RESUMO
The shoulder is the most mobile joint in the primate body, and is involved in both locomotor and manipulative activities. The presumed functional sensibility of trabecular bone can offer a way of decoding the activities to which the forelimbs of fossil primates were subjected. We examine the proximal humeral trabecular architecture in a relatively closely related group of similarly sized hominids (Pongo pygmaeus, Pan troglodytes, and Homo sapiens), in order to evaluate the effect of diverging habitual motion behaviors of the shoulder complex in a coherent phylogenetic group. In order to characterize and compare the humeral trabecular architectures of the three species, we imaged a large sample by high-resolution computed tomography (HrCT) and quantified their trabecular architectures by standard bone 3D morphometric parameters. Univariate statistical analysis was performed, showing significant differences among the species. However, univariate statistics could not highlight the structural particularity in the cancellous bone of each species. A principal component analysis also showed clear separation of the three taxa and enabled a structural characterization of the humeral trabecular bone of each species. We conclude that the differences in the architectural setup of the three hominids likely reflect multiple differences in their habitual activity patterns of their shoulder joint, although individual structural features are difficult to relate to specific loading conditions.
Assuntos
Úmero/anatomia & histologia , Pan troglodytes/anatomia & histologia , Pongo pygmaeus/anatomia & histologia , Adulto , Anatomia Comparada , Animais , Antropologia Física , Feminino , Humanos , Úmero/diagnóstico por imagem , Masculino , Análise de Componente Principal , Tomografia Computadorizada por Raios XRESUMO
Ascites tumor cells can be cultivated at a reduced serum concentration if cholesterol (2.50 mg per 100 ml of medium) is added to the culture medium. At serum concentrations of 3%, optimal growth properties are obtained; below 3%, cell cultures usually perish after a few days. Cells grown in the presence of added cholesterol have an elevated content of this molecule per cell as well as in the plasma membrane, and they also show a cholesterol concentration-dependent rate of proliferation. Precursors of the cholesterol-biosynthetic pathway like mevalonic acid, added in mM amounts, or squalene and lanosterol cannot be substituted for cholesterol itself. This is due to the observation that the biosynthetic pathway is blocked at the stage of lanosterol conversion to cholesterol. Cholesterol de novo synthesis from acetate is regulated by the cholesterol content of the cells, which also affects the production of ubiquinone and dolichol. Growth factors such as insulin, prostaglandin F2 alpha, and transferrin added to the medium do not mimic the cholesterol-induced effect. Distribution of DNA during cell cycle and the cell density-dependent reduction in macromolecule synthesis is very similar to the control cells. In contrast, cells without added cholesterol show reduced growth properties accompanied by the accumulation of cells in the mitotic and G2 phase. The cholesterol/phospholipid ratio of the plasma membranes of cholesterol-rich cells is about 15% lower than of the control cells and 40% higher compared to the cholesterol-poor cells, which, however, does not significantly alter the membrane fluidity between the cholesterol-rich and -poor cells as revealed by fluorescence polarization measurements. The most dramatic behavior of the cholesterol-rich cells is their tendency to form aggregates, which is demonstrated either by concanavalin A-induced agglutination or by cell density-dependent aggregation shown by interference microscopy in vivo.
Assuntos
Colesterol/farmacologia , Neoplasias Experimentais/fisiopatologia , Aglutinação , Animais , Agregação Celular/efeitos dos fármacos , Divisão Celular/efeitos dos fármacos , Linhagem Celular , Membrana Celular/efeitos dos fármacos , Membrana Celular/fisiologia , Replicação do DNA/efeitos dos fármacos , Camundongos , Receptores de Concanavalina A/análiseRESUMO
Aristolochic acid I (AAI), a nitrophenanthrene derivative, is the major component of the carcinogenic plant extract aristolochic acid, which has been used as a medicine since antiquity. Long term oral administration of AAI to male Wistar rats induces multiple tumors, mainly in the forestomach, ear duct, and small intestine. The presence of activated transforming genes was investigated in various tumors of 18 AAI treated rats, namely in 14 squamous cell carcinomas of the forestomach, 7 squamous cell carcinomas of the ear duct, 8 tumors of the small intestine, 3 tumors of the pancreas, 1 adenocarcinoma of the kidney, 1 lymphoma, and 2 metastases in the lung and the pancreas. By utilizing the tumorigenicity assay and Southern blot analysis, we have detected an activated c-Ha-ras gene in the DNAs of 5 of 5 squamous cell carcinomas of the forestomach. Direct sequencing of amplified material revealed an AT----TA transversion mutation at the second position of codon 61 of the c-Ha-ras gene (CAA to CTA) in all transfectants as well as in the 5 original rat tumors. Enzymatic amplification of ras sequences followed by selective oligonucleotide hybridization detected identical mutations in 93% (13 of 14) of forestomach tumors, in 100% (7 of 7) of ear duct tumors, and in the lung metastasis. Among those tumors tested, we had 4 cases in which the forestomach tumors and the ear duct tumors originated from the same rat, showing the same mutation in both tissues. Moreover, similar mutations were demonstrated at c-Ki-ras codon 61 in 1 of 7 ear duct tumors (CAA to CAT) and in 1 of 8 tumors of the small intestine (CAA to CTA) as well as at c-N-ras 61 (CAA to CTA) in a pancreatic metastasis. Additional transfection experiments of some tumors scoring negative for ras gene mutations in dot blot analyses revealed a CAA to CTA transversion at codon 61 of the c-Ha-ras gene in 1 forestomach tumor as well as at codon 61 of the c-N-ras in 1 hyperplasia of the pancreas and in 1 lymphoma. The apparent selectivity for mutations at adenine residues in AAI induced tumors is consistent with the identification of an N6-deoxyadenosine-AAI adduct formed by reaction of AAI with DNA in vitro, suggesting that carcinogen-deoxyadenosine adducts are the critical lesions in the tumor initiation by aristolochic acid.
Assuntos
Ácidos Aristolóquicos , Carcinógenos/toxicidade , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Genes ras/efeitos dos fármacos , Neoplasias Experimentais/genética , Fenantrenos/toxicidade , Animais , Sequência de Bases , Códon/genética , DNA de Neoplasias/genética , DNA de Neoplasias/isolamento & purificação , Masculino , Dados de Sequência Molecular , Mutação , Sondas de Oligonucleotídeos , Reação em Cadeia da Polimerase , Ratos , Ratos EndogâmicosRESUMO
BACKGROUND: Specific immunotherapy (SIT) is believed to modulate CD4+ T-helper cells. In order to improve safety, SIT vaccines are often formulated with allergoids (chemically modified allergens). Interaction between T-cells and allergoids is necessary to influence cellular cytokine expression. There have been few reports on identification the early cellular effects of SIT. METHOD: Patients allergic to grass and/or mugwort pollen (n= 21) were treated with a 4-shot allergy vaccine (Pollinex Quattro) containing appropriate allergoids (grass/rye and/or mugwort) adsorbed to L-tyrosine plus a Th1 adjuvant, monophosphoryl lipid A (MPL). Fourteen grass-allergic patients served as untreated controls. Using the peripheral blood mononuclear cells of these patients, an optimized lymphocyte transformation test (LTT) was employed to monitor the in vitro proliferative response of T-cells to an allergoid challenge (solubilised Pollinex Quattro) before the first and last injection and then 2 and 20 weeks after the final injection. Control challenges utilised preparations of a similar pollen vaccine without the adjuvant MPL and a tree pollen vaccine with and without MPL. RESULTS: The LTT showed increased LTT stimulation indices (SI) in 17/20 SIT patients when the solublised vaccine preparation was used as a challenge before the last injection and 2 weeks after, in comparison to pre-treatment levels. Twenty weeks after therapy, the SI decreased to baseline level. A vaccine challenge without MPL gave lower SI levels. A challenge of a clinically inappropriate tree allergoid vaccine gave no response, and a nontreated group also showed no response. CONCLUSION: Following a short-course SIT adjuvated with MPL, challenges of allergoids were shown to activate allergen-specific T cells in vitro. There was an additional stimulating effect when the challenge was in combination with MPL. There were no non-specific effects of MPL, shown by the tree allergoid/MPL control. The timing of the response was closely correlated to the treatment course; reactivity fell two weeks after the final injection and 20 weeks later it was at baseline level. Thus an immunological response to SIT was detected after very few injections. This methodology could provide a basis for monitoring the immediate progress of allergy vaccinations.
Assuntos
Hipersensibilidade/terapia , Imunoterapia , Extratos Vegetais/administração & dosagem , Linfócitos T/imunologia , Vacinas/administração & dosagem , Adjuvantes Imunológicos/administração & dosagem , Adolescente , Adulto , Alérgenos/administração & dosagem , Alérgenos/imunologia , Alergoides , Artemisia/imunologia , Feminino , Humanos , Hipersensibilidade/imunologia , Lipídeo A/administração & dosagem , Lipídeo A/análogos & derivados , Masculino , Pessoa de Meia-Idade , Extratos Vegetais/imunologia , Poaceae/imunologia , Secale/imunologia , Células Th1/imunologia , Tirosina/químicaRESUMO
The effect of platelet activating factor (PAF) on renal hemodynamics and function was examined in anesthetized dogs. The infusion of PAF into the renal artery at 5, 10, and 20 ng X min-1 X kg-1 body weight resulted in dose-dependent reductions in renal blood flow, glomerular filtration rate, urine volume, and urinary sodium excretion, whereas the infusion of vehicle alone in the contralateral kidney did not result in significant changes in these parameters. The maximum decrease expressed as the percent change from baseline was 22.2 +/- 1.7% for renal blood flow, 50.8 +/- 11% for glomerular filtration rate, 67.3 +/- 4.2% for urine volume, and 69.0 +/- 8.5% for urinary sodium excretion, respectively. These renal effects were not accompanied by significant alterations in systemic arterial blood pressure and heart rate. Pretreatment with indomethacin to block prostaglandin synthesis enhanced the effect of PAF on kidney function. Our data demonstrate that, unlike the rat kidney, intrarenal PAF infusion into the intact dog results in vasoconstriction and serve reduction in glomerular filtration rate.
Assuntos
Rim/fisiologia , Fator de Ativação de Plaquetas , Circulação Renal/efeitos dos fármacos , Animais , Cães , Feminino , Taxa de Filtração Glomerular/efeitos dos fármacos , Masculino , Natriurese/efeitos dos fármacos , Urina , Vasoconstrição/efeitos dos fármacosRESUMO
Inhibitors of histone deacetylase (HD) bear great potential as new drugs due to their ability to modulate transcription and to induce apoptosis or differentiation in cancer cells. We have described previously analogues of the complex natural HD inhibitors trapoxin B and trichostatin A with activities in the submicromolar range. Here we report structure-activity relationship analyses of further analogues of trichostatin A with respect to in vitro inhibition of maize HD-2 and their ability to induce terminal cell differentiation in Friend leukemic cells. This is the first report that shows the correlation between HD inhibitory activity and action on cancer cells on a larger series of similar compounds. Only the compounds that inhibit HD induce differentiation and/or exert antiproliferative activities in cell culture. Our studies support the use of in vitro systems as screening tools and provide structure-activity relationships that merit further investigation of this interesting target.
Assuntos
Diferenciação Celular/efeitos dos fármacos , Inibidores Enzimáticos/síntese química , Inibidores de Histona Desacetilases , Ácidos Hidroxâmicos/síntese química , Animais , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Histona Desacetilases/química , Ácidos Hidroxâmicos/química , Ácidos Hidroxâmicos/farmacologia , Camundongos , Modelos Moleculares , Relação Estrutura-Atividade , Células Tumorais CultivadasRESUMO
Arterial blood pressure, heart rate and the response of these hemodynamic parameters to exogenous norepinephrine were investigated in healthy volunteers (daily sodium intake of 150 mmol) during a control period and after a single oral dose of 5 mg of the angiotensin I converting enzyme (ACE) inhibitor ramipril (HOE 498). Norepinephrine was infused at doses of 0.1, 0.2 and 0.3 micrograms kg-1 min-1, each for 10 minutes, during control and 3 hours after ramipril administration. Exogenous norepinephrine induced a dose-dependent increase in mean arterial blood pressure from 76.4 +/- 0.9 mm Hg during control to 85.6 +/- 1.5, 92.2 +/- 1.8 and 98.4 +/- 2.4 mm Hg, respectively. Ramipril significantly affected the baroreceptor set point with a decrease in mean blood pressure (72.1 +/- 1.7 vs 76.4 +/- 0.9 mm Hg, p less than 0.01) in the presence of unchanged heart rate (71.7 +/- 0.9 vs 73.6 +/- 1.5 min-1). Baroreceptor sensitivity, estimated by the slope of the delta blood pressure versus delta heart rate relation, was not affected by ACE inhibition. Also, the pressor effect of exogenous norepinephrine was unchanged by converting enzyme inhibition. The present results show that ACE inhibition with ramipril in sodium-replete healthy volunteers induces a decrease in blood pressure that is not accompanied by changes in heart rate, pressor sensitivity to exogenous norepinephrine or baroreceptor sensitivity.
Assuntos
Inibidores da Enzima Conversora de Angiotensina , Pressão Sanguínea/efeitos dos fármacos , Compostos Bicíclicos com Pontes/farmacologia , Hidrocarbonetos Aromáticos com Pontes/farmacologia , Frequência Cardíaca/efeitos dos fármacos , Pressorreceptores/efeitos dos fármacos , Adulto , Feminino , Humanos , Masculino , Norepinefrina/farmacologia , RamiprilRESUMO
The plant extract aristolochic acid, which consists mainly of aristolochic acid I (AAI) and aristolochic acid II (AAII), induces tumors in rats and mice. Thin-tissue sections of rat tumors induced by AAI and of mouse tumors induced by aristolochic acid, were analyzed for c-Ha-ras mutations in codon 61. Areas of neoplastic and histologically normal tissue were manually scraped out and separated. Using the polymerase chain reaction (PCR) and mutation detection by selective oligonucleotide hybridization, we observed AT----TA transversion mutations in DNA of neoplastic portions, but not in DNA of adjacent normal tissue in both rat and mouse tumors.
Assuntos
Ácidos Aristolóquicos , Genes ras/efeitos dos fármacos , Mutagênicos/farmacologia , Mutação/efeitos dos fármacos , Neoplasias Experimentais/genética , Fenantrenos/farmacologia , Animais , Sequência de Bases , Códon , DNA de Neoplasias/isolamento & purificação , Feminino , Masculino , Camundongos , Dados de Sequência Molecular , Neoplasias Experimentais/induzido quimicamente , Neoplasias Experimentais/patologia , Reação em Cadeia da Polimerase , Ratos , Ratos EndogâmicosRESUMO
Two cell clones of a methylnitrosourea-induced rat mammary carcinoma, a hyperdiploid (44 chromosomes, clone A) and a hypertetraploid clone (88 chromosomes, clone B) were cultured and transplanted subcutaneously into three groups of eight rats. Group 1 was treated with 62.6 mg cyclophosphamide/kg, group 2 with 41.8 mg/kg once weekly for 3 weeks. The volume of tumors derived from clone B cells was diminished by the administration of the agent, whereas clone A cell tumors did not respond. Incubation of cells of both clones with phosphamide mustard in vitro showed that cells of clone B are much more sensitive to the activated cyclophosphamide, especially after incubation in low concentrations of 40 microM and 20 microM, than those of clone A. It is concluded that the initial success of cyclophosphamide therapy on chemically induced tumors is due to the different sensitivities of the tumor cell populations.
Assuntos
Ciclofosfamida/farmacologia , Neoplasias Mamárias Experimentais/induzido quimicamente , Animais , Células Clonais , Ciclofosfamida/uso terapêutico , Avaliação Pré-Clínica de Medicamentos , Feminino , Neoplasias Mamárias Experimentais/tratamento farmacológico , Neoplasias Mamárias Experimentais/patologia , Metilnitrosoureia , Transplante de Neoplasias , Ratos , Células Tumorais Cultivadas/efeitos dos fármacosRESUMO
Osteosarcoma treatment still is unsatisfactory owing to the development of metastases. This situation causes many problems for the patients as well as the clinicians. Tumor heterogeneity is made responsible for the development of cell lines resistant to chemotherapy. As the transplantable osteosarcoma of the rat resembles the human metastasizing osteosarcoma, studies on clones of this tumor were started. The following compounds were investigated: AMDP, cis-diammine[nitrilotris-(methylphosphonato)(2-)-O1,N1]plati num II; DADP, cis-cyclohexane-1,2-diamine[nitrilotris(methylphosphonato)(2 -)-O1,N1]- platinum II; IMD, cis-diammine[imino-bis(methylphosphonato)(2-)-O1,N1]platinum II; DIMD, cis-cyclohexane-1,2-diamine[iminobis(methylphosphonato) (2-)-O1,N1]platinum II. In vitro assays were performed with cell lines derived from a lung metastasis with the limited-dilution method. The clones varied in modal chromosome number, growth kinetics and tumorigenicity. AMDP was the most potent compound in all three clones resulting in a concentration- and time-dependent effect while IMD was somewhat less active. The diamminocyclohexane derivatives were considerably less effective, inhibiting cell growth especially in clone C10. In contrast, clone C36 was more sensitive than C25 and did not recover within the observation period of 5 days. Viability was reduced significantly only in C10, when treated with AMDP. Differences between the clones and the various compounds in inhibiting cell growth could be observed. Therefore, further experiments on the heterogeneity and sensitivity of these cell lines seem promising.
Assuntos
Neoplasias Pulmonares/tratamento farmacológico , Compostos Organofosforados/uso terapêutico , Compostos Organoplatínicos/uso terapêutico , Osteossarcoma/tratamento farmacológico , Animais , Divisão Celular/efeitos dos fármacos , Células Clonais , Relação Dose-Resposta a Droga , Técnicas In Vitro , Neoplasias Pulmonares/secundário , RatosRESUMO
The effect of an in vivo treatment with the carboxylesterase inhibitor bis-p-nitrophenylphosphate (BNPP) on the hydrolysis of 1-(N-methyl-N-nitrosamino)-methylacetate (NNMA), 1-(N-methyl-N-nitrosamino)-methylbutyrate (NNMB), 1-(N-methyl-N-nitrosamino)-methylbenzoate (NNMBz) and 1-(N-methyl-N-nitrosamino)-methylpivaloate (NMMP) in rat tissue homogenates was studied. The rates of hydrolysis were specific for each compound and different in every organ tested; the extent of inhibition of the hydrolysis by BNPP was also substrate and organ specific. In some cases no inhibition at all was observed. The rate of elimination of NNMA, NNMB, and NNMP from blood was not influenced by BNPP pretreatment. The LD50 of NNMA after i.v. application showed a rise of 85% with a BNPP pretreatment. BNPP also influenced the carcinogenicity of NNMA, whereby the total carcinogenic potency was not altered, but the organotropism had changed slightly.
Assuntos
Hidrolases de Éster Carboxílico/antagonistas & inibidores , Carcinógenos , Dimetilnitrosamina/análogos & derivados , Nitrofenóis/farmacologia , Animais , Dimetilnitrosamina/metabolismo , Dimetilnitrosamina/toxicidade , Relação Dose-Resposta a Droga , Interações Medicamentosas , Meia-Vida , Hidrólise , Dose Letal Mediana , Masculino , Neoplasias Experimentais/induzido quimicamente , Ratos , Ratos Endogâmicos , Fatores de TempoRESUMO
The influence of a 28-week treatment with disulfiram (DSF), D-penicillamine (PA), and nitrosodiethylamine (NDEA), as well as with a combination of DSF or PA with NDEA on the concentrations of eight essential trace elements in the whole liver tissue of rats was measured by means of neutron activation analysis. While NDEA treatment lowered the Zn content of the liver, DSF alone or in combination with NDEA enhanced the Zn and Se concentration by 50%-80%. Co, Cu, and Cd levels were increased by factors of 10, 60, and 110, respectively. The Mo concentration was decreased by 50% after DSF administration. PA reduced Cu, Co, and Zn in the liver. PA/NDEA treatment also lowered Cu, Co, and Zn content, but there was no strengthening effect of PA on the decrease in Zn observed with NDEA. The change of trace element concentrations, especially of Cu, is discussed with regard to the observed tumor induction in the liver, which tended to be increased by a combined NDEA/PA administration compared with NDEA treatment alone, whereas a protective action of DSF against NDEA induced liver tumors could not be established.
Assuntos
Dietilnitrosamina/toxicidade , Dissulfiram/toxicidade , Fígado/efeitos dos fármacos , Neoplasias Experimentais/induzido quimicamente , Nitrosaminas/toxicidade , Penicilamina/toxicidade , Oligoelementos/metabolismo , Animais , Dietilnitrosamina/metabolismo , Dissulfiram/metabolismo , Interações Medicamentosas , Fígado/análise , Fígado/metabolismo , Masculino , Neoplasias Experimentais/metabolismo , Penicilamina/metabolismo , Ratos , Ratos Endogâmicos , Fatores de Tempo , Oligoelementos/análiseRESUMO
The influence of a prolonged treatment with disulfiram (DSF) and D(-)penicillamine (PA) on biological and biochemical effects induced by nitrosodiethylamine (NDEA) was studied in rats. The combination of NDEA and DSF led to a massive and early development of esophageal tumors, which were fatal to the animals. No liver tumors were observed in this group, whereas PA in combination with NDEA led to an increased development of liver tumors compared with NDEA alone. In the last two groups, only incidental tumors of the esophagus were observed. Nasal cavity tumors also appeared earlier in the animals treated with DSF and NDEA than in animals treated with NDEA alone or with NDEA plus PA. At a biochemical level, DSF led to a significant inhibition of hepatic anilinehydroxylase and nitroso-dimethylaminedemethylase in contrast to PA, which had no influence on these enzymes. The reduced activities of these drug-metabolizing enzymes did not appear to be related to gross cytochrome P450 content. Highly significant increases in glutathione content and glutathione-S-transferase activity (GSH/GST) were induced by DSF but not by PA. Because N-nitrosodiethylamine requires enzymatic activation to form the ultimate carcinogen, it is suggested that the observed inhibition of nitrosamine-transforming enzymes in the liver during DSF treatment leads to an increased amount of intact nitrosamines in other organs, e.g., in the esophagus, where it could be transformed to the ultimate carcinogen. DSF treatment alone or in combination with NDEA leads to an accumulation of trace elements in the liver, whereas PA eliminated copper and cobalt. The possible influence of these elements on tumor development is discussed in part II of this study.
Assuntos
Dietilnitrosamina/toxicidade , Dissulfiram/toxicidade , Neoplasias Experimentais/induzido quimicamente , Nitrosaminas/toxicidade , Penicilamina/toxicidade , Animais , Dietilnitrosamina/metabolismo , Dissulfiram/metabolismo , Interações Medicamentosas , Inibidores Enzimáticos , Neoplasias Esofágicas/induzido quimicamente , Fígado/efeitos dos fármacos , Fígado/enzimologia , Neoplasias Hepáticas Experimentais/induzido quimicamente , Masculino , Neoplasias Experimentais/metabolismo , Neoplasias Nasais/induzido quimicamente , Penicilamina/metabolismo , Ratos , Ratos Endogâmicos , Fatores de Tempo , Oligoelementos/metabolismoRESUMO
Alkylphosphocholines, and especially their main representative hexadecylphosphocholine (HPC), show high anticancer activity in methylnitrosourea (MNU)-induced autochthonous rat mammary carcinoma. The regression of MNU-induced rat mammary carcinoma during HPC treatment can be evaluated by computed tomography and sonography. This allows a noninvasive monitoring of therapy in vivo (tumor size, morphology, and blood supply). Both diagnostic modalities can show a rapid concentric decrease in tumor volume as well as the appearance of cystic, scarry, and necrotic areas in the tumor tissue as a result of HPC treatment. In addition, prior to, during and after therapy tumor perfusion can be assessed by color Doppler sonography in vivo. A more than 4-fold difference in HPC efficacy was observed when the colony growth of explanted MNU-induced mammary carcinoma cells was measured in the methylcellulose colony assay (IC50 = 180 mumol HPC/l) and the Hamburger Salmon colony assay (IC50 = 740 mumol HPC/l). In the latter assay, growth of concomitantly seeded untransformed cells, especially of fibroblasts, is much lower than in the methyl-cellulose colony assay. We therefore assume that the antitumor efficacy of HPC against MNU-induced mammary carcinoma is enhanced by neighboring cells such as fibroblasts. Cell culture experiments with the three MNU-induced rat mammary carcinoma cell clones 1-C-2, 1-C-30, and 1-C-32 revealed IC50 values in the range of 50-70 mumol HPC/l. The volume of 1-C-2 cells increased up to 4-fold after 72 h of permanent exposure to 100 mumol HPC/l, a concentration that completely inhibited proliferation of tumor cell numbers without being cytotoxic. Nucleotide triphosphate levels dropped significantly after 24 h and were slowly restored in spite of continued exposure. After 72 h, they nearly reached those levels observed in plateau-phase cells. This suggests that HPC-induced growth inhibition has similarities with physiologically occurring growth arrest. Finally, replication of RNA viruses and DNA viruses was suppressed 30-fold and 7-fold, respectively, at low concentrations of HPC (12 mumol/l), which caused no or negligible growth inhibition in the virus-harboring cells, thus demonstrating specific antiviral activity of HPC. From these observations we conclude that HPC differs in many important aspects from conventional cytostatic agents and is certainly worth following-up in further investigations.
Assuntos
Antineoplásicos/farmacologia , Antivirais/farmacologia , Fosforilcolina/análogos & derivados , Animais , Cromatografia Líquida de Alta Pressão , DNA Viral/efeitos dos fármacos , DNA Viral/fisiologia , Relação Dose-Resposta a Droga , Herpes Simples/tratamento farmacológico , Neoplasias Mamárias Experimentais/tratamento farmacológico , Neoplasias Mamárias Experimentais/metabolismo , Neoplasias Mamárias Experimentais/microbiologia , Metilnitrosoureia , Nucleotídeos/metabolismo , Fosforilcolina/farmacologia , Ratos , Ratos Sprague-Dawley , Simplexvirus/efeitos dos fármacos , Simplexvirus/fisiologia , Vírus da Estomatite Vesicular Indiana/efeitos dos fármacos , Vírus da Estomatite Vesicular Indiana/fisiologia , Viroses/tratamento farmacológico , Replicação Viral/efeitos dos fármacosRESUMO
The present therapy experiments with two different transplantable mammary tumors were performed to compare the therapeutic efficacy in BD-VI rats of 1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine (ET-18-OCH3) and hexadecylphosphocholine (HPC). Both compounds were administered orally, subcutaneously or intracutaneously at equimolar doses ranging from 4.8 to 88 mumol/kg/day five times per week for two weeks. Under the experimental conditions, both transplanted mammary carcinomas were moderately sensitive to the therapy with either HPC or ET-18-OCH3. Comparing both tumors, TMA2 was more sensitive than TMA1. The activity and toxicity of both compounds were dose-related in both tumor lines. Females seemed to be less sensitive with respect to antineoplastic activity and toxicity. Like ET-18-OCH3, HPC was active also at low, probably noncytotoxic doses associated with no detectable toxicity according to body weight development. This suggests that there are at least two different mechanisms of action that lead to tumor growth inhibition.
Assuntos
Antineoplásicos/uso terapêutico , Colina/análogos & derivados , Neoplasias Mamárias Experimentais/tratamento farmacológico , Éteres Fosfolipídicos/uso terapêutico , Fosforilcolina/análogos & derivados , Administração Oral , Animais , Antineoplásicos/administração & dosagem , Relação Dose-Resposta a Droga , Feminino , Injeções Subcutâneas , Masculino , Éteres Fosfolipídicos/administração & dosagem , Fosforilcolina/administração & dosagem , Fosforilcolina/uso terapêutico , RatosRESUMO
The study reports on the investigation of acute and subacute toxicity and on antineoplastic activity of hexadecylphosphocholine (HPC), the first compound of a new class of antineoplastic chemotherapeutics. In rats, the LD50 of HPC was 606 mumol/kg; the maximum tolerable dose over four weeks was 39 mumol/kg. Symptoms of toxicity were enteritis, spider cell activation in the liver, hemosiderosis in the spleen and reversible transaminase increase. The best therapeutic effect was observed on methylnitrosourea (MNU)-induced mammary carcinoma in the rat. Two transplantable mammary carcinomas in the rat and autochthonous benzo(a)pyrene-induced sarcomas exhibited low-grade sensitivity to HPC. The MXT mammary carcinoma of the mouse, the Walker 256 carcinosarcoma of the rat, and autochthonous acetoxymethylmethylnitrosamine-induced colonic tumors of the rat were not chemosensitive to HPC.
Assuntos
Antineoplásicos/uso terapêutico , Colina/análogos & derivados , Neoplasias Mamárias Experimentais/tratamento farmacológico , Éteres Fosfolipídicos/uso terapêutico , Fosforilcolina/análogos & derivados , Animais , Antineoplásicos/toxicidade , Carcinoma/tratamento farmacológico , Relação Dose-Resposta a Droga , Feminino , Masculino , Éteres Fosfolipídicos/toxicidade , Fosforilcolina/uso terapêutico , Fosforilcolina/toxicidade , Ratos , Ratos Endogâmicos , Fatores SexuaisRESUMO
The paper reports on the effects of multiple whole-body infra-red-A irradiational (IRA) on 13 male patients known to have stage I or stage II essential arterial hypertension (WHO definition). The peripheral blood pressure was decreased significantly by IRA exposures. The lowered diastolic blood pressure lasted into posttreatment time. This effect is regarded as a consequence of an improvement in peripheral haemodynamics. A measure of this improvement is the different shape of the blood pressure pulse waves. Calculation and comparison of the spectral components of the recorded pulse signals show that these components are useful for a prediction of the blood pressure lowering effect.
Assuntos
Hipertensão/terapia , Hipertermia Induzida , Adulto , Pressão Sanguínea , Frequência Cardíaca , Humanos , Raios Infravermelhos , Masculino , Pessoa de Meia-Idade , Fatores de TempoRESUMO
The effect of vitamin E supplementation on the immune function of dairy cows was studied. Twelve cows were assigned to 1 of the 2 experimental groups: control (no vitamin E supplementation), and vitamin E-supplemented. Supplementation of vitamin E started 4 weeks before and continued up to 8 weeks after parturition and included oral supplementation of vitamin E at the rate of 3,000 IU/cow/d. In addition, the same group of cows received 1 injection of vitamin E (5,000 IU), 1 week prior to the expected date of parturition. Data indicated that blood neutrophils isolated from control cows produced twofold less (P < 0.05) superoxide anion after parturition, compared with the corresponding value before parturition. Furthermore, blood macrophages isolated from control cows produced 15 and 35% (P < 0.05) less interleukin 1 (IL-1) and major histocompatibility (MHC) class-II antigens, respectively, after parturition, compared with the corresponding values before parturition. These data, collectively, indicate that functions of blood macrophages and neutrophils are depressed during the early postpartum period in control cows. In contrast, there were no differences in superoxide anion production by blood neutrophils, or in IL-1 production, and MHC class-II antigen expression by blood macrophages before and after parturition in cows supplemented with vitamin E. There were no differences in lymphocyte proliferation, or IL-1 production and MHC class-II antigen expression by mammary macrophages when control and vitamin E-supplemented cows were compared. We conclude that vitamin E prevented suppression of blood neutrophil and macrophage function during the early postpatum period.
Assuntos
Bovinos/imunologia , Macrófagos/efeitos dos fármacos , Neutrófilos/efeitos dos fármacos , Vitamina E/farmacologia , Análise de Variância , Animais , Bovinos/sangue , Ensaio de Imunoadsorção Enzimática/veterinária , Feminino , Alimentos Fortificados , Antígenos de Histocompatibilidade Classe II/biossíntese , Interleucina-1/análise , Lactação/imunologia , Período Pós-Parto , Gravidez , Explosão Respiratória/efeitos dos fármacos , Selênio/sangue , Vitamina E/sangueRESUMO
OBJECTIVE: To determine the effect of vitamin E supplementation on the immune system of dairy cows. DESIGN: The following immune parameters were followed: production of chemotactic factors and superoxide by mammary macrophages and chemotactic responsiveness of blood neutrophils. ANIMALS: 16 healthy Holstein dairy cows. PROCEDURE: Dairy cows were assigned to 1 of 2 experimental groups: control (no vitamin E supplementation) and vitamin E supplemented. Supplementation of vitamin E started 4 weeks before and continued up to 8 weeks after parturition, and included oral supplementation of vitamin E at the rate of 3,000 IU/cow/d. In addition, the same group of cows received 1 injection of vitamin E (5,000 IU) 1 week prior to the expected date of parturition. Blood samples were collected weekly throughout the experimental period. RESULTS: Vitamin E supplementation enhanced by 30 to 83% (P < 0.05) chemotactic responsiveness of blood neutrophils beginning 2 weeks before to 4 weeks after parturition, compared with controls. There were no differences in production of superoxide or chemotactic factors by mammary macrophages between control and vitamin E-supplemented cows. CONCLUSIONS: Vitamin E supplementation prevents the periparturient inhibition of neutrophil chemotaxis. It is unlikely that vitamin E affects directly the function of mammary macrophages.
Assuntos
Quimiotaxia de Leucócito/efeitos dos fármacos , Macrófagos/fisiologia , Glândulas Mamárias Animais/fisiologia , Leite/citologia , Neutrófilos/fisiologia , Período Pós-Parto/fisiologia , Vitamina E/farmacologia , Ração Animal , Animais , Bovinos , Relação Dose-Resposta a Droga , Feminino , Alimentos Fortificados , Técnicas In Vitro , Macrófagos/efeitos dos fármacos , Leite/fisiologia , Neutrófilos/efeitos dos fármacos , Período Pós-Parto/sangue , Selênio/sangue , Superóxidos/metabolismo , Fatores de Tempo , Vitamina E/sangueRESUMO
Of 35 female patients with vesicoureteral reflux, 9 had a cessation of their urinary tract infections while the reflux persisted. These findings contrast with the thesis that vesicoureteral reflux is the major cause of susceptibility to urinary tract infections in these patients.