Background: Paclitaxel (PTX) is approved for the treatment of refractory ovarian cancer and breast cancer, but is problematic due to severe, dose-dependent, potentially irreversible neurotoxicity. Alternative formulations using nanoparticles and liposomes have been developed to avoid solvent-related toxicity. These formulations allow improved delivery; however, toxicity, compensatory signaling, and drug resistance still pose challenges. Conversion of cytotoxic agents to their orotate compounds offers a potentially improved approach by increasing bioavailability and reducing toxicity. Orotate salts are neutral and acquire lipophilic properties, easing diffusion through lipid membranes. The orotate salt of PTX (PTXO) may yield an improved safety profile. Combination therapy with cytotoxic drugs, antiangiogenics and/or signal transduction pathway inhibitors has shown better efficacy than cytotoxic monotherapy. The combination of carboxyamidotriazole orotate (CTO, a calcium signal transduction pathway inhibitor) and PTX may be more effective than PTX alone at non-toxic doses. Materials and Methods: PTXO alone, and combinations of CTO with PTX and PTXO were first tested in female athymic NCr-nu/nu mice to evaluate tolerance of the combinations. The tolerated combinations, PTX monotherapy, and PTXO monotherapy were then tested to evaluate their antitumor activity in female athymic NCr-nu/nu mice with subcutaneously implanted OVCAR-5 human ovarian tumor. Antitumor activity was measured by median time to doubling, median tumor growth delay, and mean percent body weight loss. Results: CTO, PTX, and PTXO showed significant inhibition of growth of the human OVCAR-5 ovarian tumor xenografts. The combination of low PTX and CTO, or high PTXO monotherapy, had significant efficacy and it was less toxic than high PTX as measured by body weight loss. Conclusions: Low-dose CTO is effective and has low toxicity, suggesting the potential for maintenance therapy for ovarian cancer. PTXO offers efficacy and a strategy for minimizing body weight loss, and may improve outcomes for patients who demonstrate toxicity to PTX.
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