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TNP-470: an angiogenesis inhibitor in clinical development for cancer
1National Cancer Institute/NIH, Medicine Branch, 9000 Rockville Pike, Bethesda, MD 20892, USA.
Abstract:
TNP-470, an analogue of fumagillin, has been shown to inhibit angiogenesis in vitro and in vivo. In 1992, TNP-470 entered clinical development for cancer as an anti-angiogenic agent. It is currently in Phase I/II trials in Kaposi's sarcoma, renal cell carcinoma, brain cancer, breast cancer, cervical cancer and prostate cancer. In early clinical reports, TNP-470 is tolerated up to 177 mg/m(2) with neurotoxic effects (fatigue, vertigo, ataxia, and loss of concentration) being the principal dose limiting toxicity (DLT). Terminal half-life values are short and have shown intermittent and intrapatient variation (range: 0.05 - 1.07 h). Recently, mechanistic studies have identified cell cycle mediators and the protein methionine aminopeptidase-2 (MetAP-2) as molecular targets of TNP-470 and fumagillin. Animal studies confirm some toxic effects on normal angiogenic processes such as the female reproductive system and wound healing, which will require caution and close monitoring in the clinic. TNP-470 is one of the first anti-angiogenic compounds to enter clinical trials, making it a valuable prototype for future trials of angiogenesis inhibitors in oncology.
Insights
TNP-470, an angiogenesis inhibitor, targets methionine aminopeptidase-2 (MetAP-2) and is in clinical trials for various cancers. Early studies show dose-limiting neurotoxicity and short half-life, requiring careful monitoring.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- TNP-470, a fumagillin analogue, inhibits angiogenesis, a process crucial for tumor growth.
- Angiogenesis inhibitors are a key strategy in modern cancer therapy.
- TNP-470 entered clinical development in 1992 for cancer treatment.
Purpose of the Study:
- To evaluate the clinical efficacy and safety of TNP-470 as an anti-angiogenic agent.
- To identify the molecular targets and mechanisms of action of TNP-470.
- To assess the pharmacokinetic profile and dose-limiting toxicities of TNP-470.
Main Methods:
- Phase I/II clinical trials in patients with Kaposi's sarcoma, renal cell carcinoma, brain, breast, cervical, and prostate cancers.
- Pharmacokinetic studies to determine terminal half-life and interpatient variability.
- Mechanistic studies to identify molecular targets, including cell cycle mediators and MetAP-2.
Main Results:
- TNP-470 is tolerated up to 177 mg/m(2), with neurotoxicity (fatigue, vertigo, ataxia) as the principal dose-limiting toxicity (DLT).
- Short and variable terminal half-life (0.05 - 1.07 h) observed.
- Mechanistic studies identified MetAP-2 as a molecular target.
- Animal studies indicated potential toxicity to normal angiogenic processes like reproduction and wound healing.
Conclusions:
- TNP-470 is a pioneering anti-angiogenic compound with potential in oncology.
- Further clinical evaluation is warranted, with careful monitoring for neurotoxicity and other side effects.
- Understanding TNP-470's mechanism and toxicity profile provides a basis for future angiogenesis inhibitor development.