RESUMO
AIMS/HYPOTHESIS: Opening of ATP-sensitive potassium (K(ATP)) channels during myocardial ischaemia shortens action potential duration and is believed to be an adaptive, energy-sparing response. Thiazolidinedione drugs block K(ATP) channels in non-cardiac cells in vitro. This study determined whether thiazolidinedione drugs block cardiac K(ATP) channels in vivo. METHODS: Experiments in 68 anaesthetised pigs determined: (1) effects of inert vehicle, troglitazone (10 mg/kg i.v.) or rosiglitazone (0.1 or 1.0 mg/kg i.v.) on epicardial monophasic action potential (MAP) during 90 min low-flow ischaemia; (2) effects of troglitazone, rosiglitazone or pioglitazone (1 mg/kg i.v.) on response of MAP to intracoronary infusion of a K(ATP) channel opener, levcromakalim; and (3) effects of inert vehicle, rosiglitazone (1 mg/kg i.v.) or the sarcolemmal K(ATP) blocker HMR-1098 on time to onset of ventricular fibrillation following complete coronary occlusion. RESULTS: With vehicle, epicardial MAP shortened by 44+/-9 ms during ischaemia. This effect was attenuated to 12+/-8 ms with troglitazone and 6+/-6 ms with rosiglitazone (p<0.01 for both vs vehicle), suggesting K(ATP) blockade. Intracoronary levcromakalim shortened MAP by 38+/-10 ms, an effect attenuated to 12+/-8, 13+/-4 and 9+/-5 ms during co-treatment with troglitazone, rosiglitazone or pioglitazone (p<0.05 for each), confirming K(ATP) blockade. During coronary occlusion, median time to ventricular fibrillation was 29 min in pigs treated with vehicle and 6 min in pigs treated with rosiglitazone or HMR-1098 (p<0.05 for both vs vehicle), indicating that K(ATP) blockade promotes ischaemic ventricular fibrillation in this model. CONCLUSIONS/INTERPRETATION: Thiazolidinedione drugs block cardiac K(ATP) channels at clinically relevant doses and promote onset of ventricular fibrillation during severe ischaemia.
Assuntos
Coração/fisiologia , Canais KATP/antagonistas & inibidores , Tiazolidinedionas/uso terapêutico , Fibrilação Ventricular/induzido quimicamente , Animais , Pressão Sanguínea/efeitos dos fármacos , Modelos Animais de Doenças , Coração/efeitos dos fármacos , Coração/fisiopatologia , Pioglitazona , Rosiglitazona , Suínos , Tiazolidinedionas/farmacologia , Tiazolidinedionas/toxicidadeAssuntos
Colecalciferol/uso terapêutico , Síndromes Mielodisplásicas/tratamento farmacológico , Administração Oral , Idoso , Idoso de 80 Anos ou mais , Colecalciferol/administração & dosagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/psicologia , Qualidade de VidaAssuntos
Calcitriol/farmacologia , Células Endoteliais/metabolismo , Ergocalciferóis/farmacologia , Inibidor 1 de Ativador de Plasminogênio/biossíntese , Agonistas dos Canais de Cálcio/farmacologia , Doenças Cardiovasculares/patologia , Células Cultivadas , Relação Dose-Resposta a Droga , Endotélio Vascular/citologia , Humanos , Diálise Renal , Veias Umbilicais/citologiaRESUMO
Radiotherapy with external beam radiation or brachytherapy is an established therapeutic modality for prostate cancer. Approximately 30% of patients with localised prostate cancer relapse at the irradiated site. Secondary effects of ionising radiation (IR), for example, bowel and bladder complications, are common. Thus, the search for biological response modifiers that could potentiate the therapeutic effects of radiation and limit the occurrence of serious side effects is an important task in prostate cancer therapy. 1alpha,25-Dihydroxyvitamin D(3) (calcitriol), the active metabolite of vitamin D, and its analogues are under investigation for the treatment of several malignancies including prostate cancer. Here, we report that 1alpha,25-dihydroxyvitamin D(3) and its less calcaemic analogue 19-nor-1alpha,25-(OH)(2)D(2) (Zemplar) act synergistically with IR to inhibit the growth of the human prostate cancer cells in vitro. 1alpha,25-dihydroxyvitamin D(3) potentiated IR-induced apoptosis of LNCaP cells, and nanomolar doses of 1alpha,25-dihydroxyvitamin D(3) and 19-nor-1alpha,25-(OH)(2)D(2) showed synergistic inhibition of growth of LNCaP cells at radiobiologically relevant doses of IR (1-2 Gy). At higher doses of IR, the combination of 1alpha,25-dihydroxyvitamin D(3) and IR or 19-nor-1alpha,25-(OH)(2)D(2) and IR resulted in moderate antagonism. The synergistic effect at radiobiologically relevant doses of radiation suggests that a combination of 1alpha,25-dihydroxyvitamin D(3) or 19-nor-1alpha,25-(OH)(2)D(2) with IR could permit a reduction in the dose of radiation given clinically and thus potentially reduce treatment-related morbidity.
Assuntos
Calcitriol/farmacologia , Ergocalciferóis/farmacologia , Neoplasias da Próstata/radioterapia , Radiossensibilizantes/farmacologia , Apoptose/efeitos da radiação , Western Blotting , Divisão Celular , DNA de Neoplasias/química , DNA de Neoplasias/genética , Humanos , Masculino , Neoplasias da Próstata/patologia , Radiação Ionizante , Células Tumorais CultivadasRESUMO
In a randomized, double-blind trial in 3086 patients with unstable angina pectoris or non-Q wave myocardial infarction we investigated if 80 mg of atorvastatin daily could improve outcome of cardiovascular events during a short period of time (16 weeks) compared with placebo. Baseline LDL cholesterol was 3.2 mmol L-1 (124 mg dL-1) and decreased by 40% to 1.9 mmol L-1 (72 mg dL-1) during atorvastatin treatment. The primary endpoint, which was a composite of death, non-fatal acute myocardial infarction, cardiac arrest with resuscitation or recurrent symptomatic myocardial ischaemia with objective evidence and requiring emergency rehospitalization occurred in 228 patients (14.8%) in the atorvastatin group and 269 patients (17.4%) in the placebo group. The relative risk was 0.84 and 95% confidence interval was 0.70-1.00 (P = 0.048). Thus for patients with acute coronary syndromes, lipid-lowering therapy with high dose atorvastatin reduces recurrent ischaemic events in the short-term. A possible mechanism behind this rapid clinical effect induced by statin treatment is on inflammatory processes. Recent studies strongly suggest that acute T-cell activation is involved in the pathogenesis of unstable angina. In another study we investigated whether circulating T cells showed signs of activation in patients with stable angina pectoris (SA). Systemic venous blood samples were taken from 38 men with SA and 42 healthy controls. The T-cell receptor expression was assessed by three-colour flow cytometry using monoclonal antibodies against CD3,CD4, CD8, CD25 and human leucocyte antigen (HLA)-DR. Soluble interleukin-2 receptor (sIL-2R) was measured as the circulating form in serum. Levels of circulating CD3+ and CD4+ T cells tended to be higher in patients compared with controls. Patients were also shown to have a significant increase in CD4+ T cells expressing the activation markers CD25 (P < 0.05) and HLA-DR (P < 0.01). Furthermore, serum levels of sIL-2R were significantly higher (P < 0.001) in patients than in controls. We also observed that the T-cell response was more pronounced in patients without simvastatin treatment (n = 18) compared with simvastatin-treated patients (n = 20). In conclusion, our findings indicate that a continuous immune system activation takes place in patients with chronic angina pectoris, predominantly involving proliferation of CD4+ T cells. Statin treatment seems to be able to decrease this inflammatory response.
Assuntos
Angina Pectoris/tratamento farmacológico , Anticolesterolemiantes/uso terapêutico , Ácidos Heptanoicos/uso terapêutico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Infarto do Miocárdio/tratamento farmacológico , Pirróis/uso terapêutico , Angina Pectoris/imunologia , Atorvastatina , Colesterol/metabolismo , Método Duplo-Cego , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/imunologia , Sinvastatina/uso terapêutico , Linfócitos TRESUMO
CONTEXT: Patients experience the highest rate of death and recurrent ischemic events during the early period after an acute coronary syndrome, but it is not known whether early initiation of treatment with a statin can reduce the occurrence of these early events. OBJECTIVE: To determine whether treatment with atorvastatin, 80 mg/d, initiated 24 to 96 hours after an acute coronary syndrome, reduces death and nonfatal ischemic events. DESIGN AND SETTING: A randomized, double-blind trial conducted from May 1997 to September 1999, with follow-up through 16 weeks at 122 clinical centers in Europe, North America, South Africa, and Australasia. PATIENTS: A total of 3086 adults aged 18 years or older with unstable angina or non-Q-wave acute myocardial infarction. INTERVENTIONS: Patients were stratified by center and randomly assigned to receive treatment with atorvastatin (80 mg/d) or matching placebo between 24 and 96 hours after hospital admission. MAIN OUTCOME MEASURES: Primary end point event defined as death, nonfatal acute myocardial infarction, cardiac arrest with resuscitation, or recurrent symptomatic myocardial ischemia with objective evidence and requiring emergency rehospitalization. RESULTS: A primary end point event occurred in 228 patients (14.8%) in the atorvastatin group and 269 patients (17.4%) in the placebo group (relative risk [RR], 0.84; 95% confidence interval [CI], 0.70-1.00; P =.048). There were no significant differences in risk of death, nonfatal myocardial infarction, or cardiac arrest between the atorvastatin group and the placebo group, although the atorvastatin group had a lower risk of symptomatic ischemia with objective evidence and requiring emergency rehospitalization (6.2% vs 8.4%; RR, 0.74; 95% CI, 0.57-0.95; P =.02). Likewise, there were no significant differences between the atorvastatin group and the placebo group in the incidence of secondary outcomes of coronary revascularization procedures, worsening heart failure, or worsening angina, although there were fewer strokes in the atorvastatin group than in the placebo group (12 vs 24 events; P =.045). In the atorvastatin group, mean low-density lipoprotein cholesterol level declined from 124 mg/dL (3.2 mmol/L) to 72 mg/dL (1.9 mmol/L). Abnormal liver transaminases (>3 times upper limit of normal) were more common in the atorvastatin group than in the placebo group (2.5% vs 0.6%; P<.001). CONCLUSION: For patients with acute coronary syndrome, lipid-lowering therapy with atorvastatin, 80 mg/d, reduces recurrent ischemic events in the first 16 weeks, mostly recurrent symptomatic ischemia requiring rehospitalization.
Assuntos
Angina Instável/tratamento farmacológico , Anticolesterolemiantes/uso terapêutico , Ácidos Heptanoicos/uso terapêutico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Infarto do Miocárdio/tratamento farmacológico , Pirróis/uso terapêutico , Idoso , Angina Instável/sangue , Atorvastatina , Método Duplo-Cego , Feminino , Humanos , Lipídeos/sangue , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/sangue , Modelos de Riscos Proporcionais , Recidiva , Análise de SobrevidaRESUMO
Mechanical properties of the myocardium at end diastole have been thought to be dominated by passive material properties rather than by active sarcomere cross-bridge interactions. This study tested the hypothesis that residual cross-bridges significantly contribute to end-diastolic mechanics in vivo and that changes in end-diastolic cross-bridge interaction parallel concurrent changes in systolic cross-bridge interaction. Open-chest anesthetized pigs were treated with intracoronary verapamil (n = 7) or 2,3-butanedione monoxime (BDM; n = 8). Regional left ventricular external work and end-diastolic pressure (EDP) versus end-diastolic segment length (EDL) relations were determined in the treated and untreated regions of each heart. Both agents reduced external work of treated regions to 31-38% of baseline and concurrently shifted EDP versus EDL relations to the right (i.e., greater EDL at a given EDP) by an average of 5% (P < 0.05). During washout of the drugs, EDP versus EDL returned to baseline in parallel with recovery of external work. Sarcomere length, measured by transmission electron microscopy in BDM-treated and untreated regions of the same hearts after diastolic arrest and perfusion fixation, was 8% greater in BDM-treated regions (P < 0.01). We concluded that residual diastolic cross-bridges significantly and reversibly influence end-diastolic mechanics in vivo. Alterations of end-diastolic and systolic cross-bridge interactions occur in parallel.
Assuntos
Diacetil/análogos & derivados , Diástole/fisiologia , Coração/fisiologia , Hemodinâmica/fisiologia , Contração Miocárdica/fisiologia , Sístole/fisiologia , Animais , Circulação Coronária/fisiologia , Diacetil/farmacologia , Diástole/efeitos dos fármacos , Coração/efeitos dos fármacos , Frequência Cardíaca/fisiologia , Ventrículos do Coração , Hemodinâmica/efeitos dos fármacos , Contração Miocárdica/efeitos dos fármacos , Miocárdio/ultraestrutura , Soluções para Preservação de Órgãos/farmacologia , Suínos , Sístole/efeitos dos fármacos , Função Ventricular Esquerda/fisiologia , Verapamil/farmacologiaRESUMO
Patients who present today with an acute coronary syndrome face a substantially lower risk of death, recurrent myocardial infarction, or severe ischemia than patients did a decade ago. Researchers are pursuing new strategies to further improve the outcomes of patients with acute coronary syndromes. These strategies may be grouped into 3 paradigms: (1) restoration and maintenance of coronary flow at the site of culprit lesion; (2) reduction of infarct size, reperfusion injury, and postischemic dysfunction; (3) stabilization of the coronary arterial wall and its interaction with the bloodstream to reduce recurrent ischemic events. The last approach encompasses strategies to alter the underlying vascular pathophysiology that leads to plaque instability and coronary thrombosis. Investigation into each of these paradigms may yield new strategies that will be incorporated into standard clinical management of acute coronary syndromes in coming years. With so many mechanistically different approaches to the management of acute coronary syndromes, clinicians have reason for optimism that continued progress will further reduce the morbidity and mortality associated with acute coronary syndromes and the likelihood of their recurrence.
Assuntos
Doença das Coronárias/terapia , Doença Aguda , Anticolesterolemiantes/uso terapêutico , Ensaios Clínicos Controlados como Assunto , Circulação Coronária , Doença das Coronárias/tratamento farmacológico , Doença das Coronárias/fisiopatologia , Humanos , Infarto do Miocárdio/prevenção & controle , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Projetos de Pesquisa , Síndrome , Disfunção Ventricular/etiologia , Disfunção Ventricular/prevenção & controleRESUMO
Severe ischemic injury or infarction of myocardium may cause activation of matrix metalloproteinases (MMPs) and damage the interstitial matrix. However, it is unknown whether MMP activation and matrix damage occur after moderate ischemia and reperfusion that result in myocardial stunning without infarction, and if so whether such changes contribute to postischemic myocardial expansion and contractile dysfunction. To address these questions, open-chest anesthetized pigs underwent 90 min of regional ischemia (subendocardial blood flow 0.4 +/- 0.1 ml. g(-1). min(-1)) and 90 min of reperfusion. After ischemia plus reperfusion, histological and ultrastructural examination revealed no myocardial infarction or inflammatory cell infiltration. Myocardial MMP-9 content increased threefold with a fourfold increase in the active form (P < 0.001). Myocardial collagenase content doubled (P < 0.01) but remained in latent form. MMP-2 and tissue inhibitors of metalloproteinases were unaffected. Despite increases in MMPs, collagen ultrastructure (assessed by cell maceration scanning electron microscopy) was unaltered. Intracoronary administration of the MMP inhibitor GM-2487 did not prevent or attenuate myocardial expansion (assessed by regional diastolic dimensions at near-zero left ventricular pressure) or contractile dysfunction. We conclude that although moderate ischemia and reperfusion alter myocardial MMP content and activity, these effects do not result in damage to interstitial collagen, nor do they contribute to myocardial expansion or contractile dysfunction.
Assuntos
Colágeno/ultraestrutura , Hemodinâmica , Metaloproteinases da Matriz/metabolismo , Isquemia Miocárdica/patologia , Isquemia Miocárdica/fisiopatologia , Reperfusão Miocárdica , Miocárdio/metabolismo , Miocárdio/ultraestrutura , Animais , Pressão Sanguínea , Colagenases/metabolismo , Circulação Coronária , Feminino , Coração/fisiopatologia , Frequência Cardíaca , Metaloproteinase 9 da Matriz/metabolismo , Isquemia Miocárdica/metabolismo , Miocárdio Atordoado/metabolismo , Miocárdio Atordoado/patologia , Miocárdio Atordoado/fisiopatologia , Miocárdio/patologia , Suínos , Inibidores Teciduais de Metaloproteinases/metabolismo , Função Ventricular EsquerdaRESUMO
Volume expansion and inotropic stimulation are used clinically to augment cardiac output during acute right ventricular (RV) pressure overload. We previously showed that a brief period of RV pressure overload causes RV free wall dysfunction that persists after normal loading conditions have been restored. However, the impact of volume expansion and inotropic stimulation on the severity of RV dysfunction after acute pressure overload is unknown. We hypothesized that the severity of RV dysfunction after RV pressure overload would be related to the level of RV free wall systolic stress during RV pressure overload, rather than to the specific interventions used to augment RV function. Chloralose-anesthetized, open-chest pigs were subjected to 1 h of RV pressure overload caused by pulmonary artery constriction, followed by 1 h of recovery after release of pulmonary artery constriction. A wide range of RV free wall systolic stress during RV pressure overload was achieved by either closing or opening the pericardium (to simulate volume expansion) and by administering or not administering dobutamine. The severity of RV free wall dysfunction 1 h after RV pressure overload was strongly and directly correlated with the values of two hemodynamic variables during RV pressure overload: RV free wall area at peak RV systolic pressure (determined by sonomicrometry) and peak RV systolic pressure, two of the major determinants of peak RV free wall systolic stress. Opening or closing the pericardium, and using or not using dobutamine during RV pressure overload, had no independent effects on the severity of RV dysfunction. The findings suggest that the goal of therapeutic intervention during RV pressure overload should be to achieve the required augmentation of cardiac output with the smallest possible increase in RV free wall systolic stress.
Assuntos
Hipertensão/fisiopatologia , Disfunção Ventricular Direita/fisiopatologia , Animais , Atropina/farmacologia , Cateterismo Cardíaco/instrumentação , Cardiotônicos/farmacologia , Fármacos Cardiovasculares/farmacologia , Diástole/efeitos dos fármacos , Dilatação Patológica/fisiopatologia , Modelos Animais de Doenças , Dobutamina/farmacologia , Feminino , Coração/efeitos dos fármacos , Coração/fisiopatologia , Hemodinâmica/efeitos dos fármacos , Hexametônio/farmacologia , Hipertensão/tratamento farmacológico , Modelos Lineares , Pericárdio/cirurgia , Artéria Pulmonar/fisiopatologia , Artéria Pulmonar/cirurgia , Suínos , Sístole/efeitos dos fármacos , Disfunção Ventricular Direita/tratamento farmacológicoRESUMO
The hormonal metabolite of vitamin D, 1alpha,25-dihydroxyvitamin D3 [1,25(OH)2D3] is known to inhibit the proliferation of prostatic epithelial cells. This has stimulated interest in vitamin D compounds as therapeutic agents for prostate cancer. However, the therapeutic use of 1,25(OH)2D3 is limited because elevations in serum 1,25(OH)2D3 can cause dangerous elevations in serum calcium levels. We wondered whether the prohormone of 1,25(OH)2D3, 25-hydroxyvitamin D3 (25-OH-D3), which is much less calcemic, could also achieve antiproliferative effects in prostatic cells. 25-OH-D3 is converted to 1,25(OH)2D3 by the mitochondrial enzyme 1-alpha-hydroxylase. We have recently shown that human prostatic cells also possess significant 1-alpha-hydroxylase activity (Schwartz et al., Cancer Epidemiol. Biomark. Prev., 7: 391-395, 1998). We studied 1-alpha-hydroxylase gene expression in four strains of primary human prostatic epithelial cells by reverse transcription PCR amplification (RT-PCR) of 1-alpha-hydroxylase. Human prostatic stromal cells were negative for 1-alpha-hydroxylase by RT-PCR. This led us to hypothesize that 25-OH-D3 would inhibit the proliferation of prostatic epithelial cells because 25-OH-D3 would be converted to 1,25(OH)2D3 intracellularly. We studied the effects of 25-OH-D3 and 1,25(OH)2D3 on the proliferation of prostatic epithelial cells using high density growth and clonal growth assays on two different primary cell strains derived from normal human prostatic peripheral zone. 25-OH-D3 and 1,25(OH)2D3 each inhibited growth in a dose- and time-dependent manner. Growth inhibition was evident at 1 nM, and maximal inhibition was observed at 100 nM within 10-12 days of exposure. The potencies of 25-OH-D3 and 1,25(OH)2D3 were not significantly different. These data demonstrate that 25-OH-D3, which previously was thought to have little biological activity, can become a potent antiproliferative hormone for prostatic cells that express 1-alpha-hydroxylase. Because 25-OH-D3 exhibits similar potency to 1,25(OH)2D3 but is less calcemic, 25-OH-D3 may offer a safer option than 1,25(OH)2D3 for prostate cancer therapy. Moreover, because 25-OH-D3 is produced endogenously from vitamin D, these findings support a potential role for vitamin D in the chemoprevention of prostate cancer.
Assuntos
Calcifediol/farmacologia , Regulação Neoplásica da Expressão Gênica , Neoplasias da Próstata/patologia , Vitamina D/farmacologia , Divisão Celular/efeitos dos fármacos , Quimioprevenção , Humanos , Masculino , Oxigenases de Função Mista/biossíntese , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Células Tumorais Cultivadas , Vitamina D/metabolismoRESUMO
BACKGROUND: This study determined whether treatment of normal (nondiabetic) pigs with the insulin-sensitizing agent troglitazone improves recovery of left ventricular (LV) function after acute ischemia and whether such effects are associated with altered myocardial substrate metabolism. METHODS AND RESULTS: Juvenile pigs (n=6) were treated with troglitazone (75 mg. kg(-1). d(-1) PO) for 8 weeks. Untreated pigs (n=8) served as controls. Under anesthetized, open-chest conditions, pigs underwent 90 minutes of moderate regional LV ischemia and 90 minutes of reperfusion. Regional LV function was assessed with subendocardial sonomicrometry crystals. Fasting plasma insulin and free fatty acid levels were lower in troglitazone-treated pigs than in untreated pigs, whereas blood glucose did not differ between groups. These findings suggest that treatment enhanced systemic insulin sensitivity. Baseline hemodynamics and regional LV function did not differ between groups. After ischemia and reperfusion, systolic function (external work) of the ischemic region recovered to 44+/-6% of baseline in troglitazone-treated pigs versus 18+/-6% of baseline in untreated pigs (P<0.05). Regional diastolic function (maximum rate of wall expansion) recovered to 78+/-7% of baseline in treated pigs versus 52+/-7% of baseline in untreated pigs (P<0.05). Recovery of global LV systolic and diastolic function was also significantly greater in treated pigs. Myocardial glucose uptake did not differ between groups under any condition; however, net myocardial lactate uptake after reperfusion was 7 times greater in troglitazone-treated pigs than in untreated pigs, suggesting that treatment enhanced myocardial carbohydrate oxidation after reperfusion. CONCLUSIONS: In nondiabetic pigs, chronic troglitazone treatment improves recovery of LV systolic and diastolic function after acute ischemia.
Assuntos
Cromanos/uso terapêutico , Hipoglicemiantes/uso terapêutico , Isquemia Miocárdica/tratamento farmacológico , Tiazóis/uso terapêutico , Tiazolidinedionas , Animais , Pressão Sanguínea/efeitos dos fármacos , Resistência à Insulina , Isquemia Miocárdica/fisiopatologia , Consumo de Oxigênio/efeitos dos fármacos , Suínos , Troglitazona , Função Ventricular Esquerda/efeitos dos fármacosRESUMO
Prostate cancer cells contain specific receptors [vitamin D receptors (VDRs)] for 1alpha,25-dihydroxyvitamin D3 (1alpha,25(OH)2D3), which is known to inhibit the proliferation and invasiveness of these cells. These findings support the use of 1alpha,25(OH)2D3 for prostate cancer therapy. However, because 1alpha,25(OH)2D3 can cause hypercalcemia, analogues of 1alpha,25(OH)2D3 that are less calcemic but that exhibit potent antiproliferative activity would be attractive as therapeutic agents. We investigated the effects of two different types of less calcemic vitamin D compounds, 25-hydroxyvitamin D3 [25(OH)D3] and 19-nor-1alpha,25-dihydroxyvitamin D2 [19-nor-1,25(OH)2D2], and compared their activity to 1alpha,25(OH)2D3 on (a) the proliferation of primary cultures and cell lines of human prostate cancer cells; and (b) the transactivation of the VDRs in the androgen-insensitive PC-3 cancer cell line stably transfected with VDR (PC-3/ VDR). 19-nor-1alpha,25(OH)2D2, an analogue of 1alpha,25(OH)2D3 that was originally developed for the treatment of parathyroid disease, has been shown to be less calcemic than 1alpha,25(OH)2D3 in clinical trials. Additionally, we recently showed that human prostate cells in primary culture possess 25(OH)D3-1alpha-hydroxylase, an enzyme that hydroxylates the inactive prohormone, 25(OH)D3, to the active hormone, 1alpha,25(OH)2D3, intracellularly. We reasoned that the hormone that is formed intracellularly would inhibit prostate cell proliferation in an autocrine fashion. We found that 1alpha,25(OH)2D3 and 19-nor-1alpha,25(OH)2D2 caused similar dose-dependent inhibition in the cell lines and primary cultures in the [3H]thymidine incorporation assay and that both compounds were significantly more active in the primary cultures than in LNCaP cells. Likewise, 25(OH)D3 had inhibitory effects comparable to those of 1alpha,25(OH)2D3 in the primary cultures. In the chloramphenicol acetyltransferase (CAT) reporter gene transactivation assay in PC-3/ VDR cells, 1alpha,25(OH)2D3 and 19-nor-1alpha,25(OH)2D2 caused similar increases in CAT activity between 10(-11)and 10(-9) M. Incubation of PC-3/VDR cells with 5 x 10(-8) M 25(OH)D3 induced a 29-fold increase in CAT activity, similar to that induced by 10(-8) M 1alpha,25(OH)2D3. In conclusion, our data indicate that 25(OH)D3 and 19-nor-1alpha,25(OH)2D2 represent two different solutions to the problem of hypercalcemia associated with vitamin D-based therapies: 25(OH)D3 requires the presence of 1alpha-hydroxylase, whereas 19-nor-1alpha,25(OH)2D2 does not. Both drugs are approved for human use and may be good candidates for human clinical trials in prostate cancer.
Assuntos
Calcifediol/farmacologia , Ergocalciferóis/farmacologia , Neoplasias da Próstata/tratamento farmacológico , Contagem de Células/efeitos dos fármacos , Divisão Celular/efeitos dos fármacos , Cloranfenicol O-Acetiltransferase/genética , Cloranfenicol O-Acetiltransferase/metabolismo , Relação Dose-Resposta a Droga , Humanos , Masculino , Neoplasias da Próstata/patologia , Receptores de Calcitriol/genética , Proteínas Recombinantes de Fusão/efeitos dos fármacos , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Timidina/metabolismo , Ativação Transcricional/efeitos dos fármacos , Trítio , Células Tumorais CultivadasRESUMO
Little is known about the etiology of pancreatic cancer, which is an important cause of cancer mortality in developed countries. We hypothesize that exposure to cadmium is a cause of pancreatic cancer. Cadmium is a nonessential metal that is known to accumulate in the human pancreas. The major risk factors for pancreatic cancer (increasing age, cigarette smoking, residence in Louisiana, and occupations involving exposure to metalworking and pesticides) are all associated with increased exposure to cadmium. Our meta-analysis of cohorts with high exposure to cadmium is also consistent with an increased risk of pancreatic cancer (standardized mortality ratio = 166; 95% confidence interval, 98-280; P = 0.059). Cadmium can cause the transdifferentiation of pancreatic cells, increases in the synthesis of pancreatic DNA, and increases in oncogene activation. Thus, cadmium is a plausible pancreatic carcinogen. The cadmium hypothesis provides a coherent explanation for much of the descriptive epidemiology of pancreatic cancer and suggests new avenues for analytical research.
Assuntos
Cádmio/efeitos adversos , Oncogenes/genética , Neoplasias Pancreáticas/etiologia , Fatores Etários , DNA/metabolismo , Humanos , Louisiana/epidemiologia , Ocupações , Neoplasias Pancreáticas/epidemiologia , Neoplasias Pancreáticas/patologia , Medição de Risco , Fumar/efeitos adversosRESUMO
Clinical and experimental studies have suggested benefit of treatment with intravenous glucose-insulin-potassium (GIK) in acute myocardial infarction. However, patients hospitalized with acute coronary syndromes often experience recurrent myocardial ischemia without infarction that may cause progressive left ventricular (LV) dysfunction. This study tested the hypothesis that anticipatory treatment with GIK attenuates both systolic and diastolic LV dysfunction resulting from ischemia and reperfusion without infarction in vivo. Open-chest, anesthetized pigs underwent 90 min of moderate regional ischemia (mean subendocardial blood flow 0.3 ml x g(-1) x min(-1)) and 90 min reperfusion. Eight pigs were treated with GIK (300 g/l glucose, 50 U/l insulin, and 80 meq/l KCl; infused at 2 ml x kg(-1) x h(-1)) beginning 30 min before ischemia and continuing through reperfusion. Eight untreated pigs comprised the control group. Regional LV wall area was measured with orthogonal pairs of sonomicrometry crystals. GIK significantly increased myocardial glucose uptake and lactate release during ischemia. After reperfusion, indexes of regional systolic function (external work and fractional systolic wall area reduction), regional diastolic function (maximum rate of diastolic wall area expansion), and global LV function (LV positive and negative maximum rate of change in pressure with respect to time) recovered to a significantly greater extent in GIK-treated pigs than in control pigs (all P < 0.05). The findings suggest that the clinical utility of GIK may extend beyond treatment of acute myocardial infarction to anticipatory metabolic protection of myocardium in patients at risk for recurrent episodes of ischemia.
Assuntos
Pressão Sanguínea/efeitos dos fármacos , Glucose/farmacologia , Insulina/farmacologia , Isquemia Miocárdica/fisiopatologia , Potássio/farmacologia , Traumatismo por Reperfusão/fisiopatologia , Animais , Circulação Coronária , Diástole , Combinação de Medicamentos , Feminino , Insulina/sangue , Miocárdio/metabolismo , Suínos , Sístole , Função Ventricular Esquerda/efeitos dos fármacosRESUMO
We analyzed data from the first National Health and Nutrition Examination Survey Epidemiologic Follow-up Study to test the hypothesis that vitamin D from sunlight exposure, diet, and supplements reduces the risk of breast cancer. We identified 190 women with incident breast cancer from a cohort of 5009 white women who completed the dermatological examination and 24-h dietary recall conducted from 1971-1974 and who were followed up to 1992. Using Cox proportional hazards regression, we estimated relative risks (RRs) for breast cancer and 95% confidence intervals, adjusting for age, education, age at menarche, age at menopause, body mass index, alcohol consumption, and physical activity. Several measures of sunlight exposure and dietary vitamin D intake were associated with reduced risk of breast cancer, with RRs ranging from 0.67-0.85. The associations with vitamin D exposures, however, varied by region of residence. The risk reductions were highest for women who lived in United States regions of high solar radiation, with RRs ranging from 0.35-0.75. No reductions in risk were found for women who lived in regions of low solar radiation. Although limited by the relatively small size of the case population, the protective effects of vitamin D observed in this prospective study are consistent for several independent measures of vitamin D. These data support the hypothesis that sunlight and dietary vitamin D reduce the risk of breast cancer.
Assuntos
Neoplasias da Mama/epidemiologia , Neoplasias da Mama/prevenção & controle , Luz Solar , Vitamina D , Adulto , Idoso , Estudos de Coortes , Suplementos Nutricionais , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de Risco , Inquéritos e Questionários , Estados Unidos/epidemiologiaRESUMO
This study tested the hypothesis that regional low-flow ischemia and reperfusion alter myocardial material properties by causing non-elastic deformation. Twenty-two anesthetized, open-chest pigs were studied. Pigs underwent 90 min of regional low-flow ischemia (anterior LV subendocardial blood flow 29+/-7% of baseline) followed by 90 min reperfusion. LV pressure and regional subendocardial segment length were recorded to derive end-diastolic pressure vs segment length (EDP vs EDL) and preload-recruitable stroke work (PRSW) relations. In vivo, non-elastic myocardial deformation was inferred from increases in minimally loaded myocardial dimensions: the EDL at zero EDP (L0) and the EDL at which no regional external work was performed (Lw, the PRSW intercept). In 15 pigs, ultrastructural confirmation of non-elastic deformation was obtained from sarcomere dimensions measured by transmission electron microscopy after in situ perfusion fixation under non-ischemic conditions, after 90 min ischemia, or after 90 min ischemia plus 90 min reperfusion. Ischemia increased L0 and Lw to 1.17+/-0.05 and 1. 13+/-0.04 times baseline, respectively. After reperfusion, L0 and Lw remained increased to 1.09+/-0.03 and 1.15+/-0.02 times baseline (all P<0.05). After reperfusion, PRSW slope was not different from baseline, but regional external work remained depressed (0.38+/-0.03 times baseline) due to the persistent increase in Lw. Neither L0 nor Lw changed in the posterior (non-ischemic) region. In hearts fixed after ischemia or after ischemia plus reperfusion, sarcomere length was significantly greater and transverse distance between thick myofilaments was significantly smaller in the anterior (ischemic) subendocardium than in the posterior (non-ischemic) subendocardium (P<0.01). We conclude that regional low-flow ischemia and reperfusion cause non-elastic deformation of myocardium, manifest in vivo by increased minimally loaded myocardial dimensions (L0 and Lw) and ultrastructurally by increased sarcomere length and decreased transverse interfilament distance. Non-elastic deformation of myocardium may contribute to contractile dysfunction in low-flow ischemia and reperfusion.
Assuntos
Circulação Coronária/fisiologia , Traumatismo por Reperfusão Miocárdica/patologia , Animais , Velocidade do Fluxo Sanguíneo , Elasticidade , Hemodinâmica/fisiologia , Microscopia Eletrônica , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Suínos , Função Ventricular/fisiologiaRESUMO
The steroid hormone 1,25-dihydroxyvitamin D [1,25(OH)2D, also known as calcitriol] is known to inhibit the proliferation and to promote the differentiation of human prostate cancer cells. Additionally, we showed that 1,25(OH)2D markedly inhibits the invasiveness of human prostate cancer cells in vitro (G. G. Schwartz et al., Cancer Epidemiol. Biomark. Prev., 6: 727-732, 1997). These properties support the use of 1,25(OH)2D as differentiation therapy in prostate cancer. However, the use of 1,25(OH)2D in vivo is limited by the risk of hypercalcemia. We therefore compared the effects of 1,25(OH)2D and of EB1089, an analogue of 1,25(OH)2D with reduced calcemic effects, in an in vivo model of androgen-insensitive metastatic prostate cancer, the rat Dunning MAT LyLu prostate cancer model. Tumor growth and metastasis were studied using Copenhagen rats given s.c. injections of MAT LyLu cells. Fifty male rats were divided into five groups of 10 rats each. Four experimental groups received i.p. injections of low and high doses of 1,25(OH)2D and EB1089 (0.5 and 1.0 microg/kg, low and high, respectively). A control group received injections of vehicle only. Tumor volumes were measured three times per week. Rats were weighed weekly. The number of metastases to the lungs and the extent of hypercalcemia were evaluated. Compared with controls, tumor volumes were significantly smaller in all experimental groups. Similarly, the number of lung metastases (number of foci/lung) was reduced markedly by both 1,25(OH)2D and EB1089. Control rats developed 22.7 (+/- 1.98 SE) tumor foci per lung. Rats treated with 1,25(OH)2D and with EB1089 (1.0 microg/kg) developed 10.4 (+/- 2.81) and 7.70 (+/- 1.29) tumor foci, respectively (P < 0.001 and P < 0.0001, respectively; drug versus control). Compared with controls (10.79 +/- 0.1 mg/dl), serum calcium levels were significantly elevated in both 1,25(OH)2D and EB1089-treated rats (P < 0.01). However, EB1089 was significantly less calcemic than 1,25(OH)2D (12.59 +/- 0.21 mg/dl versus 14.47 +/- 0.46 mg/dl; 1.0 microg/kg; P < 0.001). Rats treated with 1,25(OH)2D showed marked weight loss: 20.0 +/- 1.9% and 26.3 +/- 1.7% of their initial weight (low and high doses, respectively, P < 0.001). Weight loss was significantly lower in rats treated with EB1089 at the high dose 8.4 (+/- 2.9) %. Moreover, rats treated with low-dose EB1089 gained 5.2 (+/- 3.7) % of their initial weight. In conclusion, 1,25(OH)2D and EB1089 showed marked and equivalent inhibition of prostate cancer metastasis in vivo. EB1089 was significantly less calcemic than 1,25(OH)2D and did not induce severe weight loss. This is the first report of a vitamin D analogue that significantly inhibits prostate cancer metastasis in vivo and that does so without producing cachexia or unacceptable hypercalcemia.