role for these agents in combination treatment of solid tumors. Although TNP-470 is not approved for systemic use, this compound has one of the highest efficacies for the treatment of the broadest spectrum of tumor types. TNP-470 does exhibit side effects such as neurotoxicity that have deterred its acceptance as a viable treatment, but the current body of research on the synthesis of novel analogs and formulations of this molecule shows an exciting and promising resurrection of this drug as a potent antiangiogenic agent.

Original languageEnglish
Title of host publicationAngiogenesis
Subtitle of host publicationAn Integrative Approach From Science to Medicine
PublisherSpringer US
Number of pages20
ISBN (Print)9780387715179
StatePublished - 2008


  • TNP-470
  • angiogenesis
  • clinical trials
  • first angiogenesis inhibitor
  • fumagillin
  • polymer therapeutics
  • vascular permeability


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