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 Carboxyamidotriazole orotate

Carboxyamidotriazole orotate (CTO) is the orotate salt form of carboxyamidotriazole (CAI), an orally bioavailable small molecule with potential antiangiogenic and antiproliferative activities. Carboxyamidotriazole binds to and inhibits non-voltage-operated calcium channels, blocking both Ca2+ influx into cells and Ca2+ release from intracellular stores, resulting in the disruption of calcium channel-mediated signal transduction. CAI inhibits PI3 activity and vascular endothelial growth factor (VEGF) signaling. This may inhibit endothelial proliferation, tumor cell growth, invasion and metastasis. Check for active clinical trials or closed clinical trials using this agent. (NCI Thesaurus) .

Carboxyamidotriazole (CAI) was originally developed as an anti-parasitic agent but has since been shown to have anti-angiogenic effects, probably due to inhibition of voltage-independent calcium signal transduction necessary for VEGF-induced endothelial proliferation. This has led to investigation of this agent as an inhibitor of tumor growth due to interference with the formation of an adequate microvasculature to support such growth. Such anti-angiogenic activity has been shown in chick chorioallantotic membrane assay and human umbilical vein endothelial cells in vitro. CAI inhibits proliferation characteristics in several tumor cell lines in vitro such as prostate, glioblastoma, breast cell lines and others  and in cancer patients. Orally administered CAI showed a decrease in tumor volume and blood vessel density in tumors from nude mouse xenografts of human melanoma implants.

CAI is a small molecule inhibitor of non-voltage gated channels, calcium influx and intracellular calcium signaling and regulation. It inhibits transmembrane calcium flux in nonexcitable cells including endothelium and cancer cells. CAI down regulates inhibits production of basic fibroblast growth factor signaling, matrix metalloproteinase-2 production and VEGF-stimulted proliferation and motility. CAI also reduces production of VEGF and IL-8 from tumor and endothelial cells. The effects on calcium flux center around disruption of thapsigargin induced calcium entry, G-protein coupled recetor mediated calcium influx and influx downstream of IP3.

Clinical trials have been done characterizing its pharmacokinetic and pharmacodynamic profile with variable results, perhaps due in part to the variable pharmacokinetic profile and poor bioavailability of CAI . Due to its hydrophobic properties, oral absorption of CAI is variable and low, most likely <57%. Increasing aqueous solubility by synthesizing the orotate salt form of CAI may increase oral bioavailability and reduce the time of appearance of CAI into the bloodstream. (source: http://www.cancer-therapy.org/CT/v5/B/HTML/48.%20Grover_et_al,_437-442.html).

Current developer:    Tactical Therapeutics.

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