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Combinatorial treatment with carboxyamidotriazole- orotate and temozolomide in sc-implanted human LOX IMVI melanoma xenografts

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Author(s): Rashida A Karmali | Yulia Y. Maxuitenko | Greg S. Gorman | Zhican Qu

Journal: Journal of Solid Tumors
ISSN 1925-4067

Volume: 2;
Issue: 5;
Date: 2012;
Original page

ABSTRACT
Background: Carboxyamidotriazole orotate (CTO) is the orotic acid salt of 5-amino-1(4-(4-chlorobenzoyl)-3, 5-dichlorobenzyl)-1, 2, 3-triazole-4-carboxamide (CAI). CTO possesses increased solubility as compared to CAI as the free base. The antiproliferative and antimetastatic effects of CTO are related to inhibition of receptor-operated, calcium-channel-mediated calcium influx. CTO can inhibit calcium-sensitive signal transduction in the VEGF and the PI3K pathways, inhibition of FGF-2-induced tyrosine kinase, VEGF-mediated activation of phospholipase Cy, generation of IP3 and nitric oxide synthase activation, and induction of apoptosis in imatinib mesylate resistant CML cells by downregulating bcr-abl. Methods: Different combinations of CTO and temozolomide were first tested in female athymic NCr-nu/nu mice to evaluate tolerance of the combination. The tolerated combinations were then tested to evaluate the antitumor activity against subcutaneously implanted human LOX IMVI melanoma xenografts. Results: Oral CTO at doses of 513 or 342 mg/kg/dose Q1D×14 resulted in inhibition of tumor growth (p

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