TNP-470 (AGM-1470, (3R,4S,5S,6R)-5-methoxy-4- [(2R,3R)-2-methyl-3-(3-methyl-2-butenyl) -oxiranyl]-1-oxaspiro[2,5]oct-6-yl(chloroacetyl) carbamate) is an anti-angiogenic, semisynthetic analogue of fumagillin, a known antibiotic secreted by the fungus Aspergillus fumigatus fresenius, which is under clinical development for the treatment of cancer by Takeda Chemical Industries Ltd. in Japan and TAP Pharmaceuticals, Inc. in the United States. TNP-470 binds to and irreversibly inactivates methionine aminopeptidase-2 (MetAP2), resulting in endothelial cell cycle arrest late in the G1 phase and inhibition of tumor angiogenesis. This agent may also induce the p53 pathway, thereby stimulating the production of cyclin-dependent kinase inhibitor p21 and inhibiting angiogenesis. 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). TNP-470 is being evaluated in Phase I-II trials in the US in patients with Kaposi’s sarcoma, cervical cancer, breast cancer, brain cancer, prostate cancer and renal cell carcinoma.

Fumagillin, an antimicrobial compound first isolated in 1949 from the fungus Aspergillus fumigatusa, naturally occurring water-insoluble antibacterial agent developed by sanofi-aventis, is approved in France for the treatment of microsporidiosis. Fumagillin (Flisint, Sanofi-Aventis, Paris, France) has been approved in France since 2002 for the treatment of intestinal microsporidiosis due to E. bieneusi in patients with AIDS, and is also available through an expanded access program for patients without AIDS. It has not been approved, however, by the US Food and Drug Administration. The discovery of fumagillin, a MetAP-2 inhibitor, with potent antiangiogenic and antiproliferative activities promoted the development of fumagillin analogues as a novel class of anticancer agents. It has been the subject of research in cancer treatments by employing its angiogenesis inhibitory properties.

Nitroxoline (8-hydroxy-5-nitroquinoline) has been used since 1962 in the treatment of urinary tract infections especially those due to gram negative bacilli (E. coli). Nitroxoline is active against most Gram-negative and –positive uropathogenic bacteria, against mycoplasmas (M. hominis, Ureaplasma urealyticum) and human pathogenic Candida spp. The mode of antibacterial and antifungal action is based on the ability of nitroxoline to chelate with various metallic bivalent cations. Nitroxoline is a fluorquinolone that is active against bacterial gyrases. This drug may also have antitumor activity by inhibition of type 2 methionine aminopeptidase (MetAP2) protein which is involved in angiogenesis. Nitroxoline induces apoptosis and inhibits glioma growth in vivo and in vitro. Due to the excellent anticancer activity and its well-known safety profile and pharmacokinetic properties, nitroxoline has been approved to enter into a phase II clinical trial in China for non-muscle invasive bladder cancer treatment

Fumagillin, an antimicrobial compound first isolated in 1949 from the fungus Aspergillus fumigatusa, naturally occurring water-insoluble antibacterial agent developed by sanofi-aventis, is approved in France for the treatment of microsporidiosis. Fumagillin (Flisint, Sanofi-Aventis, Paris, France) has been approved in France since 2002 for the treatment of intestinal microsporidiosis due to E. bieneusi in patients with AIDS, and is also available through an expanded access program for patients without AIDS. It has not been approved, however, by the US Food and Drug Administration. The discovery of fumagillin, a MetAP-2 inhibitor, with potent antiangiogenic and antiproliferative activities promoted the development of fumagillin analogues as a novel class of anticancer agents. It has been the subject of research in cancer treatments by employing its angiogenesis inhibitory properties.