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 formulat...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.展开更多
Pre-clinical studies suggest carboxyamidotriazole orotate (CTO) demonstrates anti-tumor activity through modulation of multiple tyrosine kinase signaling pathways and interactions with the tumor microenvironment. We d...Pre-clinical studies suggest carboxyamidotriazole orotate (CTO) demonstrates anti-tumor activity through modulation of multiple tyrosine kinase signaling pathways and interactions with the tumor microenvironment. We determined the safety and tolerability, pharmacokinetic profile, maximum tolerated dose, and recommended Phase II dose of CTO monotherapy in patients with advanced solid tumors. In this first-in-human Phase I clinical trial, eligible patients with advanced solid tumors were enrolled to receive a once-daily dose of CTO following a standard 3 + 3 Phase I design (starting at 50 mg/m2/day) with dose escalations of 30% - 100%. Dose limiting toxicity (DLT) was defined in the first cycle of treatment. Measurable disease and response were defined by RECIST version 1.1. Forty-four patients were evaluable for safety. CTO-related grade 3 toxicities included diarrhea (2.5%), fatigue (5.0%), lymphopenia (2.5%) and transient creatine phosphokinase (CPK) elevation (2.5%). There were no grade 4 or 5 toxicities. Steady state plasma levels of CAI (CTO metabolite) were achieved by day 12 with a half life estimate of 55 hr. Although no objective response rates were observed, nine patients with rapidly progressive and treatment-refractory tumors achieved stable disease (SD) durable for up to 14 months. The maximum tolerated dose for CTO alone was 427 mg/m2/day. The dose-limiting toxicity was grade 3 fatigue. CTO is orally bioavailable, safe, well tolerated and produces disease stabilization in a broad range of heavily treated refractory tumors. Combination trials of CTO with other antineoplastic agents are ongoing.展开更多
Background: Doxorubicin (DOX) is an effective treatment for many cancers across the age spectrum, but its therapeutic potential is limited because of dose-dependent relation to both progressive and irreversible cardio...Background: Doxorubicin (DOX) is an effective treatment for many cancers across the age spectrum, but its therapeutic potential is limited because of dose-dependent relation to both progressive and irreversible cardiomyopathy leading to congestive heart failure. While decreases in cardiotoxicity have been reported with liposomal doxorubicin, the long-term cardiac effects are not known. Orotate salts of cytotoxic drugs have been shown to confer antitumor effects with a better safety profile than unconverted drug, and therefore may offer an improved approach to cancer treatment. Materials and Methods: Male, athymic NCr-nu/nu mice with subcutaneously implanted CAKI-1 human renal tumor xenografts were treated with DOX and its orotate salt (DOX-O) to evaluate antitumor activity, measured by median tumor mass doubling time and tumor weight. Nontumored male, athymic NCr-nu/nu mice were treated with DOX, DOX-O and liposomal doxorubicin formulations to determine DOX concentration in liver and heart;and to evaluate their effect on body weight. Non-tumored female, athymic NCr-nu/nu mice were treated with daunorubicin and daunorubicin orotate to evaluate tolerance. Results: DOX and DOX-O exhibited significant, similar levels of antitumor activity. Mice treated with DOX-O had a lower percentage body weight loss. In the animals treated with DOX, DOX-O, or liposomal doxorubicin, liposomal doxorubicin was associated with the lowest percentage of body weight loss, but the highest concentration of DOX in heart. In daunorubicin tolerance experiments, animals showed a better tolerance for daunorubicin orotate as measured by a smaller percentage change in body weight. Conclusions: DOX-O is effective as an antitumor therapy and may offer a less toxic alternative to DOX for maintaining therapy. The lower percentage of body weight loss in animals treated with DOX-O and daunorubicin orotate is a measure of improved tolerance and may translate into better patient outcomes.展开更多
文摘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.
文摘Pre-clinical studies suggest carboxyamidotriazole orotate (CTO) demonstrates anti-tumor activity through modulation of multiple tyrosine kinase signaling pathways and interactions with the tumor microenvironment. We determined the safety and tolerability, pharmacokinetic profile, maximum tolerated dose, and recommended Phase II dose of CTO monotherapy in patients with advanced solid tumors. In this first-in-human Phase I clinical trial, eligible patients with advanced solid tumors were enrolled to receive a once-daily dose of CTO following a standard 3 + 3 Phase I design (starting at 50 mg/m2/day) with dose escalations of 30% - 100%. Dose limiting toxicity (DLT) was defined in the first cycle of treatment. Measurable disease and response were defined by RECIST version 1.1. Forty-four patients were evaluable for safety. CTO-related grade 3 toxicities included diarrhea (2.5%), fatigue (5.0%), lymphopenia (2.5%) and transient creatine phosphokinase (CPK) elevation (2.5%). There were no grade 4 or 5 toxicities. Steady state plasma levels of CAI (CTO metabolite) were achieved by day 12 with a half life estimate of 55 hr. Although no objective response rates were observed, nine patients with rapidly progressive and treatment-refractory tumors achieved stable disease (SD) durable for up to 14 months. The maximum tolerated dose for CTO alone was 427 mg/m2/day. The dose-limiting toxicity was grade 3 fatigue. CTO is orally bioavailable, safe, well tolerated and produces disease stabilization in a broad range of heavily treated refractory tumors. Combination trials of CTO with other antineoplastic agents are ongoing.
文摘Background: Doxorubicin (DOX) is an effective treatment for many cancers across the age spectrum, but its therapeutic potential is limited because of dose-dependent relation to both progressive and irreversible cardiomyopathy leading to congestive heart failure. While decreases in cardiotoxicity have been reported with liposomal doxorubicin, the long-term cardiac effects are not known. Orotate salts of cytotoxic drugs have been shown to confer antitumor effects with a better safety profile than unconverted drug, and therefore may offer an improved approach to cancer treatment. Materials and Methods: Male, athymic NCr-nu/nu mice with subcutaneously implanted CAKI-1 human renal tumor xenografts were treated with DOX and its orotate salt (DOX-O) to evaluate antitumor activity, measured by median tumor mass doubling time and tumor weight. Nontumored male, athymic NCr-nu/nu mice were treated with DOX, DOX-O and liposomal doxorubicin formulations to determine DOX concentration in liver and heart;and to evaluate their effect on body weight. Non-tumored female, athymic NCr-nu/nu mice were treated with daunorubicin and daunorubicin orotate to evaluate tolerance. Results: DOX and DOX-O exhibited significant, similar levels of antitumor activity. Mice treated with DOX-O had a lower percentage body weight loss. In the animals treated with DOX, DOX-O, or liposomal doxorubicin, liposomal doxorubicin was associated with the lowest percentage of body weight loss, but the highest concentration of DOX in heart. In daunorubicin tolerance experiments, animals showed a better tolerance for daunorubicin orotate as measured by a smaller percentage change in body weight. Conclusions: DOX-O is effective as an antitumor therapy and may offer a less toxic alternative to DOX for maintaining therapy. The lower percentage of body weight loss in animals treated with DOX-O and daunorubicin orotate is a measure of improved tolerance and may translate into better patient outcomes.
