The Experts below are selected from a list of 312 Experts worldwide ranked by ideXlab platform
Xiaofei Ning - One of the best experts on this subject based on the ideXlab platform.
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Tepoxalin a dual 5-LOX-COX inhibitor and erlotinib an EGFR inhibitor halts progression of gastric cancer in tumor xenograft mice
American journal of translational research, 2018Co-Authors: Lunhua Huang, Wei Zhang, Xiaofei NingAbstract:GC is associated with over expression of epidermal growth factor receptor (EGRF), Cyclooxygenase-2 (COX-2) and 5-Lipoxygenase (5-LOX). We postulated that targeting these pathways will result in better treatment efficacy than using a single agent with higher dose which may cause toxicity and resistance. We evaluated Tepoxalin (TPX) a dual 5-LOX-COX inhibitor and Erlotinib (ERB) an EGFR inhibitor alone and combination in MGC-803 injected tumor xenografts mice. Female nude mice were selected and injected subcutaneously with MGC-803 GC cells and were grouped after the tumor model was formed. The treatment of TPX, ERB and their combination was given for 21 days. After treatment protocol proliferating index was measured, expression of apoptosis related proteins, 5-LOX, COX-2, EGFR, vascular endothelial growth factor-C (VEGF-C) and density of lymphatic vessel density was evaluated in tumor tissues. TUNEL assay was done for apoptosis. The outcomes of study revealed that TPX and ERB alone inhibited the growth of tumor but their combination showed a synergistic antitumor activity. TPX and ERB alone resulted in apoptosis and antiproliferative effect, whereas their combination showed highly significant results (P
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Tepoxalin a dual 5 lox cox inhibitor and erlotinib an egfr inhibitor halts progression of gastric cancer in tumor xenograft mice
American Journal of Translational Research, 2018Co-Authors: Lunhua Huang, Wei Zhang, Xiaofei NingAbstract:GC is associated with over expression of epidermal growth factor receptor (EGRF), Cyclooxygenase-2 (COX-2) and 5-Lipoxygenase (5-LOX). We postulated that targeting these pathways will result in better treatment efficacy than using a single agent with higher dose which may cause toxicity and resistance. We evaluated Tepoxalin (TPX) a dual 5-LOX-COX inhibitor and Erlotinib (ERB) an EGFR inhibitor alone and combination in MGC-803 injected tumor xenografts mice. Female nude mice were selected and injected subcutaneously with MGC-803 GC cells and were grouped after the tumor model was formed. The treatment of TPX, ERB and their combination was given for 21 days. After treatment protocol proliferating index was measured, expression of apoptosis related proteins, 5-LOX, COX-2, EGFR, vascular endothelial growth factor-C (VEGF-C) and density of lymphatic vessel density was evaluated in tumor tissues. TUNEL assay was done for apoptosis. The outcomes of study revealed that TPX and ERB alone inhibited the growth of tumor but their combination showed a synergistic antitumor activity. TPX and ERB alone resulted in apoptosis and antiproliferative effect, whereas their combination showed highly significant results (P<0.01). TPX alone and its combination with ERB suppressed 5-LOX, COX-2, EGFR and VEGF-C and caused inhibition of lymphangiogenesis, however ERB alone was unable to affect expression of VEGF-C and lymphangiogenesis. The results confirmed combination of TPX and ERB produced a synergistic anticancer and antitumor activity, possibly by promoting apoptosis and antiproliferative effect on tumor cells via suppressing expression of COX-2, 5-LOX, EGFR and VEGF-C.
Dennis C. Argentieri - One of the best experts on this subject based on the ideXlab platform.
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Pharmacokinetics and pharmacodynamics of Tepoxalin after single oral dose administration to healthy volunteers.
Journal of clinical pharmacology, 1996Co-Authors: Scott A. Waldman, Cheryl Vitow, Barbara Osborne, Lisa Gillen, Dennis C. Argentieri, Francis A. Wong, Ian L. Smith, Andrew T. Chow, John Misiti, Thorir D. BjornssonAbstract:This study was conducted to examine the pharmacokinetics and pharmacodynamics of Tepoxalin in healthy volunteers, an antiinflammatory compound that inhibits cyclooxygenase and lipoxygenase. Tepoxalin was absorbed after oral administration of single doses from 35 to 300 mg, after which it was rapidly converted to an acidic metabolite, RWJ 20142, which inhibits cyclooxygenase but not lipoxygenase. The areas under the concentration-time curve (AUC) of Tepoxalin and RWJ 20142 in plasma increased in a dose-dependent fashion. Administration of the lowest dose of Tepoxalin completely inhibited whole blood cyclooxygenase for the entire period of observation. This inhibition correlated closely with that of secretion and aggregation induced by collagen of platelets obtained from these subjects. Similarly, administration of Tepoxalin was associated with significant inhibition of lipoxygenase in whole blood. Lipoxygenase was inhibited a maximum of 60% in a time-dependent fashion, and the duration of inhibition was dose-dependent. These studies demonstrate that Tepoxalin inhibits whole blood cyclooxygenase, lipoxygenase, and platelet function after oral administration in humans.
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antinociceptive effects of a novel dual cyclooxygenase 5 lipoxygenase inhibitor Tepoxalin and its primary carboxylic acid metabolite rwj 20142 in acute tests in mice and rats
Drug Development Research, 1995Co-Authors: Robert B. Raffa, Monica Singer, Dennis C. Argentieri, Charlene D. Connelly, Rebecca P. Martinez, James J. Schupsky, Ian L. SmithAbstract:Tepoxalin is a novel dual inhibitor of cyclooxygenase (CO) and lipoxygenase (LO) pathways of arachidonic acid metabolism with a relative lack of gastrointestinal side effects within its preclinical therapeutic dose range. The present study investigated the antinociceptive action of Tepoxalin and its primary (carboxylic acid) metabolite (RWJ 20142) in several acute tests in mice and rats. Tepoxalin produced dose-related, non-opioid (i.e., naloxone-insensitive) antinociception in the mouse acetylcholine (ACh) induced abdominal irritant test (AIT) with an onset within 15 min and an exceptional duration (about 12 h). The oral ED50 value at peak effect (30 min) was 0.3 mg/kg (0.8 μmol/kg), compared to 0.9, 38.0, and 164 mg/kg (2.5, 160.8, and 1, 085 μmol/kg), respectively, for indomethacin, zileuton, and acetaminophen. Tepoxalin was inactive via intracerebroventricular (i.c.v.) administration (up to 200μg) or (up to 100mg/kg [259 μg/kg] p.o. or s.c.) in the endothelin-1 (ET-1) AIT and mouse 48°C hot-plate tests. RWJ 20142 (a CO inhibitor), produced dose-related, non-opioid antinociception in the ACh test following oral (ED50 = 0.3 mg/kg [0.8 μmol/kg] at 30 min) or i.c.v. administration (ED50 = 3.3 μg [0.1 μmol] at 15 min) and was active p.o. in the phenyl-p -quinone (PpQ) (ED50 = 0.2 mg/kg [0.6 μmol/kg] at 30 min) and ET-1 tests (ED50 = 19.6 mg/kg [54.9 μmol/kg] at 30 min). It was the only compound active p.o. in the 48°C hot-plate test and was significantly more potent than Tepoxalin in the rat air-induced AIT. Measurement of plasma levels suggests RWJ 20142 might be a major contributor to Tepoxalin-induced antinociception. The inactivity of Tepoxalin in the ET-1 test suggests a separate antinociceptive action of the parent compound. In summary, it appears that both Tepoxalin and its primary metabolite contribute to Tepoxalin-induced antinociception in rodents, possibly by different mechanisms or at different sites, i.e., peripheral vs. central. © 1995 Wiley-Liss, Inc.
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Antinociceptive effects of a novel dual cyclooxygenase/5‐lipoxygenase inhibitor (Tepoxalin) and its primary (carboxylic acid) metabolite (RWJ 20142) in acute tests in mice and rats
Drug Development Research, 1995Co-Authors: Robert B. Raffa, Monica Singer, Dennis C. Argentieri, Charlene D. Connelly, Rebecca P. Martinez, James J. Schupsky, Ian L. SmithAbstract:Tepoxalin is a novel dual inhibitor of cyclooxygenase (CO) and lipoxygenase (LO) pathways of arachidonic acid metabolism with a relative lack of gastrointestinal side effects within its preclinical therapeutic dose range. The present study investigated the antinociceptive action of Tepoxalin and its primary (carboxylic acid) metabolite (RWJ 20142) in several acute tests in mice and rats. Tepoxalin produced dose-related, non-opioid (i.e., naloxone-insensitive) antinociception in the mouse acetylcholine (ACh) induced abdominal irritant test (AIT) with an onset within 15 min and an exceptional duration (about 12 h). The oral ED50 value at peak effect (30 min) was 0.3 mg/kg (0.8 μmol/kg), compared to 0.9, 38.0, and 164 mg/kg (2.5, 160.8, and 1, 085 μmol/kg), respectively, for indomethacin, zileuton, and acetaminophen. Tepoxalin was inactive via intracerebroventricular (i.c.v.) administration (up to 200μg) or (up to 100mg/kg [259 μg/kg] p.o. or s.c.) in the endothelin-1 (ET-1) AIT and mouse 48°C hot-plate tests. RWJ 20142 (a CO inhibitor), produced dose-related, non-opioid antinociception in the ACh test following oral (ED50 = 0.3 mg/kg [0.8 μmol/kg] at 30 min) or i.c.v. administration (ED50 = 3.3 μg [0.1 μmol] at 15 min) and was active p.o. in the phenyl-p -quinone (PpQ) (ED50 = 0.2 mg/kg [0.6 μmol/kg] at 30 min) and ET-1 tests (ED50 = 19.6 mg/kg [54.9 μmol/kg] at 30 min). It was the only compound active p.o. in the 48°C hot-plate test and was significantly more potent than Tepoxalin in the rat air-induced AIT. Measurement of plasma levels suggests RWJ 20142 might be a major contributor to Tepoxalin-induced antinociception. The inactivity of Tepoxalin in the ET-1 test suggests a separate antinociceptive action of the parent compound. In summary, it appears that both Tepoxalin and its primary metabolite contribute to Tepoxalin-induced antinociception in rodents, possibly by different mechanisms or at different sites, i.e., peripheral vs. central. © 1995 Wiley-Liss, Inc.
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Cytokine-modulating activity of Tepoxalin, a new potential antirheumatic
International journal of immunopharmacology, 1995Co-Authors: David M. Ritchie, Catherine Y. Lau, Richard K. Plante, Dennis C. Argentieri, Beatriz L. Aparicio, Arminda G. BarboneAbstract:Abstract Tepoxalin is a new dual cyclooxygenase/5-lipoxygenase anti-inflammatory compound currently under clinical investigation. It has been shown to possess anti-inflammatory activity in a variety of animal models and more recently to inhibit IL-2 induced signal transduction. The current study was conducted to evaluate the cytokine modulating activity of Tepoxalin and the role of iron in these effects. In human peripheral blood mononuclear cells (PBMC) stimulated with OKT3/PMA, Tepoxalin inhibited lymphocyte proliferation with an ic 50 of 6 μM. Additionally, it inhibited the production of LTB 4 (ic 50 = 0.5 μM) and the cytokines IL-2, IL-6 and TNFα (ic 50 = 10–12 μM). Cytotoxicity was not demonstrated at these concentrations. Add-back experiments with either cytokines (IL-2 or IL-6), LTB 4 or conditioned media failed to restore the proliferative response in the presence of Tepoxalin. However, the concurrent addition of iron (in the form of ferrous or ferric chloride and other iron salts) reversed the inhibition of proliferation caused by Tepoxalin. Tepoxalin also inhibits the activation of NFκB, a transcription factor which acts on several cytokine genes. Tepoxalin's effect on NFκB is also reversed by the addition of iron salts. These data suggest that the action of Tepoxalin to inhibit proliferation in PBMC may be at least in part due to its ability to reduce the amount of available iron resulting in decreased activation of NFκB and subsequent inhibition of cytokine production.
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Tepoxalin a dual cyclooxygenase 5 lipoxygenase inhibitor of arachidonic acid metabolism with potent anti inflammatory activity and a favorable gastrointestinal profile
Journal of Pharmacology and Experimental Therapeutics, 1994Co-Authors: Dennis C. Argentieri, David M. Ritchie, Michael P. Wachter, M P Ferro, T. Kirchner, David W. Anderson, M E Rosenthale, R. J. CapetolaAbstract:Tepoxalin [5-(4-chlorophenyl)-N-hydroxy-(4-methoxyphenyl)-N-methyl-1H- pyrazole-3-propanamide] is a potent inhibitor of sheep seminal vesicle cyclooxygenase (CO) (IC50 = 4.6 microM), rat basophilic leukemia cell (RBL-1) lysate CO (IC50 = 2.85 microM) and CO from intact RBL-1 cells (IC50 = 4.2 microM). The compound inhibits the production of thromboxane B2 (TxB2) in Ca++ ionophore A-23187-stimulated human peripheral blood leukocytes (HPBL; IC50 = 0.01 microM) and human whole blood (IC50 = 0.08 microM) and is a potent inhibitor of epinephrine-induced human platelet aggregation (IC50 = 0.045 microM). Tepoxalin inhibits lipoxygenase (LO) in RBL-1 lysates (IC50 = 0.15 microM) and intact RBL-1 cells (IC50 = 1.7 microM) and inhibits the generation of leukotriene B4 (LTB4) in calcium ionophore A-23187-stimulated HPBL (IC50 = 0.07 microM) and human whole blood (IC50 = 1.57 microM). Human platelet 12-LO (IC50 = 3.0 microM) is inhibited, but 15-LO is only weakly so (IC50 = 157 microM). In vivo, Tepoxalin, administered orally, demonstrated potent anti-inflammatory activity in the established adjuvant arthritic rat (ED50 = 3.5 mg/kg) and potent analgesic activity in the acetic acid abdominal construction assay in mice (ED50 = 0.45 mg/kg). In an ex vivo whole blood eicosanoid production assay, Tepoxalin produces a dose-related inhibition of prostaglandin (PG) and LT production in dogs (PGF2 alpha - ED50 = 0.015 mg/kg; LTB4 - ED50 = 2.37 mg/kg) and adjuvant arthritic rats following oral administration. In adjuvant arthritic rats, Tepoxalin is devoid of ulcerogenic activity within its anti-inflammatory therapeutic range (1-33 mg/kg p.o.) and does not exhibit ulcerogenic activity in normal rats at doses lower than 100 mg/kg (UD50 = 173 mg/kg p.o.). Tepoxalin represents a new class of anti-inflammatory drugs which may exhibit less gastrointestinal toxicity and may be efficacious in immunoinflammatory disease states where excessive PG and LT production has been implicated and may offer a significant alternative to nonsteroidal and corticosteroidal anti-inflammatory therapy.
Ian L. Smith - One of the best experts on this subject based on the ideXlab platform.
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Pharmacokinetics and pharmacodynamics of Tepoxalin after single oral dose administration to healthy volunteers.
Journal of clinical pharmacology, 1996Co-Authors: Scott A. Waldman, Cheryl Vitow, Barbara Osborne, Lisa Gillen, Dennis C. Argentieri, Francis A. Wong, Ian L. Smith, Andrew T. Chow, John Misiti, Thorir D. BjornssonAbstract:This study was conducted to examine the pharmacokinetics and pharmacodynamics of Tepoxalin in healthy volunteers, an antiinflammatory compound that inhibits cyclooxygenase and lipoxygenase. Tepoxalin was absorbed after oral administration of single doses from 35 to 300 mg, after which it was rapidly converted to an acidic metabolite, RWJ 20142, which inhibits cyclooxygenase but not lipoxygenase. The areas under the concentration-time curve (AUC) of Tepoxalin and RWJ 20142 in plasma increased in a dose-dependent fashion. Administration of the lowest dose of Tepoxalin completely inhibited whole blood cyclooxygenase for the entire period of observation. This inhibition correlated closely with that of secretion and aggregation induced by collagen of platelets obtained from these subjects. Similarly, administration of Tepoxalin was associated with significant inhibition of lipoxygenase in whole blood. Lipoxygenase was inhibited a maximum of 60% in a time-dependent fashion, and the duration of inhibition was dose-dependent. These studies demonstrate that Tepoxalin inhibits whole blood cyclooxygenase, lipoxygenase, and platelet function after oral administration in humans.
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antinociceptive effects of a novel dual cyclooxygenase 5 lipoxygenase inhibitor Tepoxalin and its primary carboxylic acid metabolite rwj 20142 in acute tests in mice and rats
Drug Development Research, 1995Co-Authors: Robert B. Raffa, Monica Singer, Dennis C. Argentieri, Charlene D. Connelly, Rebecca P. Martinez, James J. Schupsky, Ian L. SmithAbstract:Tepoxalin is a novel dual inhibitor of cyclooxygenase (CO) and lipoxygenase (LO) pathways of arachidonic acid metabolism with a relative lack of gastrointestinal side effects within its preclinical therapeutic dose range. The present study investigated the antinociceptive action of Tepoxalin and its primary (carboxylic acid) metabolite (RWJ 20142) in several acute tests in mice and rats. Tepoxalin produced dose-related, non-opioid (i.e., naloxone-insensitive) antinociception in the mouse acetylcholine (ACh) induced abdominal irritant test (AIT) with an onset within 15 min and an exceptional duration (about 12 h). The oral ED50 value at peak effect (30 min) was 0.3 mg/kg (0.8 μmol/kg), compared to 0.9, 38.0, and 164 mg/kg (2.5, 160.8, and 1, 085 μmol/kg), respectively, for indomethacin, zileuton, and acetaminophen. Tepoxalin was inactive via intracerebroventricular (i.c.v.) administration (up to 200μg) or (up to 100mg/kg [259 μg/kg] p.o. or s.c.) in the endothelin-1 (ET-1) AIT and mouse 48°C hot-plate tests. RWJ 20142 (a CO inhibitor), produced dose-related, non-opioid antinociception in the ACh test following oral (ED50 = 0.3 mg/kg [0.8 μmol/kg] at 30 min) or i.c.v. administration (ED50 = 3.3 μg [0.1 μmol] at 15 min) and was active p.o. in the phenyl-p -quinone (PpQ) (ED50 = 0.2 mg/kg [0.6 μmol/kg] at 30 min) and ET-1 tests (ED50 = 19.6 mg/kg [54.9 μmol/kg] at 30 min). It was the only compound active p.o. in the 48°C hot-plate test and was significantly more potent than Tepoxalin in the rat air-induced AIT. Measurement of plasma levels suggests RWJ 20142 might be a major contributor to Tepoxalin-induced antinociception. The inactivity of Tepoxalin in the ET-1 test suggests a separate antinociceptive action of the parent compound. In summary, it appears that both Tepoxalin and its primary metabolite contribute to Tepoxalin-induced antinociception in rodents, possibly by different mechanisms or at different sites, i.e., peripheral vs. central. © 1995 Wiley-Liss, Inc.
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Antinociceptive effects of a novel dual cyclooxygenase/5‐lipoxygenase inhibitor (Tepoxalin) and its primary (carboxylic acid) metabolite (RWJ 20142) in acute tests in mice and rats
Drug Development Research, 1995Co-Authors: Robert B. Raffa, Monica Singer, Dennis C. Argentieri, Charlene D. Connelly, Rebecca P. Martinez, James J. Schupsky, Ian L. SmithAbstract:Tepoxalin is a novel dual inhibitor of cyclooxygenase (CO) and lipoxygenase (LO) pathways of arachidonic acid metabolism with a relative lack of gastrointestinal side effects within its preclinical therapeutic dose range. The present study investigated the antinociceptive action of Tepoxalin and its primary (carboxylic acid) metabolite (RWJ 20142) in several acute tests in mice and rats. Tepoxalin produced dose-related, non-opioid (i.e., naloxone-insensitive) antinociception in the mouse acetylcholine (ACh) induced abdominal irritant test (AIT) with an onset within 15 min and an exceptional duration (about 12 h). The oral ED50 value at peak effect (30 min) was 0.3 mg/kg (0.8 μmol/kg), compared to 0.9, 38.0, and 164 mg/kg (2.5, 160.8, and 1, 085 μmol/kg), respectively, for indomethacin, zileuton, and acetaminophen. Tepoxalin was inactive via intracerebroventricular (i.c.v.) administration (up to 200μg) or (up to 100mg/kg [259 μg/kg] p.o. or s.c.) in the endothelin-1 (ET-1) AIT and mouse 48°C hot-plate tests. RWJ 20142 (a CO inhibitor), produced dose-related, non-opioid antinociception in the ACh test following oral (ED50 = 0.3 mg/kg [0.8 μmol/kg] at 30 min) or i.c.v. administration (ED50 = 3.3 μg [0.1 μmol] at 15 min) and was active p.o. in the phenyl-p -quinone (PpQ) (ED50 = 0.2 mg/kg [0.6 μmol/kg] at 30 min) and ET-1 tests (ED50 = 19.6 mg/kg [54.9 μmol/kg] at 30 min). It was the only compound active p.o. in the 48°C hot-plate test and was significantly more potent than Tepoxalin in the rat air-induced AIT. Measurement of plasma levels suggests RWJ 20142 might be a major contributor to Tepoxalin-induced antinociception. The inactivity of Tepoxalin in the ET-1 test suggests a separate antinociceptive action of the parent compound. In summary, it appears that both Tepoxalin and its primary metabolite contribute to Tepoxalin-induced antinociception in rodents, possibly by different mechanisms or at different sites, i.e., peripheral vs. central. © 1995 Wiley-Liss, Inc.
Lunhua Huang - One of the best experts on this subject based on the ideXlab platform.
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Tepoxalin a dual 5-LOX-COX inhibitor and erlotinib an EGFR inhibitor halts progression of gastric cancer in tumor xenograft mice
American journal of translational research, 2018Co-Authors: Lunhua Huang, Wei Zhang, Xiaofei NingAbstract:GC is associated with over expression of epidermal growth factor receptor (EGRF), Cyclooxygenase-2 (COX-2) and 5-Lipoxygenase (5-LOX). We postulated that targeting these pathways will result in better treatment efficacy than using a single agent with higher dose which may cause toxicity and resistance. We evaluated Tepoxalin (TPX) a dual 5-LOX-COX inhibitor and Erlotinib (ERB) an EGFR inhibitor alone and combination in MGC-803 injected tumor xenografts mice. Female nude mice were selected and injected subcutaneously with MGC-803 GC cells and were grouped after the tumor model was formed. The treatment of TPX, ERB and their combination was given for 21 days. After treatment protocol proliferating index was measured, expression of apoptosis related proteins, 5-LOX, COX-2, EGFR, vascular endothelial growth factor-C (VEGF-C) and density of lymphatic vessel density was evaluated in tumor tissues. TUNEL assay was done for apoptosis. The outcomes of study revealed that TPX and ERB alone inhibited the growth of tumor but their combination showed a synergistic antitumor activity. TPX and ERB alone resulted in apoptosis and antiproliferative effect, whereas their combination showed highly significant results (P
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Tepoxalin a dual 5 lox cox inhibitor and erlotinib an egfr inhibitor halts progression of gastric cancer in tumor xenograft mice
American Journal of Translational Research, 2018Co-Authors: Lunhua Huang, Wei Zhang, Xiaofei NingAbstract:GC is associated with over expression of epidermal growth factor receptor (EGRF), Cyclooxygenase-2 (COX-2) and 5-Lipoxygenase (5-LOX). We postulated that targeting these pathways will result in better treatment efficacy than using a single agent with higher dose which may cause toxicity and resistance. We evaluated Tepoxalin (TPX) a dual 5-LOX-COX inhibitor and Erlotinib (ERB) an EGFR inhibitor alone and combination in MGC-803 injected tumor xenografts mice. Female nude mice were selected and injected subcutaneously with MGC-803 GC cells and were grouped after the tumor model was formed. The treatment of TPX, ERB and their combination was given for 21 days. After treatment protocol proliferating index was measured, expression of apoptosis related proteins, 5-LOX, COX-2, EGFR, vascular endothelial growth factor-C (VEGF-C) and density of lymphatic vessel density was evaluated in tumor tissues. TUNEL assay was done for apoptosis. The outcomes of study revealed that TPX and ERB alone inhibited the growth of tumor but their combination showed a synergistic antitumor activity. TPX and ERB alone resulted in apoptosis and antiproliferative effect, whereas their combination showed highly significant results (P<0.01). TPX alone and its combination with ERB suppressed 5-LOX, COX-2, EGFR and VEGF-C and caused inhibition of lymphangiogenesis, however ERB alone was unable to affect expression of VEGF-C and lymphangiogenesis. The results confirmed combination of TPX and ERB produced a synergistic anticancer and antitumor activity, possibly by promoting apoptosis and antiproliferative effect on tumor cells via suppressing expression of COX-2, 5-LOX, EGFR and VEGF-C.
Wei Zhang - One of the best experts on this subject based on the ideXlab platform.
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Tepoxalin a dual 5-LOX-COX inhibitor and erlotinib an EGFR inhibitor halts progression of gastric cancer in tumor xenograft mice
American journal of translational research, 2018Co-Authors: Lunhua Huang, Wei Zhang, Xiaofei NingAbstract:GC is associated with over expression of epidermal growth factor receptor (EGRF), Cyclooxygenase-2 (COX-2) and 5-Lipoxygenase (5-LOX). We postulated that targeting these pathways will result in better treatment efficacy than using a single agent with higher dose which may cause toxicity and resistance. We evaluated Tepoxalin (TPX) a dual 5-LOX-COX inhibitor and Erlotinib (ERB) an EGFR inhibitor alone and combination in MGC-803 injected tumor xenografts mice. Female nude mice were selected and injected subcutaneously with MGC-803 GC cells and were grouped after the tumor model was formed. The treatment of TPX, ERB and their combination was given for 21 days. After treatment protocol proliferating index was measured, expression of apoptosis related proteins, 5-LOX, COX-2, EGFR, vascular endothelial growth factor-C (VEGF-C) and density of lymphatic vessel density was evaluated in tumor tissues. TUNEL assay was done for apoptosis. The outcomes of study revealed that TPX and ERB alone inhibited the growth of tumor but their combination showed a synergistic antitumor activity. TPX and ERB alone resulted in apoptosis and antiproliferative effect, whereas their combination showed highly significant results (P
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Tepoxalin a dual 5 lox cox inhibitor and erlotinib an egfr inhibitor halts progression of gastric cancer in tumor xenograft mice
American Journal of Translational Research, 2018Co-Authors: Lunhua Huang, Wei Zhang, Xiaofei NingAbstract:GC is associated with over expression of epidermal growth factor receptor (EGRF), Cyclooxygenase-2 (COX-2) and 5-Lipoxygenase (5-LOX). We postulated that targeting these pathways will result in better treatment efficacy than using a single agent with higher dose which may cause toxicity and resistance. We evaluated Tepoxalin (TPX) a dual 5-LOX-COX inhibitor and Erlotinib (ERB) an EGFR inhibitor alone and combination in MGC-803 injected tumor xenografts mice. Female nude mice were selected and injected subcutaneously with MGC-803 GC cells and were grouped after the tumor model was formed. The treatment of TPX, ERB and their combination was given for 21 days. After treatment protocol proliferating index was measured, expression of apoptosis related proteins, 5-LOX, COX-2, EGFR, vascular endothelial growth factor-C (VEGF-C) and density of lymphatic vessel density was evaluated in tumor tissues. TUNEL assay was done for apoptosis. The outcomes of study revealed that TPX and ERB alone inhibited the growth of tumor but their combination showed a synergistic antitumor activity. TPX and ERB alone resulted in apoptosis and antiproliferative effect, whereas their combination showed highly significant results (P<0.01). TPX alone and its combination with ERB suppressed 5-LOX, COX-2, EGFR and VEGF-C and caused inhibition of lymphangiogenesis, however ERB alone was unable to affect expression of VEGF-C and lymphangiogenesis. The results confirmed combination of TPX and ERB produced a synergistic anticancer and antitumor activity, possibly by promoting apoptosis and antiproliferative effect on tumor cells via suppressing expression of COX-2, 5-LOX, EGFR and VEGF-C.