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1.
Clin Cancer Res ; 25(8): 2403-2413, 2019 Apr 15.
Article in English | MEDLINE | ID: mdl-30425090

ABSTRACT

PURPOSE: This first-in-human, open-label phase I study evaluated AMG 337, an oral, highly selective small-molecule inhibitor of MET in advanced solid tumors.Patients and Methods: Patients enrolled into dose-escalation cohorts received AMG 337 up to 400 mg once daily or up to 250 mg twice daily, following a modified 3+3+3 design. Dose expansion was conducted in MET-amplified patients at the maximum tolerated dose (MTD). Primary endpoints included assessment of adverse events (AEs), establishment of the MTD, and pharmacokinetics; clinical response was a secondary endpoint. RESULTS: The safety analysis set included 111 patients who received ≥1 dose of AMG 337. Thirteen patients had ≥1 AE qualifying as dose-limiting toxicity. The MTD was determined to be 300 mg once daily; the MTD for twice-daily dosing was not reached. Most frequent treatment-related AEs were headache (63%) and nausea (31%). Grade ≥3 treatment-related AEs occurred in 23 patients (21%), most commonly headache (n = 6) and fatigue (n = 5). Maximum plasma concentration occurred at 3.0 hours following 300-mg once-daily dosing, indicating AMG 337 absorption soon after treatment. Objective response rate was 9.9% (11/111; 95% CI, 5.1%-17.0%) in all patients and 29.6% (8/27; 95% CI, 13.8%-50.2%) in MET-amplified patients; median (range) duration of response was 202 (51-1,430+) days in all patients and 197 (64-1,430+) days in MET-amplified patients. CONCLUSIONS: Oral AMG 337 was tolerated with manageable toxicities, with an MTD and recommended phase II dose of 300 mg once daily. The promising response rate observed in patients with heavily pretreated MET-amplified tumors warrants further investigation.See related commentary by Ma, p. 2375.


Subject(s)
Neoplasms , Protein Kinase Inhibitors , Humans , Maximum Tolerated Dose , Pyridones , Treatment Outcome , Triazoles
2.
Clin Cancer Res ; 22(18): 4574-84, 2016 Sep 15.
Article in English | MEDLINE | ID: mdl-27076631

ABSTRACT

PURPOSE: To assess the toxicity, pharmacokinetics, tumor vascular response, tumor response, and pharmacodynamics of AMG 780, a mAb designed to inhibit the interaction between angiopoietin-1 and -2 and the Tie2 receptor. EXPERIMENTAL DESIGN: This was a phase I dose-escalation study of patients with advanced solid tumors refractory to standard treatment without previous antiangiogenic treatment. AMG 780 was administered by intravenous infusion every 2 weeks in doses from 0.1 to 30 mg/kg. The primary endpoints were incidences of dose-limiting toxicity (DLT) and adverse events (AE), and pharmacokinetics. Secondary endpoints included tumor response, changes in tumor volume and vascularity, and anti-AMG 780 antibody formation. RESULTS: Forty-five patients were enrolled across nine dose cohorts. Three patients had DLTs (0.6, 10, and 30 mg/kg), none of which prevented dose escalation. At 30 mg/kg, no MTD was reached. Pharmacokinetics of AMG 780 were dose proportional; median terminal elimination half-life was 8 to 13 days. No anti-AMG 780 antibodies were detected. At week 5, 6 of 16 evaluable patients had a >20% decrease in volume transfer constant (K(trans)), suggesting reduced capillary blood flow/permeability. The most frequent AEs were hypoalbuminemia (33%), peripheral edema (29%), decreased appetite (27%), and fatigue (27%). Among 35 evaluable patients, none had an objective response; 8 achieved stable disease. CONCLUSIONS: AMG 780 could be administered at doses up to 30 mg/kg every 2 weeks in patients with advanced solid tumors. AMG 780 treatment resulted in tumor vascular effects in some patients. AEs were in line with toxicity associated with antiangiopoietin treatment. Clin Cancer Res; 22(18); 4574-84. ©2016 AACR.


Subject(s)
Angiogenesis Inhibitors/therapeutic use , Antineoplastic Agents/therapeutic use , Neoplasms/drug therapy , Neoplasms/pathology , Aged , Angiogenesis Inhibitors/administration & dosage , Angiogenesis Inhibitors/adverse effects , Angiogenesis Inhibitors/pharmacokinetics , Angiopoietin-1/metabolism , Angiopoietin-2/metabolism , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/adverse effects , Antineoplastic Agents/pharmacokinetics , Dose-Response Relationship, Drug , Drug Monitoring , Female , Humans , Male , Middle Aged , Neoplasm Staging , Treatment Outcome
3.
Oncotarget ; 6(21): 18693-706, 2015 Jul 30.
Article in English | MEDLINE | ID: mdl-26155941

ABSTRACT

BACKGROUND: This first-in-human study evaluated AMG 208, a small-molecule MET inhibitor, in patients with advanced solid tumors. METHODS: Three to nine patients were enrolled into one of seven AMG 208 dose cohorts (25, 50, 100, 150, 200, 300, and 400 mg). Patients received AMG 208 orally on days 1 and days 4-28 once daily. The primary objectives were to evaluate the safety, tolerability, pharmacokinetics, and maximum tolerated dose (MTD) of AMG 208. RESULTS: Fifty-four patients were enrolled. Six dose-limiting toxicities were observed: grade 3 increased aspartate aminotransferase (200 mg), grade 3 thrombocytopenia (200 mg), grade 4 acute myocardial infarction (300 mg), grade 3 prolonged QT (300 mg), and two cases of grade 3 hypertension (400 mg). The MTD was not reached. The most frequent grade ≥3 treatment-related adverse event was anemia (n = 3) followed by hypertension, prolonged QT, and thrombocytopenia (two patients each). AMG 208 exposure increased linearly with dose; mean plasma half-life estimates were 21.4-68.7 hours. One complete response (prostate cancer) and three partial responses (two in prostate cancer, one in kidney cancer) were observed. CONCLUSIONS: In this study, AMG 208 had manageable toxicities and showed evidence of antitumor activity, particularly in prostate cancer.


Subject(s)
Biomarkers, Tumor/metabolism , Neoplasms/drug therapy , Protein Kinase Inhibitors/pharmacokinetics , Protein Kinase Inhibitors/therapeutic use , Proto-Oncogene Proteins c-met/antagonists & inhibitors , Pyridazines/pharmacokinetics , Pyridazines/therapeutic use , Triazoles/pharmacokinetics , Triazoles/therapeutic use , Administration, Oral , Adult , Aged , Aged, 80 and over , Area Under Curve , Biomarkers, Tumor/genetics , Dose-Response Relationship, Drug , Fatigue/chemically induced , Female , Humans , Hypertension/chemically induced , Immunohistochemistry , In Situ Hybridization, Fluorescence , Male , Metabolic Clearance Rate , Middle Aged , Nausea/chemically induced , Neoplasms/metabolism , Protein Kinase Inhibitors/adverse effects , Proto-Oncogene Proteins c-met/genetics , Proto-Oncogene Proteins c-met/metabolism , Pyridazines/adverse effects , Remission Induction , Treatment Outcome , Triazoles/adverse effects
4.
Clin Cancer Res ; 18(12): 3414-27, 2012 Jun 15.
Article in English | MEDLINE | ID: mdl-22510349

ABSTRACT

PURPOSE: This phase 1b dose-escalation study assessed safety, tolerability, and pharmacokinetics of ganitumab, a fully human monoclonal antibody against the insulin-like growth factor 1 (IGF1) receptor, combined with targeted agents or cytotoxic chemotherapy in patients with advanced solid tumors. EXPERIMENTAL DESIGN: Patients with treatment-refractory advanced solid tumors were sequentially enrolled at 2 ganitumab dose levels (6 or 12 mg/kg i.v. every 2 weeks) combined with either sorafenib 400 mg twice daily, panitumumab 6 mg/kg every 2 weeks, erlotinib 150 mg once daily, or gemcitabine 1,000 mg/m(2) on days 1, 8, and 15 of each 4-week cycle. The primary end points were safety and pharmacokinetics of ganitumab. RESULTS: Ganitumab up to 12 mg/kg appeared well tolerated combined with sorafenib, panitumumab, erlotinib, or gemcitabine. Treatment-emergent adverse events were generally mild and included fatigue, nausea, vomiting, and chills. Three patients had dose-limiting toxicities: grade 3 hyperglycemia (ganitumab 6 mg/kg and panitumumab), grade 4 neutropenia (ganitumab 6 mg/kg and gemcitabine), and grade 4 thrombocytopenia (ganitumab 12 mg/kg and erlotinib). Ganitumab-binding and panitumumab-binding antibodies were detected in 5 and 2 patients, respectively; neutralizing antibodies were not detected. The pharmacokinetics of ganitumab and each cotherapy did not appear affected by coadministration. Circulating total IGF1 and IGF binding protein 3 increased from baseline following treatment. Four patients (9%) had partial responses. CONCLUSIONS: Ganitumab up to 12 mg/kg was well tolerated, without adverse effects on pharmacokinetics in combination with either sorafenib, panitumumab, erlotinib, or gemcitabine. Ganitumab is currently under investigation in combination with some of these and other agents.


Subject(s)
Antibodies, Monoclonal/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Neoplasms/drug therapy , Adult , Aged , Antibodies, Monoclonal/adverse effects , Antibodies, Monoclonal/pharmacokinetics , Antibodies, Monoclonal, Humanized , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Benzenesulfonates/administration & dosage , Benzenesulfonates/adverse effects , Biomarkers, Tumor , Deoxycytidine/administration & dosage , Deoxycytidine/adverse effects , Deoxycytidine/analogs & derivatives , Erlotinib Hydrochloride , Female , Humans , Male , Middle Aged , Niacinamide/analogs & derivatives , Panitumumab , Phenylurea Compounds , Pyridines/administration & dosage , Pyridines/adverse effects , Quinazolines/administration & dosage , Quinazolines/adverse effects , Quinazolines/therapeutic use , Receptor, IGF Type 1/antagonists & inhibitors , Sorafenib , Gemcitabine
5.
Clin Cancer Res ; 16(23): 5883-91, 2010 Dec 01.
Article in English | MEDLINE | ID: mdl-20947515

ABSTRACT

PURPOSE: To determine the safety, tolerability, pharmacokinetics, and maximum tolerated dose (MTD) of conatumumab, an investigational, fully human monoclonal agonist antibody against human death receptor 5, in patients with advanced solid tumors. EXPERIMENTAL DESIGN: In the dose-escalation phase, patients received escalating intravenous doses of conatumumab (0.3, 1, 3, 10, or 20 mg/kg, 3-9 per cohort) every 2 weeks. In the dose-expansion phase, 10 patients with colorectal cancer (CRC) and 7 with non-small cell lung cancer (NSCLC) received 20 mg/kg of conatumumab every 2 weeks. RESULTS: Thirty-seven patients received 1 or more doses of conatumumab. Conatumumab seemed to be well tolerated; there were no dose-limiting toxicities. Of adverse events possibly related to treatment, only 3 patients (8%) had a grade 3 event (fatigue and/or elevated lipase), and no anticonatumumab antibodies were detected. An MTD was not reached. Conatumumab exhibited dose linear kinetics from 3 to 20 mg/kg, with a mean terminal half-life of 13 to 19 days. One patient with NSCLC (0.3 mg/kg) had a confirmed partial response (PR) at week 32 (38% reduction in tumor size), with further reduction (48%) by week 96; this patient remains on conatumumab after 4.2 years with a sustained PR. Fourteen patients had a best response of stable disease, 2 for 32 weeks or more. One patient with CRC (0.3 mg/kg) and stable disease for 24 weeks had a 24% reduction in tumor size by RECIST (Response Evaluation Criteria in Solid Tumors) and a 35% reduction in the sum of standardized uptake values of all lesions measured by [18F]fluorodeoxyglucose positron emission tomographic scan. Changes in tumor levels of activated caspase-3 did not appear to be associated with tumor response. CONCLUSIONS: Conatumumab can be administered safely up to the target dose of 20 mg/kg every 2 weeks.


Subject(s)
Antibodies, Monoclonal/therapeutic use , Neoplasms/drug therapy , Adult , Aged , Antibodies, Monoclonal/administration & dosage , Antibodies, Monoclonal/adverse effects , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/adverse effects , Antineoplastic Agents/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Colorectal Neoplasms/drug therapy , Disease Progression , Dose-Response Relationship, Drug , Female , Humans , Infusions, Intravenous , Lung Neoplasms/drug therapy , Male , Maximum Tolerated Dose , Middle Aged , Neoplasms/pathology , Pilot Projects
6.
J Clin Oncol ; 27(21): 3557-65, 2009 Jul 20.
Article in English | MEDLINE | ID: mdl-19546406

ABSTRACT

PURPOSE AMG 386 is an investigational peptide-Fc fusion protein (ie, peptibody) that inhibits angiogenesis by preventing the interaction of angiopoietin-1 and angiopoietin-2 with their receptor, Tie2. This first-in-human study evaluated the safety, pharmacokinetics (PK), pharmacodynamics, and antitumor activity of AMG 386 in adults with advanced solid tumors. PATIENTS AND METHODS Patients in sequential cohorts received weekly intravenous AMG 386 doses of 0.3, 1, 3, 10, or 30 mg/kg. Results Thirty-two patients were enrolled on the study and received AMG 386. One occurrence of dose-limiting toxicity was seen at 30 mg/kg: respiratory arrest, which likely was caused by tumor burden that was possibly related to AMG 386. The most common toxicities were fatigue and peripheral edema. Proteinuria (n = 11) was observed without clinical sequelae. Only four patients (12%) experienced treatment-related toxicities greater than grade 1. A maximum-tolerated dose was not reached. PK was dose-linear and the mean terminal-phase elimination half-life values ranged from 3.1 to 6.3 days. Serum AMG 386 levels appeared to reach steady-state after four weekly doses, and there was minimal accumulation. No anti-AMG 386 neutralizing antibodies were detected. Reductions in volume transfer constant (K(trans); measured by dynamic contrast-enhanced magnetic resonance imaging) were observed in 10 patients (13 lesions) 48 hours to 8 weeks after treatment. One patient with refractory ovarian cancer achieved a confirmed partial response (ie, 32.5% reduction by Response Evaluation Criteria in Solid Tumors) and withdrew from the study with a partial response after 156 weeks of treatment; four patients experienced stable disease for at least 16 weeks. CONCLUSION Weekly AMG 386 appeared well tolerated, and its safety profile appeared distinct from that of vascular endothelial growth factor-axis inhibitors. AMG 386 also appeared to impact tumor vascularity and showed antitumor activity in this patient population.


Subject(s)
Angiogenesis Inhibitors/adverse effects , Angiopoietins/antagonists & inhibitors , Antibodies, Monoclonal/adverse effects , Fatigue/etiology , Neoplasms/metabolism , Adult , Aged , Angiogenesis Inhibitors/administration & dosage , Angiogenesis Inhibitors/pharmacokinetics , Angiopoietins/adverse effects , Angiopoietins/metabolism , Antibodies, Monoclonal/pharmacokinetics , Antibodies, Monoclonal, Humanized , Antimetabolites, Antineoplastic/adverse effects , Antimetabolites, Antineoplastic/pharmacokinetics , Bevacizumab , Dose-Response Relationship, Drug , Drug-Related Side Effects and Adverse Reactions , Female , Humans , Infusions, Intravenous , Male , Maximum Tolerated Dose , Middle Aged , Neoplasm Staging , Treatment Outcome
7.
Am J Physiol Heart Circ Physiol ; 296(2): H333-41, 2009 Feb.
Article in English | MEDLINE | ID: mdl-19060123

ABSTRACT

Aldose reductase (AR), a member of the aldo-keto reductase family, has been demonstrated to play a central role in mediating myocardial ischemia-reperfusion (I/R) injury. Recently, using transgenic mice broadly overexpressing human AR (ARTg), we demonstrated that AR is an important component of myocardial I/R injury and that inhibition of this enzyme protects heart from I/R injury (20-22, 48, 49, 56). To rigorously delineate mechanisms by which AR pathway influences myocardial ischemic injury, we investigated the role played by reactive oxygen species (ROS), antioxidant enzymes, and mitochondrial permeability transition (MPT) pore opening in hearts from ARTg or littermates [wild type (WT)] subjected to I/R. MPT pore opening after I/R was determined using mitochondrial uptake of 2-deoxyglucose ratio, while H2O2 was measured as a key indicator of ROS. Myocardial 2-deoxyglucose uptake ratio and calcium-induced swelling were significantly greater in mitochondria from ARTg mice than in WT mice. Blockade of MPT pore with cyclosphorin A during I/R reduced ischemic injury significantly in ARTg mice hearts. H2O2 measurements indicated mitochondrial ROS generation after I/R was significantly greater in ARTg mitochondria than in WT mice hearts. Furthermore, the levels of antioxidant GSH were significantly reduced in ARTg mitochondria than in WT. Resveratrol treatment or pharmacological blockade of AR significantly reduced ROS generation and MPT pore opening in mitochondria of ARTg mice hearts exposed to I/R stress. This study demonstrates that MPT pore opening is a key event by which AR pathway mediates myocardial I/R injury, and that the MPT pore opening after I/R is triggered, in part, by increases in ROS generation in ARTg mice hearts. Therefore, inhibition of AR pathway protects mitochondria and hence may be a useful adjunct for salvaging ischemic myocardium.


Subject(s)
Aldehyde Reductase/metabolism , Mitochondria, Heart/enzymology , Mitochondrial Membrane Transport Proteins/metabolism , Myocardial Reperfusion Injury/enzymology , Myocardium/enzymology , Aldehyde Reductase/genetics , Animals , Antioxidants/metabolism , Antioxidants/pharmacology , Calcium/metabolism , Cyclosporine/pharmacology , Deoxyglucose/metabolism , Disease Models, Animal , Glutathione/metabolism , Humans , Hydrogen Peroxide/metabolism , Mice , Mice, Inbred C57BL , Mice, Transgenic , Mitochondria, Heart/drug effects , Mitochondria, Heart/pathology , Mitochondrial Membrane Transport Proteins/antagonists & inhibitors , Mitochondrial Permeability Transition Pore , Mitochondrial Swelling , Myocardial Reperfusion Injury/pathology , Myocardium/pathology , Reactive Oxygen Species/metabolism , Resveratrol , Stilbenes/pharmacology
8.
Cardiovasc Diabetol ; 7: 33, 2008 Oct 28.
Article in English | MEDLINE | ID: mdl-18957123

ABSTRACT

We investigated the role of polyol pathway enzymes aldose reductase (AR) and sorbitol dehydrogenase (SDH) in mediating injury due to ischemia-reperfusion (IR) in Type 2 diabetic BBZ rat hearts. Specifically, we investigated, (a) changes in glucose flux via cardiac AR and SDH as a function of diabetes duration, (b) ischemic injury and function after IR, (c) the effect of inhibition of AR or SDH on ischemic injury and function. Hearts isolated from BBZ rats, after 12 weeks or 48 weeks diabetes duration, and their non-diabetic littermates, were subjected to IR protocol. Myocardial function, substrate flux via AR and SDH, and tissue lactate:pyruvate (L/P) ratio (a measure of cytosolic NADH/NAD+), and lactate dehydrogenase (LDH) release (a marker of IR injury) were measured. Zopolrestat, and CP-470,711 were used to inhibit AR and SDH, respectively. Myocardial sorbitol and fructose content, and associated changes in L/P ratios were significantly higher in BBZ rats compared to non-diabetics, and increased with disease duration. Induction of IR resulted in increased ischemic injury, reduced ATP levels, increases in L/P ratio, and poor cardiac function in BBZ rat hearts, while inhibition of AR or SDH attenuated these changes and protected hearts from IR injury. These data indicate that AR and SDH are key modulators of myocardial IR injury in BBZ rat hearts and that inhibition of polyol pathway could in principle be used as a therapeutic adjunct for protection of ischemic myocardium in Type 2 diabetic patients.


Subject(s)
Diabetes Mellitus, Type 2/metabolism , Myocardium/metabolism , Polymers/metabolism , Reperfusion Injury/metabolism , Signal Transduction/physiology , Adenosine Triphosphate/metabolism , Aldehyde Reductase/metabolism , Animals , Disease Models, Animal , L-Iditol 2-Dehydrogenase/metabolism , Lactates/metabolism , Pyruvates/metabolism , Rats , Rats, Inbred BB
9.
Diabetes ; 57(7): 1941-51, 2008 Jul.
Article in English | MEDLINE | ID: mdl-18420491

ABSTRACT

OBJECTIVE: Subjects with diabetes experience an increased risk of myocardial infarction and cardiac failure compared with nondiabetic age-matched individuals. The receptor for advanced glycation end products (RAGE) is upregulated in diabetic tissues. In this study, we tested the hypothesis that RAGE affected ischemia/reperfusion (I/R) injury in the diabetic myocardium. In diabetic rat hearts, expression of RAGE and its ligands was enhanced and localized particularly to both endothelial cells and mononuclear phagocytes. RESEARCH DESIGN AND METHODS: To specifically dissect the impact of RAGE, homozygous RAGE-null mice and transgenic (Tg) mice expressing cytoplasmic domain-deleted RAGE (DN RAGE), in which RAGE-dependent signal transduction was deficient in endothelial cells or mononuclear phagocytes, were rendered diabetic with streptozotocin. Isolated perfused hearts were subjected to I/R. RESULTS: Diabetic RAGE-null mice were significantly protected from the adverse impact of I/R injury in the heart, as indicated by decreased release of LDH and lower glycoxidation products carboxymethyl-lysine (CML) and pentosidine, improved functional recovery, and increased ATP. In diabetic Tg mice expressing DN RAGE in endothelial cells or mononuclear phagocytes, markers of ischemic injury and CML were significantly reduced, and levels of ATP were increased in heart tissue compared with littermate diabetic controls. Furthermore, key markers of apoptosis, caspase-3 activity and cytochrome c release, were reduced in the hearts of diabetic RAGE-modified mice compared with wild-type diabetic littermates in I/R. CONCLUSIONS: These findings demonstrate novel and key roles for RAGE in I/R injury in the diabetic heart.


Subject(s)
Diabetes Mellitus, Experimental/genetics , Diabetic Angiopathies/genetics , Myocardial Ischemia/genetics , Receptors, Immunologic/deficiency , Receptors, Immunologic/metabolism , Animals , Diabetes Mellitus, Experimental/complications , Diabetes Mellitus, Experimental/drug therapy , Insulin/therapeutic use , Male , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Knockout , Mice, Transgenic , Rats , Rats, Inbred BB , Receptor for Advanced Glycation End Products , Receptors, Immunologic/genetics , Ventricular Dysfunction, Left/genetics
10.
Circulation ; 113(9): 1226-34, 2006 Mar 07.
Article in English | MEDLINE | ID: mdl-16505177

ABSTRACT

BACKGROUND: The beneficial effects of reperfusion therapies have been limited by the amount of ischemic damage that occurs before reperfusion. To enable development of interventions to reduce cell injury, our research has focused on understanding mechanisms involved in cardiac cell death after ischemia/reperfusion (I/R) injury. In this context, our laboratory has been investigating the role of the receptor for advanced-glycation end products (RAGE) in myocardial I/R injury. METHODS AND RESULTS: In this study we tested the hypothesis that RAGE is a key modulator of I/R injury in the myocardium. In ischemic rat hearts, expression of RAGE and its ligands was significantly enhanced. Pretreatment of rats with sRAGE, a decoy soluble part of RAGE receptor, reduced ischemic injury and improved functional recovery of myocardium. To specifically dissect the impact of RAGE, hearts from homozygous RAGE-null mice were isolated, perfused, and subjected to I/R. RAGE-null mice were strikingly protected from the adverse impact of I/R injury in the heart, as indicated by decreased release of LDH, improved functional recovery, and increased adenosine triphosphate (ATP). In rats and mice, activation of the RAGE axis was associated with increases in inducible nitric oxide synthase expression and levels of nitric oxide, cyclic guanosine monophosphate (cGMP), and nitrotyrosine. CONCLUSIONS: These findings demonstrate novel and key roles for RAGE in I/R injury in the heart. The findings also demonstrate that the interaction of RAGE with advanced-glycation end products affects myocardial energy metabolism and function during I/R.


Subject(s)
Myocardial Ischemia/pathology , Myocardial Reperfusion Injury/pathology , Receptors, Immunologic/physiology , Animals , Cyclic GMP/analysis , Energy Metabolism , Male , Mice , Mice, Knockout , Myocardial Ischemia/metabolism , Myocardial Reperfusion Injury/metabolism , Nitric Oxide/analysis , Nitric Oxide Synthase Type II/analysis , Rats , Receptor for Advanced Glycation End Products , Receptors, Immunologic/deficiency , Tyrosine/analogs & derivatives , Tyrosine/analysis , Up-Regulation
11.
Ann N Y Acad Sci ; 1043: 702-9, 2005 Jun.
Article in English | MEDLINE | ID: mdl-16037296

ABSTRACT

Cardiovascular disease represents the major cause of morbidity and mortality in patients with diabetes mellitus. The impact of cardiac disease includes increased sensitivity of diabetic myocardium to ischemic episodes and diabetic cardiomyopathy, manifested as a subnormal functional response of the diabetic heart independent of coronary artery disease. In this context, we were to our knowledge the first to demonstrate that diabetes increases glucose flux via the first and key enzyme, aldose reductase, of the polyol pathway, resulting in impaired glycolysis under normoxic and ischemic conditions in diabetic myocardium. Our laboratory has been investigating the role of the polyol pathway in mediating myocardial ischemic injury in diabetics. Furthermore, the influence of the aldose reductase pathway in facilitating generation of key potent glycating compounds has led us to investigate the impact of advanced glycation end products (AGEs) in myocardial ischemic injury in diabetics. The potent impact of increased flux via the aldose reductase pathway and the increased AGE interactions with its receptor (RAGE) resulting in cardiac dysfunction will be discussed in this chapter.


Subject(s)
Aldehyde Reductase/physiology , Glycation End Products, Advanced/physiology , Myocardial Ischemia/physiopathology , Receptors, Immunologic/physiology , Animals , Cardiovascular Diseases/physiopathology , Diabetic Angiopathies/physiopathology , Humans , Myocardial Ischemia/etiology , Receptor for Advanced Glycation End Products
12.
FASEB J ; 19(7): 795-7, 2005 May.
Article in English | MEDLINE | ID: mdl-15746188

ABSTRACT

The aldose reductase pathway has been demonstrated to be a key component of myocardial ischemia reperfusion injury. Previously, we demonstrated that increased lactate/pyruvate ratio, a measure of cytosolic NADH/NAD+, is an important change that drives the metabolic cascade mediating ischemic injury. This study investigated signaling mechanisms by which the aldose reductase pathway mediates myocardial ischemic injury. Specifically, the influence of the aldose reductase pathway flux on JAK-STAT signaling was examined in perfused hearts. Induction of global ischemia in rats resulted in JAK2 activation followed by STAT5 activation. Pharmacological inhibition of aldose reductase or sorbitol dehydrogenase blocked JAK2 and STAT5 activation and was associated with lower lactate/pyruvate ratio and lower protein kinase C activity. Niacin, known to lower cytosolic NADH/NAD+ ratio independent of the aldose reductase pathway inhibition, also blocked JAK2 and STAT5 activation. Inhibition of protein kinase C also blocked JAK2 and STAT5 activation. Transgenic mice overexpressing human aldose reductase exhibited increased JAK2 and STAT5 activation. Pharmacological inhibition of JAK2 reduced ischemic injury and improved functional recovery similar to that observed in aldose reductase pathway inhibited mice hearts. These data, for the first time, demonstrate JAK-STAT signaling by the aldose reductase pathway in ischemic hearts and is, in part, due to changes in cytosolic redox state.


Subject(s)
Aldehyde Reductase/physiology , Myocardial Ischemia/enzymology , Protein-Tyrosine Kinases/metabolism , Proto-Oncogene Proteins/metabolism , STAT5 Transcription Factor/metabolism , Signal Transduction/physiology , Aldehyde Reductase/antagonists & inhibitors , Aldehyde Reductase/genetics , Animals , Blotting, Western , Enzyme Activation/drug effects , Enzyme Inhibitors/pharmacology , Humans , Janus Kinase 2 , L-Iditol 2-Dehydrogenase/antagonists & inhibitors , L-Iditol 2-Dehydrogenase/metabolism , Lactic Acid/analysis , Mice , Mice, Inbred C57BL , Mice, Transgenic , Myocardium/chemistry , Niacin/pharmacology , Oxidation-Reduction , Phosphorylation , Protein Kinase C/metabolism , Protein-Tyrosine Kinases/analysis , Protein-Tyrosine Kinases/antagonists & inhibitors , Proto-Oncogene Proteins/analysis , Proto-Oncogene Proteins/antagonists & inhibitors , Pyruvic Acid/analysis , Rats , Rats, Wistar , STAT5 Transcription Factor/analysis , STAT5 Transcription Factor/antagonists & inhibitors
13.
Am J Physiol Endocrinol Metab ; 288(6): E1229-35, 2005 Jun.
Article in English | MEDLINE | ID: mdl-15701679

ABSTRACT

Hearts with overexpression of anchored lipoprotein lipase (LpL) by cardiomyocytes (hLpL(GPI) mice) develop a lipotoxic cardiomyopathy. To characterize cardiac fatty acid (FA) and triglyceride (TG) metabolism in these mice and to determine whether changes in lipid metabolism precede cardiac dysfunction, hearts from young mice were perfused in Langendorff mode with [14C]palmitate. In hLpL(GPI) hearts, FA uptake and oxidation were decreased by 59 and 82%, respectively. This suggests reliance on an alternative energy source, such as TG. Indeed, these hearts oxidized 88% more TG. Hearts from young hLpL(GPI) mice also had greater uptake of intravenously injected cholesteryl ester-labeled Intralipid and VLDL. To determine whether perfusion of normal hearts would mimic the metabolic alterations found in hLpL(GPI) mouse hearts, wild-type hearts were perfused with [14C]palmitate and either human VLDL or Intralipid (0.4 mM TG). Both sources of TG reduced [14C]palmitate uptake (48% with VLDL and 45% with Intralipid) and FA oxidation (71% with VLDL and 65% with Intralipid). Addition of either heparin or LpL inhibitor P407 to Intralipid-containing perfusate restored [14C]palmitate uptake and confirmed that Intralipid inhibition requires local LpL. Our data demonstrate that reduced FA uptake and oxidation occur before mechanical dysfunction in hLpL(GPI) lipotoxicity. This physiology is reproduced with perfusion of hearts with TG-containing particles. Together, the results demonstrate that cardiac uptake of TG-derived FA reduces utilization of albumin-FA.


Subject(s)
Cardiomyopathies/metabolism , Lipoprotein Lipase/metabolism , Myocardium/metabolism , Palmitates/metabolism , Age Factors , Animals , Cardiomyopathies/etiology , Disease Models, Animal , Enzyme Inhibitors/pharmacology , Fat Emulsions, Intravenous/administration & dosage , In Vitro Techniques , Lipoprotein Lipase/antagonists & inhibitors , Lipoprotein Lipase/genetics , Male , Mice , Mice, Inbred C57BL , Mice, Transgenic , Myocytes, Cardiac/metabolism , Palmitates/administration & dosage , Perfusion
14.
FASEB J ; 18(11): 1192-9, 2004 Aug.
Article in English | MEDLINE | ID: mdl-15284219

ABSTRACT

Aldose reductase (AR), a member of the aldo-keto reductase family, has been implicated in the development of vascular and neurological complications of diabetes. Recently, we demonstrated that aldose reductase is a component of myocardial ischemic injury and that inhibitors of this enzyme protect rat hearts from ischemia-reperfusion injury. To rigorously test the effect of aldose reductase on myocardial ischemia-reperfusion injury, we used transgenic mice broadly overexpressing human aldose reductase (ARTg) driven by the major histocompatibility complex I promoter. Hearts from these ARTg or littermate mice (WT) (n=6 in each group) were isolated, perfused under normoxic conditions, then subjected to 50 min of severe low flow ischemia followed by 60 min of reperfusion. Creatine kinase (CK) release (a marker of ischemic injury) was measured during reperfusion; left ventricular developed pressure (LVDP), end diastolic pressure (EDP), and ATP were measured throughout the protocol. CK release was significantly greater in ARTg mice compared with the WT mice. LVDP recovery was significantly reduced in ARTg mice compared with the WT mice. Furthermore, ATP content was higher in WT mice compared with ARTg mice during ischemia and reperfusion. Infarct size measured by staining techniques and myocardial damage evaluated histologically were also significantly worse in ARTg mice hearts than in controls. Pharmacological inhibition of aldose reductase significantly reduced ischemic injury and improved functional recovery in ARTg mice. These data strongly support key roles for AR in ischemic injury and impairment of functional and metabolic recovery after ischemia. We propose that interventions targeting AR may provide a novel adjunctive approach to protect ischemic myocardium.


Subject(s)
Aldehyde Reductase/physiology , Myocardial Ischemia/enzymology , Myocardial Reperfusion Injury/enzymology , Adenosine Triphosphate/metabolism , Aldehyde Reductase/antagonists & inhibitors , Aldehyde Reductase/biosynthesis , Aldehyde Reductase/genetics , Animals , Coronary Vessels , Cytosol/metabolism , Enzyme Inhibitors/pharmacology , Glucose/metabolism , Glycolysis , L-Iditol 2-Dehydrogenase/pharmacology , Ligation , Mice , Mice, Inbred C57BL , Mice, Transgenic , Myocardial Ischemia/pathology , Myocardial Reperfusion Injury/pathology , Myocardium/metabolism , NAD/metabolism , Niacin/pharmacology , Organ Culture Techniques , Oxidation-Reduction , Palmitic Acid/metabolism , Recombinant Fusion Proteins/physiology , Ventricular Function, Left
15.
Circulation ; 109(13): 1668-73, 2004 Apr 06.
Article in English | MEDLINE | ID: mdl-15051645

ABSTRACT

BACKGROUND: Drugs that selectively block nitric oxide synthase (NOS) 2 enzyme activity by inhibiting dimerization of NOS2 monomers have recently been developed. METHODS AND RESULTS: To investigate whether selective inhibition of NOS2 is cardioprotective, rats were pretreated for 2 days with BBS2, an inhibitor of NOS2 dimerization, at 15 mg/kg SC. Isolated buffer-perfused hearts from treated (n=9) and control (n=7) hearts were subjected to 20 minutes of ischemia followed by 60 minutes of reperfusion. NOS2 protein was upregulated in all hearts at the end of ischemia and of reperfusion; NOS2 enzyme activity was 60% lower in hearts from the treated animals. In the treated hearts, the increase in end-diastolic pressure was significantly attenuated at the end of ischemia, and the return of developed pressure at reperfusion was greater (P<0.05). Creatine kinase release at reperfusion was lower in treated hearts than in controls (P=0.02). At the end of ischemia and of reperfusion, myocardial ATP levels were significantly higher in the treated hearts than in controls (P<0.05). In the treated hearts under ischemic conditions, lactate content was higher and the lactate/pyruvate ratio was lower than in controls (P<0.05); GAPDH activity was higher; and G-3-P and aldose reductase activity were lower. At reperfusion, in the treated hearts, there was less histological damage and less apoptosis of cardiac muscle cells. CONCLUSIONS: Pretreatment with BBS2, a selective inhibitor of NOS2, improves contractile performance, preserves myocardial ATP, and reduces damage and death of cardiac myocytes during ischemia and reperfusion of isolated buffer-perfused rat hearts.


Subject(s)
Cardiotonic Agents/therapeutic use , Enzyme Inhibitors/therapeutic use , Imidazoles/therapeutic use , Myocardial Ischemia/enzymology , Myocardial Reperfusion Injury/prevention & control , Nitric Oxide Synthase/antagonists & inhibitors , Piperazines/therapeutic use , Pyrimidines/therapeutic use , Adenosine Triphosphate/metabolism , Animals , Apoptosis , Cardiotonic Agents/pharmacology , Creatine Kinase/metabolism , Creatine Kinase, MM Form , Dimerization , Drug Evaluation, Preclinical , Energy Metabolism/drug effects , Enzyme Induction/drug effects , Enzyme Inhibitors/pharmacology , Imidazoles/pharmacology , Isoenzymes/metabolism , Male , Myocardial Ischemia/pathology , Myocardial Reperfusion Injury/enzymology , Myocardial Reperfusion Injury/pathology , Myocytes, Cardiac/pathology , Nitric Oxide Synthase/biosynthesis , Nitric Oxide Synthase/genetics , Nitric Oxide Synthase/physiology , Nitric Oxide Synthase Type II , Piperazines/pharmacology , Premedication , Pyrimidines/pharmacology , Rats , Rats, Inbred WF , Reverse Transcriptase Polymerase Chain Reaction , Ventricular Function, Left/drug effects
16.
FASEB J ; 17(15): 2331-3, 2003 Dec.
Article in English | MEDLINE | ID: mdl-14525943

ABSTRACT

Sorbitol dehydrogenase (SDH) is a polyol pathway enzyme that catalyzes conversion of sorbitol to fructose. Recent studies have demonstrated that activation of aldose reductase, the first enzyme of the polyol pathway, is a key response to ischemia and that inhibition of aldose reductase reduces myocardial ischemic injury. In our efforts to understand the role of pathway in affecting metabolism under normoxic and ischemic conditions, as well as in ischemic injury in myocardium, we investigated the importance of SDH by use of a specific inhibitor (SDI), CP-470,711. SDH inhibition increased glucose oxidation, whereas palmitate oxidation remained unaffected. Global ischemia increased myocardial SDH activity by approximately 1.5 fold. The tissue lactate/pyruvate ratio, a measure of cytosolic NADH/NAD+, was reduced by SDH inhibition under both normoxic and ischemic conditions. ATP was higher in SDI hearts during ischemia and reperfusion. Creatine kinase release during reperfusion, a marker of myocardial ischemic injury, was markedly attenuated in SDH-inhibited hearts. These data indicate that myocardial SDH activation is a component of ischemic response and that interventions that inhibit SDH protect ischemic myocardium. Furthermore, these data identify SDH as a novel target for adjunctive cardioprotective interventions.


Subject(s)
L-Iditol 2-Dehydrogenase/antagonists & inhibitors , Myocardium/enzymology , Animals , Cardiotonic Agents/therapeutic use , Chemotherapy, Adjuvant , Drug Delivery Systems , Enzyme Inhibitors/therapeutic use , Glucose/metabolism , Heart/drug effects , Models, Cardiovascular , Myocardial Ischemia/enzymology , Myocardial Ischemia/prevention & control , Myocardium/metabolism , Organ Culture Techniques , Pyrimidines/therapeutic use , Rats
17.
Coron Artery Dis ; 13(6): 313-8, 2002 Sep.
Article in English | MEDLINE | ID: mdl-12436025

ABSTRACT

BACKGROUND: A number of experimental studies have shown that increasing glucose use or decreasing accumulation of long-chain acyl carnitines (LCAC) protect ischemic hearts. METHODS: To evaluate the relative importance of these two strategies in protecting ischemic myocardium, isolated rat hearts (n = 6 in each group) were paced at 300 bpm and subjected to 50 min of low-flow ischemia followed by 60 min of reperfusion. Buffer contained 0.4 m mol/l albumin, 0.4 m mol/l palmitate, and 70 mU/l insulin, and either normal glucose (5 m mol/l) (CON), high glucose (10 m mol/l total) (HG, known to increase glucose use), 5 m mol/l glucose and niacin (10 micromol/l) (NIA, known to increase glucose use and decrease LCAC) or carnitine (10 m mol/l) (CAR, known to increase glucose use and decrease LCAC). Separate groups of hearts were perfused in the presence of 10 micromol/l cytochalasin-B (CB), an inhibitor of insulin-sensitive glucose transporters. RESULTS: Ischemic injury, as assessed by creatine kinase (CK) release was diminished by an average of 50% in HG, NIA, and CAR hearts, and the percentage recovery of left ventricular (LV) function with reperfusion was enhanced by approximately 20% compared with CON hearts (P < 0.05 for each comparison). Cytochalasin-B abolished all of the salutary effects. Long-chain acyl carnitines levels were higher in HG hearts compared with NIA- and CAR-treated hearts ( P < 0.05), but ischemic protection and functional recovery was greater in HG hearts. CONCLUSIONS: The data support the adjunctive use of agents that promote glucose uptake during ischemia and suggest that increasing glucose use is more important than decreasing LCAC in the protection against ischemic injury or in the recovery of contractile function.


Subject(s)
Carnitine/analogs & derivatives , Carnitine/metabolism , Glucose/metabolism , Myocardial Ischemia/prevention & control , Myocardial Ischemia/physiopathology , Animals , Carnitine/pharmacology , Creatine Kinase/drug effects , Creatine Kinase/metabolism , Cytochalasin B/antagonists & inhibitors , Disease Models, Animal , Models, Cardiovascular , Myocardial Contraction/drug effects , Myocardial Contraction/physiology , Myocardial Ischemia/metabolism , Myocardial Reperfusion Injury/metabolism , Myocardial Reperfusion Injury/physiopathology , Myocardial Reperfusion Injury/prevention & control , Niacin/pharmacology , Oxygen Consumption/drug effects , Oxygen Consumption/physiology , Rats , Recovery of Function/drug effects , Recovery of Function/physiology , Stroke Volume/drug effects , Stroke Volume/physiology , Vasodilator Agents/pharmacology , Ventricular Pressure/drug effects , Ventricular Pressure/physiology
18.
FASEB J ; 16(2): 243-5, 2002 Feb.
Article in English | MEDLINE | ID: mdl-11772943

ABSTRACT

Aldose reductase, a member of the aldo-keto reductase family, has been implicated in the development of vascular and neurological complications in diabetes. Despite recent studies from our laboratory demonstrating protection of ischemic hearts by an aldose reductase inhibitor, the presence and influence of aldose reductase in cardiac tissue remain unknown. Our goal in this study was to isolate and characterize the kinetic properties of cardiac aldose reductase, as well as to study the impact of flux via this enzyme on glucose metabolism and contractile function in hearts subjected to ischemia-reperfusion. Results demonstrate that ischemia increases myocardial aldose reductase activity and that these increases are, in part, due to activation by nitric oxide. The kinetic parameter of cardiac aldose reductase (Kcat) was significantly higher in ischemic tissues. Aldose reductase inhibition increased glycolysis and glucose oxidation. Aldose reductase inhibited hearts, when subjected to ischemia/reperfusion, exhibited less ischemic injury and was associated with lower lactate/pyruvate ratios (a measure of cytosolic NADH/NAD+), greater tissue content of adenosine triphosphate, and improved cardiac function. These findings indicate that aldose reductase is a component of ischemic injury and that pharmacological inhibitors of aldose reductase present a novel adjunctive approach for protecting ischemic hearts.


Subject(s)
Aldehyde Reductase/metabolism , Myocardial Ischemia/physiopathology , Myocardium/enzymology , Penicillamine/analogs & derivatives , Aldehyde Reductase/antagonists & inhibitors , Aldehyde Reductase/drug effects , Animals , Benzothiazoles , Enzyme Inhibitors/pharmacology , Glucose/metabolism , Myocardial Ischemia/prevention & control , Myocardium/metabolism , Myocardium/pathology , Nitric Oxide/metabolism , Nitric Oxide Donors/pharmacology , Penicillamine/pharmacology , Phthalazines/pharmacology , Rats , Thiazoles/pharmacology
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