The anti-angiogenic agent, diamino propane tetraiodothyroacetic acid (DAT), is a thyro-integrin (... more The anti-angiogenic agent, diamino propane tetraiodothyroacetic acid (DAT), is a thyro-integrin (integrin αvβ3) antagonist anticancer agent that works via genetic and nongenetic actions. Tetraiodothyroacetic acid (tetrac) and DAT as thyroid hormone derivatives influence gene expression after they transport across cellular membranes. To restrict the action of DAT to the integrin αvβ3 receptors on the cell surface, we used DAT-conjugated PLGA nanoparticles (NDAT) in an active targeting mode to bind to these receptors. Preparation and characterization of NDAT is described, and both in vitro and in vivo experiments were done to compare DAT to NDAT. Intracellular uptake and distribution of DAT and NDAT in U87 glioblastoma cells were evaluated using confocal microscopy and showed that DAT reached the nucleus, but NDAT was restricted from the nucleus. Pharmacokinetic studies using LC-MS/MS analysis in male C57BL/6 mice showed that administration of NDAT improved the area under the drug con...
The focus of this review is to discuss the hypothesis that justifies the use of dual antiplatelet... more The focus of this review is to discuss the hypothesis that justifies the use of dual antiplatelet therapy of aspirin and clopidogrel versus monotherapy with aspirin in arterial vascular disease. By analyzing the CLARITY-TIMI and COMMIT trials, the authors discuss the appropriate use of aspirin plus clopidogrel for patients suffering acute myocardial infarction. In contrast, in the CHARISMA trial, the combination was not justified in stable high-risk patients with documented coronary disease, cerebrovascular disease or symptomatic peripheral artery disease. In two additional cardiovascular studies, the CURE and the PCI-CURE trials, the benefit of the drug combination was evident in those patients who underwent percutaneous coronary intervention and coronary artery bypass grafting. Finally, two focused cerebrovascular studies, the CARESS and the MATCH trials, were analyzed. The CARESS trial demonstrated the clinical benefit of this combination in an acute clinical setting. However, the combination proved to be ineffective in the longer-term MATCH trial. It appears from these large clinical trials that the risk-benefit of dual antiplatelet therapy with aspirin and clopidogrel is justified in high-risk symptomatic patients but not in asymptomatic patients. The exact dose regimen and duration of combination therapy await definition and require careful assessment to optimize the anticoagulant benefit, while minimizing the hemorrhagic risk.
Chemically modified forms of tetraiodothyroacetic acid (tetrac), an L-thyroxine derivative, have ... more Chemically modified forms of tetraiodothyroacetic acid (tetrac), an L-thyroxine derivative, have been shown to exert their anticancer activity at plasma membrane integrin αvβ3 of tumor cells. Via a specific hormone receptor on the integrin, tetrac-based therapeutic agents modulate expression of genes relevant to cancer cell proliferation, survival and energy metabolism. P-bi-TAT, a novel bivalent tetrac-containing synthetic compound has anticancer activity in vitro and in vivo against Glioblastoma Multiforme (GBM) and other types of human cancers. In the current study, microarray analysis was carried out on a primary culture of human GBM cells exposed to P-bi-TAT (10-6 tetrac equivalent) for 24 h. P-bi-TAT significantly affected expression of a large panel of genes implicated in cancer cell stemness, growth, survival, and angiogenesis. Recent interest elsewhere in ATP synthase as a target in GBM cells caused us to focus attention on expression of genes involved in energy metabolism....
Cancer is a multifactorial disorder that induces mortality worldwide, and the colorectal type is ... more Cancer is a multifactorial disorder that induces mortality worldwide, and the colorectal type is the third most common cancer globally. Resveratrol (RSV) is a natural compound with an effective anticancer effect, especially against colorectal cancer, and therefore numerous studies recommended its use in colorectal cancer prevention and treatment. The current study investigated the effect of either RSV or its nanoformulation (NP-RSV) on the growth and vascularity of xenograft and orthotopic mice models in colon cancer (COLO205-luc). Both RSV and NP-RSV induced significant reductions in tumor growth and the hemoglobin percentages of the tumor mass, but NP-RSV showed greater bioavailability and efficacy than RSV. Generally, we recommend using NP-RSV as a therapeutic to control colon cancer.
Angiogenesis Modulations in Health and Disease, 2013
ABSTRACT Tetraiodothyroacetic acid (tetrac) is a naturally occurring derivative of thyroid hormon... more ABSTRACT Tetraiodothyroacetic acid (tetrac) is a naturally occurring derivative of thyroid hormone, T4. In the absence or presence of L-T4 or L-T3, tetrac has been found to disrupt a number of functions or events that are important to cancer cells via the known thyroid hormone-tetrac receptor on the plasma membrane integrin αvβ3. These functions include regulation of cell division, local stimulation of angiogenesis, chemo-resistance and resistance to radiation. It is desirable to reformulate tetrac as a nanoparticle whose activity is exclusively at the cell surface integrin. Nanotetrac has been designed to limit tetrac to the extracellular space on the basis of the size of the nanoparticle and to provide optimized exposure of the biphenyl structure and acetic acid side chain of its inner ring to the receptor site on αvβ3. Tetrac and its novel nanoparticulate formulation have anti-angiogenesis activity that transcends the inhibition of thyroid hormone-binding at the integrin. Restriction of nanotetrac to the extracellular space has been verified, and nanotetrac has been shown to be up to 10-fold more potent than unmodified tetrac at its integrin target. Nanotetrac formulations have potential applications as inhibitors of tumor-related angiogenesis and of angiogenesis that is unrelated to malignancy, including clinically significant disorders ranging from skin diseases to vascular proliferation in the retina and neovascularization associated with inflammatory states.
International angiology : a journal of the International Union of Angiology, 2005
Pharmacodynamic effects of the low molecular weight heparin tinzaparin on plasma levels of tissue... more Pharmacodynamic effects of the low molecular weight heparin tinzaparin on plasma levels of tissue factor pathway inhibitor (TFPI) and nitric oxide (NO) were compared in obese subjects, as well as in normal healthy controls. Obese (n = 13) patients received a single 75 IU/kg SC injection (the deep vein thrombosis prophylaxis dose) of tinzaparin. Blood samples were obtained pre- and postadministration of drug and at different intervals over 24 h and assayed for total TFPI and NO stable metabolites (nitrates and nitrites) plasma levels, using a specific immunoassay and calorimetric methods. Mean maximum plasma TFPI levels approached 150-230 ng/ml at the 0.8 h and up to 5 h posttinzaparin dose compared to basal TFPI levels of 35-90 ng/mL. Plasma TFPI levels were still about 2-fold above basal levels at 12 h and fell to basal levels at 16 h after tinzaparin dose. Basal plasma levels of NO, but not TFPI, were significantly lower (P < 0.01) in obese patients compared to controls. Simila...
Anticoagulants, Antiplatelets, and Thrombolytics, 2010
It is well established that the blood coagulation system is activated in cancer. In addition, the... more It is well established that the blood coagulation system is activated in cancer. In addition, there is considerable evidence to suggest that clotting activation plays an important role in the biology of malignant tumors, including the process of blood-borne metastasis. For many years our laboratory has used experimental models of lung metastasis to study the events that follow the introduction of procoagulant-bearing tumor cells into circulating blood. This chapter focuses on the basic methods involved in assessing the anti-metastatic effects of anticoagulants and anti-platelet agents using rodent models of experimental metastasis. In addition, it summarizes our experience with these models, which collectively suggests that intravascular coagulation and platelet activation are a necessary prelude to lung tumor formation and that interruption of coagulation pathways or platelet aggregation may be an effective anti-metastatic strategy.
Tetraiodothyroacetic acid (tetrac) and its nanoparticle formulation (Tetrac NP) act at an integri... more Tetraiodothyroacetic acid (tetrac) and its nanoparticle formulation (Tetrac NP) act at an integrin cell surface receptor to inhibit tumor cell proliferation and tumor-related angiogenesis. Human pancreatic cancer cell (PANC-1 and MPanc96) xenografts were established in nude mice, and the effects of tetrac versus Tetrac NP on tumor growth and tumor angiogenesis were determined. The in vitro effects of tetrac and Tetrac NP were also determined by reverse transcription polymerase chain reaction or immunoblot on gene expression or gene products relevant to cell cycle arrest, apoptosis, or angiogenesis. Tetrac and Tetrac NP reduced both PANC-1 tumor mass by 45-55 % and PANC-1 tumor hemoglobin content, a marker of angiogenesis, by 50-60 % (*P < 0.05) in treated groups vs. controls by treatment day 15. Comparable results were obtained with tetrac and Tetrac NP in suppressing tumor growth and tumor angiogenesis in MPanc96 xenografts. In vitro studies showed that tetrac and Tetrac NP caus...
The anti-angiogenic agent, diamino propane tetraiodothyroacetic acid (DAT), is a thyro-integrin (... more The anti-angiogenic agent, diamino propane tetraiodothyroacetic acid (DAT), is a thyro-integrin (integrin αvβ3) antagonist anticancer agent that works via genetic and nongenetic actions. Tetraiodothyroacetic acid (tetrac) and DAT as thyroid hormone derivatives influence gene expression after they transport across cellular membranes. To restrict the action of DAT to the integrin αvβ3 receptors on the cell surface, we used DAT-conjugated PLGA nanoparticles (NDAT) in an active targeting mode to bind to these receptors. Preparation and characterization of NDAT is described, and both in vitro and in vivo experiments were done to compare DAT to NDAT. Intracellular uptake and distribution of DAT and NDAT in U87 glioblastoma cells were evaluated using confocal microscopy and showed that DAT reached the nucleus, but NDAT was restricted from the nucleus. Pharmacokinetic studies using LC-MS/MS analysis in male C57BL/6 mice showed that administration of NDAT improved the area under the drug con...
The focus of this review is to discuss the hypothesis that justifies the use of dual antiplatelet... more The focus of this review is to discuss the hypothesis that justifies the use of dual antiplatelet therapy of aspirin and clopidogrel versus monotherapy with aspirin in arterial vascular disease. By analyzing the CLARITY-TIMI and COMMIT trials, the authors discuss the appropriate use of aspirin plus clopidogrel for patients suffering acute myocardial infarction. In contrast, in the CHARISMA trial, the combination was not justified in stable high-risk patients with documented coronary disease, cerebrovascular disease or symptomatic peripheral artery disease. In two additional cardiovascular studies, the CURE and the PCI-CURE trials, the benefit of the drug combination was evident in those patients who underwent percutaneous coronary intervention and coronary artery bypass grafting. Finally, two focused cerebrovascular studies, the CARESS and the MATCH trials, were analyzed. The CARESS trial demonstrated the clinical benefit of this combination in an acute clinical setting. However, the combination proved to be ineffective in the longer-term MATCH trial. It appears from these large clinical trials that the risk-benefit of dual antiplatelet therapy with aspirin and clopidogrel is justified in high-risk symptomatic patients but not in asymptomatic patients. The exact dose regimen and duration of combination therapy await definition and require careful assessment to optimize the anticoagulant benefit, while minimizing the hemorrhagic risk.
Chemically modified forms of tetraiodothyroacetic acid (tetrac), an L-thyroxine derivative, have ... more Chemically modified forms of tetraiodothyroacetic acid (tetrac), an L-thyroxine derivative, have been shown to exert their anticancer activity at plasma membrane integrin αvβ3 of tumor cells. Via a specific hormone receptor on the integrin, tetrac-based therapeutic agents modulate expression of genes relevant to cancer cell proliferation, survival and energy metabolism. P-bi-TAT, a novel bivalent tetrac-containing synthetic compound has anticancer activity in vitro and in vivo against Glioblastoma Multiforme (GBM) and other types of human cancers. In the current study, microarray analysis was carried out on a primary culture of human GBM cells exposed to P-bi-TAT (10-6 tetrac equivalent) for 24 h. P-bi-TAT significantly affected expression of a large panel of genes implicated in cancer cell stemness, growth, survival, and angiogenesis. Recent interest elsewhere in ATP synthase as a target in GBM cells caused us to focus attention on expression of genes involved in energy metabolism....
Cancer is a multifactorial disorder that induces mortality worldwide, and the colorectal type is ... more Cancer is a multifactorial disorder that induces mortality worldwide, and the colorectal type is the third most common cancer globally. Resveratrol (RSV) is a natural compound with an effective anticancer effect, especially against colorectal cancer, and therefore numerous studies recommended its use in colorectal cancer prevention and treatment. The current study investigated the effect of either RSV or its nanoformulation (NP-RSV) on the growth and vascularity of xenograft and orthotopic mice models in colon cancer (COLO205-luc). Both RSV and NP-RSV induced significant reductions in tumor growth and the hemoglobin percentages of the tumor mass, but NP-RSV showed greater bioavailability and efficacy than RSV. Generally, we recommend using NP-RSV as a therapeutic to control colon cancer.
Angiogenesis Modulations in Health and Disease, 2013
ABSTRACT Tetraiodothyroacetic acid (tetrac) is a naturally occurring derivative of thyroid hormon... more ABSTRACT Tetraiodothyroacetic acid (tetrac) is a naturally occurring derivative of thyroid hormone, T4. In the absence or presence of L-T4 or L-T3, tetrac has been found to disrupt a number of functions or events that are important to cancer cells via the known thyroid hormone-tetrac receptor on the plasma membrane integrin αvβ3. These functions include regulation of cell division, local stimulation of angiogenesis, chemo-resistance and resistance to radiation. It is desirable to reformulate tetrac as a nanoparticle whose activity is exclusively at the cell surface integrin. Nanotetrac has been designed to limit tetrac to the extracellular space on the basis of the size of the nanoparticle and to provide optimized exposure of the biphenyl structure and acetic acid side chain of its inner ring to the receptor site on αvβ3. Tetrac and its novel nanoparticulate formulation have anti-angiogenesis activity that transcends the inhibition of thyroid hormone-binding at the integrin. Restriction of nanotetrac to the extracellular space has been verified, and nanotetrac has been shown to be up to 10-fold more potent than unmodified tetrac at its integrin target. Nanotetrac formulations have potential applications as inhibitors of tumor-related angiogenesis and of angiogenesis that is unrelated to malignancy, including clinically significant disorders ranging from skin diseases to vascular proliferation in the retina and neovascularization associated with inflammatory states.
International angiology : a journal of the International Union of Angiology, 2005
Pharmacodynamic effects of the low molecular weight heparin tinzaparin on plasma levels of tissue... more Pharmacodynamic effects of the low molecular weight heparin tinzaparin on plasma levels of tissue factor pathway inhibitor (TFPI) and nitric oxide (NO) were compared in obese subjects, as well as in normal healthy controls. Obese (n = 13) patients received a single 75 IU/kg SC injection (the deep vein thrombosis prophylaxis dose) of tinzaparin. Blood samples were obtained pre- and postadministration of drug and at different intervals over 24 h and assayed for total TFPI and NO stable metabolites (nitrates and nitrites) plasma levels, using a specific immunoassay and calorimetric methods. Mean maximum plasma TFPI levels approached 150-230 ng/ml at the 0.8 h and up to 5 h posttinzaparin dose compared to basal TFPI levels of 35-90 ng/mL. Plasma TFPI levels were still about 2-fold above basal levels at 12 h and fell to basal levels at 16 h after tinzaparin dose. Basal plasma levels of NO, but not TFPI, were significantly lower (P < 0.01) in obese patients compared to controls. Simila...
Anticoagulants, Antiplatelets, and Thrombolytics, 2010
It is well established that the blood coagulation system is activated in cancer. In addition, the... more It is well established that the blood coagulation system is activated in cancer. In addition, there is considerable evidence to suggest that clotting activation plays an important role in the biology of malignant tumors, including the process of blood-borne metastasis. For many years our laboratory has used experimental models of lung metastasis to study the events that follow the introduction of procoagulant-bearing tumor cells into circulating blood. This chapter focuses on the basic methods involved in assessing the anti-metastatic effects of anticoagulants and anti-platelet agents using rodent models of experimental metastasis. In addition, it summarizes our experience with these models, which collectively suggests that intravascular coagulation and platelet activation are a necessary prelude to lung tumor formation and that interruption of coagulation pathways or platelet aggregation may be an effective anti-metastatic strategy.
Tetraiodothyroacetic acid (tetrac) and its nanoparticle formulation (Tetrac NP) act at an integri... more Tetraiodothyroacetic acid (tetrac) and its nanoparticle formulation (Tetrac NP) act at an integrin cell surface receptor to inhibit tumor cell proliferation and tumor-related angiogenesis. Human pancreatic cancer cell (PANC-1 and MPanc96) xenografts were established in nude mice, and the effects of tetrac versus Tetrac NP on tumor growth and tumor angiogenesis were determined. The in vitro effects of tetrac and Tetrac NP were also determined by reverse transcription polymerase chain reaction or immunoblot on gene expression or gene products relevant to cell cycle arrest, apoptosis, or angiogenesis. Tetrac and Tetrac NP reduced both PANC-1 tumor mass by 45-55 % and PANC-1 tumor hemoglobin content, a marker of angiogenesis, by 50-60 % (*P < 0.05) in treated groups vs. controls by treatment day 15. Comparable results were obtained with tetrac and Tetrac NP in suppressing tumor growth and tumor angiogenesis in MPanc96 xenografts. In vitro studies showed that tetrac and Tetrac NP caus...
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