RESUMO
Regorafenib (RGF) has a great success in the treatment of colorectal cancer, gastrointestinal stromal tumours and hepatocellular carcinoma by inhibiting angiogenic, stromal and oncogenic kinases. However, RGF can induce life-threatening cardiotoxicity including hypertension and cardiac ischemia/infarction. The molecular mechanism of the adverse effects has not been elucidated. Mitochondrial dysfunction is one of the major causes of cardiac diseases since cardiac cells highly need ATP for their contractility. Therefore, we aimed to investigate molecular mechanisms of RGF-induced cardiac adverse effects using H9c2 cell model by focusing on mitochondria. Cells were treated with 0-20 µM RGF for 48 and 72 h. According to our results, RGF inhibited cell proliferation and decreased the ATP content of the cells depending on the exposure time and concentration. Loss of mitochondrial membrane potential was also observed at high dose. Mitochondrial fusion/fission genes and antioxidant SOD2 (superoxide dismutase) gene expression levels increased at high doses in both treatments. Mitochondrial DNA content decreased as exposure time and concentration increased. Also, protein expression levels of mitochondrial complex I and V have reduced and stress protein HSP70 level has increased following RGF treatment. Structural abnormalities in mitochondria was seen with transmission electron microscopy at the applied higher doses. Our findings suggest that RGF-induced cardiotoxicity may be associated with mitochondrial damage in cardiac cells.
Assuntos
Antineoplásicos/toxicidade , Cardiopatias/induzido quimicamente , Mitocôndrias Cardíacas/efeitos dos fármacos , Dinâmica Mitocondrial/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Compostos de Fenilureia/toxicidade , Piridinas/toxicidade , Trifosfato de Adenosina/metabolismo , Animais , Cardiotoxicidade , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , DNA Mitocondrial/genética , DNA Mitocondrial/metabolismo , Relação Dose-Resposta a Droga , Proteínas de Choque Térmico HSP70/metabolismo , Cardiopatias/genética , Cardiopatias/metabolismo , Cardiopatias/patologia , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias Cardíacas/genética , Mitocôndrias Cardíacas/metabolismo , Mitocôndrias Cardíacas/patologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Ratos , Fatores de TempoRESUMO
Paradoxically, some TRPV1 agonists are, at the organismal level, both nonpungent and clinically useful as topical analgesics. Here, we describe the scaled-up synthesis and characterization in mouse models of a novel, nonpungent vanilloid. Potent analgesic activity was observed in models of neuropathic pain, and the compound blocked capsaicin induced allodynia, showing dermal accumulation with little transdermal absorption. Finally, it displayed much weaker systemic toxicity compared to capsaicin and was negative in assays of genotoxicity.
Assuntos
Analgésicos/uso terapêutico , Compostos de Fenilureia/uso terapêutico , Canais de Cátion TRPV/agonistas , Tiazóis/uso terapêutico , Analgésicos/síntese química , Analgésicos/farmacocinética , Analgésicos/toxicidade , Animais , Células CHO , Capsaicina , Cricetulus , Descoberta de Drogas , Hiperalgesia/induzido quimicamente , Hiperalgesia/tratamento farmacológico , Camundongos Endogâmicos ICR , Neuralgia/tratamento farmacológico , Compostos de Fenilureia/síntese química , Compostos de Fenilureia/farmacocinética , Compostos de Fenilureia/toxicidade , Suínos , Tiazóis/síntese química , Tiazóis/farmacocinética , Tiazóis/toxicidadeRESUMO
Assessing the ecological risk of combined pollution, especially from a holistic perspective with the consideration of the overarching functions of soil ecosystem, is crucial and beneficial to the improvement of ecological risk assessment (ERA) framework. In this study, four soils with similar physicochemical properties but contrasting heavy metals contamination levels were selected to explore changes in the integrated functional sensitivity (MSI), resistance (MRS) and resilience (MRL) of soil microbial communities subjected to herbicide siduron, based on which the ecological risk of the accumulation of siduron in the four studied soils were evaluated. The results suggested that the microbial biomass carbon, activity of denitrification enzyme and nitrogenase were indicative of MSI and MRS, and the same three parameters plus soil basal respiration were indicative of MRL. Significant dose-effect relationships between siduron residues in soils and MSI, MRS and MRL under combined pollution were observed. Heavy metal polluted soils showed higher sensitivity and lower resistance to the additional disturbance of herbicide siduron due to the lower microbial biomass, while the resilience of heavy metal polluted soils was much higher due to the pre-adaption to the chemical stresses. The quantifiable indicator microbial functional stability was incorporated in the framework of ERA and the results showed that the accumulation of siduron in the studied soils could exhibit potential harm to the integrated functional stability of soil microbial community. Thus, this work provides insights into the application of integrated function of soil microbial community into the framework of ERA.
Assuntos
Herbicidas/toxicidade , Compostos de Fenilureia/toxicidade , Microbiologia do Solo , Poluentes do Solo/toxicidade , Solo/química , Biomassa , Ecossistema , Metais Pesados/toxicidade , Medição de RiscoRESUMO
Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related death worldwide, and prognosis remains unsatisfactory since the disease is often diagnosed at the advanced stages. Currently, the multikinase inhibitor sorafenib is the only drug approved for the treatment of advanced HCC. However, primary or acquired resistance to sorafenib develops, generating a roadblock in HCC therapy. Autophagy is an intracellular lysosomal pathway involved in protein and organelle degradation, with an astonishing number of connections to human disease and physiology. Current understanding of the role of autophagy in the progression of cancer and the response to cancer therapy remains controversial. Sorafenib is able to induce autophagy in HCC, but the effect of autophagy is indistinct. Some studies established that sorafenib-induced autophagy serves as a pro-survival response. However, other studies found that sorafenib-induced autophagy improves the lethality of sorafenib against HCC cells. The mechanisms underlying autophagy and sorafenib resistance remain elusive. The purpose of this review is to summarize the progress of research focused on autophagy and sorafenib resistance and to update current knowledge of how cellular autophagy impacts sorafenib sensitivity in HCC treatment.
Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Niacinamida/análogos & derivados , Compostos de Fenilureia/uso terapêutico , Antineoplásicos/toxicidade , Autofagia/efeitos dos fármacos , Proteínas Relacionadas à Autofagia/metabolismo , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Resistencia a Medicamentos Antineoplásicos , Quimioterapia Combinada , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Niacinamida/uso terapêutico , Niacinamida/toxicidade , Compostos de Fenilureia/toxicidade , SorafenibeRESUMO
Owing to the recent declines in honey bee (Apis mellifera L.) populations, there is a need for field and laboratory studies to investigate threats to pollinator health. This study examines the hypothesis that the organophosphate alternative, Rimon 0.83EC, can have consequences to honey bee health by combining newly acquired field residue data, laboratory bioassays, and colony level feeding studies. Following label rate applications of Rimon 0.83EC to apple trees, average residue concentrations of the active ingredient, novaluron, were found to be 3.38 ppm in tree-collected pollen. Residues of the major co-formulant in Rimon 0.83EC, N-methyl-2-pyrrolidone (NMP), were below the limit of detection in the field, but a growth chamber study described here found that NMP can persist in pollen for up to 7 d with average concentrations of 69.3 ppm. Concurrent larval rearing studies found novaluron and NMP to be toxic to developing honey bees at doses as low as 100 ppb and 100 ppm, respectively. Nucleus colony feeding studies found that chronic exposure to Rimon 0.83EC at doses as low as 200 ppm (18.6 ppm novaluron) can result in interruptions to brood production that can last for up to 2 wk after exposure. Taken together, these data indicate the use of Rimon 0.83EC on blooming flowers is a significant threat to honey bee reproduction, and suggest the need for more strict and clear usage guidelines.
Assuntos
Abelhas/efeitos dos fármacos , Inseticidas/toxicidade , Resíduos de Praguicidas/toxicidade , Compostos de Fenilureia/toxicidade , Pirrolidinonas/toxicidade , Animais , Abelhas/crescimento & desenvolvimento , Inseticidas/análise , Larva/efeitos dos fármacos , Larva/crescimento & desenvolvimento , Resíduos de Praguicidas/análise , Pólen/química , Pirrolidinonas/análise , Reprodução/efeitos dos fármacosRESUMO
Oncogenic activation of RET kinase has been found in several neoplastic diseases, like medullary thyroid carcinoma, multiple endocrine neoplasia, papillary thyroid carcinoma, and non-small-cell lung cancer. Currently approved RET inhibitors were not originally designed to be RET inhibitors, and their potency against RET kinase has not been optimized. Hence, novel compounds able to inhibit both wild-type RET (wt RET) and its mutants (e.g., V804M RET) are needed. Herein we present the development and the preliminary evaluation of a new sub-micromolar wt RET/V804M RET inhibitor, N-(2-fluoro-5-trifluoromethylphenyl)-N'-{4'-[(2''-benzamido)pyridin-4''-ylamino]phenyl}urea (69), endowed with a 4-anilinopyridine structure, starting from our previously identified 4-anilinopyrimidine hit compound. Profiling against a panel of kinases indicated 69 as a multi cKIT/wt RET/V804M RET inhibitor.
Assuntos
Aminopiridinas/química , Compostos de Fenilureia/química , Inibidores de Proteínas Quinases/química , Proteínas Proto-Oncogênicas c-ret/metabolismo , Aminopiridinas/síntese química , Aminopiridinas/toxicidade , Sítios de Ligação , Linhagem Celular Tumoral , Avaliação Pré-Clínica de Medicamentos , Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/química , Compostos Heterocíclicos/farmacologia , Humanos , Ligação de Hidrogênio , Concentração Inibidora 50 , Simulação de Acoplamento Molecular , Mutação , Compostos de Fenilureia/síntese química , Compostos de Fenilureia/toxicidade , Fosforilação/efeitos dos fármacos , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Estrutura Terciária de Proteína , Proteínas Proto-Oncogênicas c-ret/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-ret/genética , Ureia/análogos & derivados , Ureia/síntese química , Ureia/farmacologiaRESUMO
Sorafenib has been used as a standard therapy for advanced hepatocellular carcinoma (HCC). In Asia, patients with HCC are potentially treated with the combination of sorafenib and Chinese herbal medicines to improve the efficiency and reduce the side effects of sorafenib. However, limited information about the herb-drug interactions is available. We hypothesize that the Chinese herbal medicine may exert hepatoprotective effects on the sorafenib-treated group. The aim of this study is to investigate the pharmacokinetic mechanism of drug-drug interactions of sorafenib including interacting with hepatoprotective formulation, Long-Dan-Xie-Gan-Tang formulation (LDXGT) and with two cytochrome P450 3A4 (CYP3A4) inhibitors, grapefruit juice and ketoconazole. Liver enzyme levels and histopathology of liver slices were used to evaluate sorafenib-induced hepatotoxicity and the potential hepatoprotective effects of the LDXGT formulation on subjects treated with the combination of sorafenib and the herbal medicine. In this study, a validated HPLC-photodiode array analytical system was developed for the pharmacokinetic study of sorafenib in rats. As the result of the pharmacokinetic data, pretreatment with the LDXGT formulation did not significantly interact with sorafenib compared with sorafenib oral administration alone. Furthermore, grapefruit juice and ketoconazole did not significantly affect sorafenib metabolism. Furthermore, pretreatment with variable, single or repeat doses of the LDXGT formulation did not suppress or exacerbate the sorafenib-induced hepatotoxicity and histopathological alterations. According to these results, the LDXGT formulation is safe, but has no beneficial effects on sorafenib-induced hepatotoxicity. A detailed clinical trial should be performed to further evaluate the efficacy or adverse effects of the LDXGT formulation in combination with sorafenib in humans.
Assuntos
Antineoplásicos/farmacologia , Medicamentos de Ervas Chinesas/farmacologia , Interações Ervas-Drogas , Fígado/efeitos dos fármacos , Medicina Tradicional Chinesa/métodos , Niacinamida/análogos & derivados , Compostos de Fenilureia/farmacologia , Animais , Antineoplásicos/sangue , Antineoplásicos/farmacocinética , Relação Dose-Resposta a Droga , Medicamentos de Ervas Chinesas/farmacocinética , Fígado/patologia , Masculino , Niacinamida/sangue , Niacinamida/farmacocinética , Niacinamida/farmacologia , Niacinamida/toxicidade , Compostos de Fenilureia/sangue , Compostos de Fenilureia/farmacocinética , Compostos de Fenilureia/toxicidade , Ratos , Ratos Sprague-Dawley , SorafenibeRESUMO
PURPOSE: To investigate feasibility, safety, and effect of transarterial chemoembolization using sorafenib on degree of tumor necrosis in a rabbit VX2 liver tumor model. MATERIALS AND METHODS: New Zealand White rabbits (n = 20) with a VX2 tumor were divided into two groups; one group was treated with hepatic arterial administration of 0.5 mL ethiodized oil alone (Lipiodol; Guerbet, Aulnay-sous-Bois, France) (transarterial embolization with Lipiodol [TAE-L] group), and one group was treated with 0.5 mL ethiodized oil plus 10 mg sorafenib (transarterial embolization with sorafenib [TAE-S] group). Liquid chromatography tandem mass spectrometry was used to measure sorafenib concentration in peripheral blood and tissue. Hepatic enzymes, vascular endothelial growth factor (VEGF), and hypoxia-inducible factor 1α (HIF-1α) were measured at 0, 24, and 72 hours after treatment. Histopathologic examination was performed to evaluate extent of tumor necrosis and normal parenchymal damage. RESULTS: Serum sorafenib concentration peaked at 2 hours after treatment. The mean tissue concentration was 406.8 times greater than the serum concentration. Aspartate aminotransferase and alanine aminotransferase levels were significantly elevated in the TAE-S group at 24 hours after treatment. Serum VEGF and HIF-1α concentrations were not significantly different between the TAE-L and TAE-S groups. Hepatic parenchymal damage was more severe in the TAE-S group. Mean fraction of tumor necrosis after treatment was significantly greater in the TAE-S group. CONCLUSIONS: Transarterial chemoembolization using sorafenib resulted in a high intrahepatic concentration of sorafenib. The degree of tumor necrosis was significantly greater in the TAE-S group compared with the TAE-L group, but more severe toxicity of normal liver tissue also occurred.
Assuntos
Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Carcinoma Hepatocelular/terapia , Quimioembolização Terapêutica/métodos , Neoplasias Hepáticas Experimentais/terapia , Niacinamida/análogos & derivados , Compostos de Fenilureia/administração & dosagem , Compostos de Fenilureia/farmacocinética , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/farmacocinética , Alanina Transaminase/sangue , Animais , Antineoplásicos/sangue , Antineoplásicos/toxicidade , Aspartato Aminotransferases/sangue , Carcinoma Hepatocelular/sangue , Carcinoma Hepatocelular/patologia , Quimioembolização Terapêutica/efeitos adversos , Óleo Etiodado/administração & dosagem , Estudos de Viabilidade , Subunidade alfa do Fator 1 Induzível por Hipóxia/sangue , Neoplasias Hepáticas Experimentais/sangue , Neoplasias Hepáticas Experimentais/patologia , Masculino , Necrose , Niacinamida/administração & dosagem , Niacinamida/farmacocinética , Niacinamida/toxicidade , Compostos de Fenilureia/toxicidade , Inibidores de Proteínas Quinases/sangue , Inibidores de Proteínas Quinases/toxicidade , Coelhos , Sorafenibe , Distribuição Tecidual , Fator A de Crescimento do Endotélio Vascular/sangueRESUMO
BACKGROUND: Sorafenib is a kinase inhibitor anticancer drug whose repeated administration causes the onset of a peripheral painful neuropathy. Notably, the efficacy of common analgesic drugs is not adequate and this often leads pre-mature discontinuation of anticancer therapy. The aim of this study was to establish a rat model of sorafenib-induced neuropathic pain, and to assess the effect of the new anti-neuropathic compound dimiracetam in comparison with gabapentin, pregabalin and duloxetine. METHODS: Male Sprague-Dawley rats were treated i.v. (10 mg kg(-1)), i.p. (10 and 30 mg kg(-1)) or p.o. (80 and 160 mg kg(-1)) with sorafenib once daily for 21 days. Pain behaviour measurements (cold plate, paw pressure, electronic von Frey) were performed on days 0, 7, 14 and 21. RESULTS: Sorafenib lowered the paw-licking threshold to non-noxious cold stimuli on day 14 of all protocols evaluated. The i.p. administration resulted in greater efficacy than the other administration routes. Sorafenib treatments did not affect paw-withdrawal responses to non-noxious or to noxious mechanical stimuli. On day 14, dimiracetam (300 mg kg(-1)), gabapentin (100 mg kg(-1)), pregabalin (30 mg kg(-1)) and duloxetine (30 mg kg(-1)) were acutely administered p.o. in sorafenib i.p.-treated rats. A single oral dose of dimiracetam induced a statistically significant increase of the pain threshold 15 min after administration. Pregabalin induced a comparable effect, whereas gabapentin and duloxetine were ineffective. Repeated twice-daily administration of dimiracetam (150 mg kg(-1) p.o.), starting on the first day of i.p sorafenib administration, significantly protected rats from sorafenib-induced decrease in the paw-licking threshold. CONCLUSIONS: A rat model of sorafenib-induced hypersensitivity to cold stimulation has been established. Dimiracetam and pregabalin are effective in prevention of sorafenib-induced neuropathy in this model.
Assuntos
Analgésicos/uso terapêutico , Antineoplásicos/toxicidade , Imidazóis/uso terapêutico , Neuralgia/induzido quimicamente , Niacinamida/análogos & derivados , Compostos de Fenilureia/toxicidade , Pirróis/uso terapêutico , Análise de Variância , Animais , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Hiperalgesia/tratamento farmacológico , Masculino , Niacinamida/toxicidade , Medição da Dor , Limiar da Dor/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Tempo de Reação/efeitos dos fármacos , Sorafenibe , Fatores de TempoRESUMO
The aim of the present study was to observe the effects of sorafenib on the proliferation, apoptosis and invasion of A549/DDP cisplatin-resistant lung adenocarcinoma cells cultured in vitro. The A549/DDP cisplatin-resistant lung adenocarcinoma cell strain was cultured in vitro, the cell culture group incubated in culture medium only was set as the control group (Group S0) and the four concentration gradients of sorafenib were added to the culture groups as the experimental groups: S1, 2 µmol/l; S2, 4 µmol/l; S3, 8 µmol/l; and S4, 16 µmol/l. The MTT assay was used to determine the growth inhibition rate of the cells, which were respectively subjected to sorafenib treatment for 24, 48 and 72 h. Flow cytometry was used to determine the rate of apoptosis of cells in each group following sorafenib treatment for 72 h. Furthermore, the Transwell invasion experiment was used to determine the effect on A549/DDP cell invasion following sorafenib treatment for 24 h. Based on the MTT assay, it was found that the inhibition rates of A549/DDP cisplatin-resistant lung adenocarcinoma cells in groups S1-4 following sorafenib treatment for 24 h were 4.58±2.82, 14.93±2.62, 37.58±7.13 and 58.39±8.15%, respectively. For 48 h, inhibition rates in S1-4 were 14.98±2.93, 26.28±7.31, 63.00±3.05 and 78.84±3.96%, respectively, and for 72 h, inhibition rates were 18.80±2.82, 32.71±2.55, 75.51±4.73 and 87.50±3.36%, respectively. The difference in the inhibition rates of cells among the experimental groups for the same incubation time showed statistical significance (P<0.05). Flow cytometric analysis indicated that the rate of apoptosis in the control group was 8.88±0.81% following sorafenib treatment for 72 h, and the rates of apoptosis in groups S1-4 were, 12.84±0.24, 17.27±0.78, 21.98±0.75 and 49.67±1.38%, respectively. The rate of apoptosis in each experimental group was higher compared with that in the control group (P<0.05). The difference in the rate of apoptosis among the experimental groups was statistically significant (P<0.05). The Transwell assay showed that the number of cells permeating the septum in the control group was 82.7±2.3/high power lens (HP), while the average number of cells permeating septum in groups S1-4 following treatment with sorafenib for 24 h was 58.2±2.5, 41.3±1.3, 22.6±2.1 and 14.7±1.1/HP, which was significantly lower compared with the control group. The number of cells permeating the septum in each experimental group decreased with the enhancement of the concentration gradient. The differences were statistically significant (P<0.05). In conclusion, sorafenib inhibits the proliferation of A549/DDP cisplatinresistant lung adenocarcinoma cells in a time and concentrationdependent manner. In addition, sorafenib induces apoptosis in A549/DDP cisplatinresistant lung adenocarcinoma cells, thus reducing their invasiveness.
Assuntos
Antineoplásicos/toxicidade , Apoptose/efeitos dos fármacos , Niacinamida/análogos & derivados , Compostos de Fenilureia/toxicidade , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Adenocarcinoma de Pulmão , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Cisplatino/toxicidade , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Niacinamida/toxicidade , Sorafenibe , Fatores de TempoRESUMO
Antiangiogenic therapy, specially sorafenib, has become the standard of care for patients with advanced hepatocellular carcinoma (HCC), however, the improvement in survival time is not satisfactory. Previous studies have found that, in some circumstances, antiangiogenic therapy promoted tumor metastasis and the mechanistic studies were mainly focus on cancer-cell-autonomous manners. In two experimental metastasis models with tail-vein injection with hepatoma cells and an orthotopic HCC mouse model, we found that pretreatment with two vascular endothelial growth factor receptor (VEGFR) inhibitors, sunitinib and sorafenib, facilitated tumor cell survival in blood stream and promoted lung metastasis from tumors that were subsequently incubated after drug discontinuation, indicating that host response joined into the pro-metastatic effects. An antibody microarray identified that interleukin (IL)-12b was decreased in the peripheral blood of the mice treated with the two VEGFR inhibitors. IL-12b suppression in macrophages and dendritic cells from host organs was found to play a crucial role in treatment-induced metastasis. Supplement with recombinant mouse IL-12b or restoration of IL-12b expression in the host by zoledronic acid, which was previously reported to enhance IL-12 expression in vitro and in vivo, alleviated the metastasis-promoting effects of sunitinib and sorafenib. These studies suggest that host response to VEGFR inhibitors facilitates HCC metastasis and restoration of IL-12b expression could translate into clinical benefits.
Assuntos
Inibidores da Angiogênese/toxicidade , Carcinoma Hepatocelular/secundário , Indóis/toxicidade , Subunidade p40 da Interleucina-12/fisiologia , Neoplasias Hepáticas/patologia , Neoplasias Pulmonares/secundário , Niacinamida/análogos & derivados , Compostos de Fenilureia/toxicidade , Pirróis/toxicidade , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Inibidores da Angiogênese/administração & dosagem , Inibidores da Angiogênese/farmacologia , Animais , Carcinoma Hepatocelular/irrigação sanguínea , Linhagem Celular Tumoral , Células Dendríticas/imunologia , Difosfonatos/uso terapêutico , Xenoenxertos , Humanos , Imidazóis/uso terapêutico , Terapia de Imunossupressão , Indóis/administração & dosagem , Indóis/farmacologia , Subunidade p40 da Interleucina-12/deficiência , Subunidade p40 da Interleucina-12/genética , Células Matadoras Naturais/imunologia , Neoplasias Pulmonares/irrigação sanguínea , Macrófagos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Nus , Transplante de Neoplasias , Células Neoplásicas Circulantes , Neovascularização Patológica/tratamento farmacológico , Niacinamida/administração & dosagem , Niacinamida/farmacologia , Niacinamida/toxicidade , Compostos de Fenilureia/administração & dosagem , Compostos de Fenilureia/farmacologia , Pirróis/administração & dosagem , Pirróis/farmacologia , Sorafenibe , Sunitinibe , Ácido ZoledrônicoRESUMO
PURPOSE: To test the feasibility of targeted intraarterial administration of the tyrosine kinase inhibitor chemotherapeutic agent sorafenib to inhibit embolotherapy-induced tumor angiogenesis and reduce systemic drug side effects. MATERIALS AND METHODS: The left hepatic lobes of five New Zealand White rabbits (mean weight, 2.7 kg±0.2) were treated with chemoembolization with sorafenib and ethiodized oil emulsion, followed by immediate euthanasia. Postprocedure noncontrast computed tomography (CT) was used to evaluate intrahepatic chemotherapy mixture distribution. Liquid chromatography/tandem mass spectrometry (LC-MS/MS) was then used to directly measure sorafenib concentration in the treated liver tissue. Histopathologic assessment of treated left lobes was performed to identify any immediate toxic effects of the sorafenib solution. RESULTS: Lobar sorafenib chemoembolization was successfully performed in all cases via the left hepatic artery. Sorafenib and ethiodized oil (mean, 6.4 mg±3.8 and 0.95 mL±0.7, respectively) were injected, and CT confirmed targeted left hepatic lobe sorafenib emulsion delivery in all cases. Corresponding LC-MS/MS analysis yielded a mean sorafenib concentration of 94.2 µg/mL±48.3 in treated left lobe samples (n = 5), significantly greater than typical therapeutic drug levels (2-10 µg/mL) achieved with oral sorafenib systemic therapy. Histopathologic assessment showed only mild or moderate nonspecific ballooning degeneration in zone 3 hepatocytes, without tissue necrosis. CONCLUSIONS: Targeted transarterial sorafenib delivery is feasible and results in higher tissue drug levels than reported for systemic sorafenib therapy, without immediate histopathologic tissue toxicity. Future studies should aim to determine the utility of sorafenib chemoembolization in reducing hypoxia-induced vasculogenesis in liver tumors.
Assuntos
Quimioembolização Terapêutica/métodos , Óleo Etiodado/administração & dosagem , Óleo Etiodado/farmacocinética , Fígado/metabolismo , Niacinamida/análogos & derivados , Compostos de Fenilureia/administração & dosagem , Compostos de Fenilureia/farmacocinética , Animais , Antineoplásicos/administração & dosagem , Quimioembolização Terapêutica/efeitos adversos , Relação Dose-Resposta a Droga , Óleo Etiodado/toxicidade , Fígado/efeitos dos fármacos , Fígado/patologia , Masculino , Niacinamida/administração & dosagem , Niacinamida/farmacocinética , Niacinamida/toxicidade , Compostos de Fenilureia/toxicidade , Projetos Piloto , Coelhos , Sorafenibe , Distribuição Tecidual , Resultado do TratamentoRESUMO
The bi-aryl urea multi-kinase inhibitor Sorafenib (BAY 43-9006, Nexavar) was initially approved for the treatment of unresectable hepatocellular carcinoma and advanced renal cell carcinoma. Eleven years after its first description in PubMed, the therapeutic potential of Sorafenib has been evaluated in an increasing number of studies, mainly focused on solid tumors. More recently, the potential usefullness of Sorafenib has started to emerge also against hematological malignancies. At the molecular level, besides the RAF kinase pathway, which represents the first therapeutic target of Sorafenib, additional kinases, in particular the vascular endothelial growth factor receptor, have been identified as important targets of Sorafenib. A great interest for the potential use of Sorafenib against acute myeloid leukemia (AML) arose when it was demonstrated that a specific mutation of a kinase gene, called FMS-like tyrosin-kinase-3- internal tandem duplication (FLT-3-ITD) and occurring in more than 30% of AML, represents a molecular target of Sorafenib. However, recent phase I and II clinical studies showed that, in spite of its ability to suppress the activity of this mutated kinase, resistence to Sorafenib rapidly occurs in AML, suggesting that Sorafenib will be more effective in combined therapy than used as single drug. Another critical molecular target of Sorafenib is the anti-apoptotic protein Mcl-1. The ability of Sorafenib to rapidly shut-off Mcl-1 in virtually all the hematological malignancies investigated, including the B-chronic lymphocytic leukemia, represents a key element for its antileukemic activity as well as for therapeutic combinations based on Sorafenib. In this respect, it is of particular interest that many chemotherapeutic drugs or innovative anti-neoplastic compounds, such as recombinant TRAIL or inibitors of MDM2 protein, are either unable to down-regulate Mcl-1 or in some instances promote a paradoxical induction of Mcl-1. In this review, the growing evidences for the role of Mcl-1 in mediating the anti-leukemic activity of Sorafenib will be discussed in relationship with promising therapeutic perspectives.
Assuntos
Neoplasias Hematológicas/tratamento farmacológico , Niacinamida/análogos & derivados , Compostos de Fenilureia/uso terapêutico , Apoptose/efeitos dos fármacos , Ensaios Clínicos como Assunto , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Proteína de Sequência 1 de Leucemia de Células Mieloides , Niacinamida/química , Niacinamida/uso terapêutico , Niacinamida/toxicidade , Compostos de Fenilureia/química , Compostos de Fenilureia/toxicidade , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteínas Proto-Oncogênicas c-mdm2/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Receptores de Fatores de Crescimento do Endotélio Vascular/metabolismo , Sorafenibe , Ligante Indutor de Apoptose Relacionado a TNF/genética , Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Ligante Indutor de Apoptose Relacionado a TNF/uso terapêutico , Tirosina Quinase 3 Semelhante a fms/genética , Tirosina Quinase 3 Semelhante a fms/metabolismoRESUMO
The intensive use of herbicides over the last few decades has caused a general increase of environmental pollution. It is thus very important to evaluate the possible genotoxic properties of these chemical compounds as well as identifying their mode of action. Phenylurea herbicides are selective agents widely used for the control of infestant plants. Of these herbicides, which are widely used in agriculture, we analysed four of the less intensively studied molecules. More precisely, we investigated the genotoxic effects of fenuron, chlorotoluron, diuron, and difenoxuron by analyses of chromosomal aberrations (CAs) and sister chromatid exchange (SCE) in exposed mammalian cells. We used the Chinese hamster ovary (CHO) and epithelial liver (CHEL) cell lines, endowed with the absence or the presence, respectively, of an enzymatic system to activate pro-mutagenic compounds. Our results show that all herbicides tested induce, at high concentrations, an increasing number of CAs in non-metabolising CHO cells. Instead, in the exposed CHEL cell line, the four herbicides induced CAs also at the lowest dose-level. In the CHEL cells, a statistically significant increase of SCE was also observed. The phenylurea herbicides showed direct genotoxic activity, but the cytogenetic effects were greatly enhanced after metabolic conversion. These data, together with other information on phenylurea herbicides, are of great interest from the environmental point of view, and for human health. In fact, intensive use of herbicides contaminates soil, surface water, groundwater and agricultural products, and thus should be taken in particular consideration not only for those initiatives to specifically protect exposed workers, but also to safeguard the health of consumers of agricultural products.
Assuntos
Herbicidas/toxicidade , Mutagênicos/toxicidade , Compostos de Fenilureia/toxicidade , Animais , Linhagem Celular , Aberrações Cromossômicas , Cricetinae , Cricetulus , Testes de Mutagenicidade , Troca de Cromátide IrmãRESUMO
A novel lipid regulator (PD132301-2) produces degeneration and necrosis of adrenal fasciculata in guinea pigs. Primary adrenocortical cell cultures from male Hartley guinea pigs were utilized to investigate potential mechanisms of this toxicity. Concentration-dependent loss of viability, measured by neutral red (NR) accumulation or MTT reduction, was observed within 6 hr at concentrations of 0.01 to 10 microM PD132301-2. At 10 microM, NR and MTT indices were 50% of those of control after 6 hr exposure. Maximal decreases in NR and MTT indices to 20% of control values occurred by 24 hr at > or = 1 microM PD132301-2. Adenine nucleotide analysis after PD132301-2 challenge indicated that ATP depletion preceded loss of viability. At 10 microM PD132301-2, ATP levels were 80% of those of control after 30 min and 25% of those of control after 6 hr. Supplementation of glucose-free buffer with 20 mM fructose protected adrenocortical cells from PD132301-2-induced toxicity. Fructose protection was blocked by inhibiting glycolysis with 1 mM sodium fluoride. Pretreatment of cultures with 100 microM metyrapone, an inhibitor of cytochrome P-450, did not block cytotoxicity induced by 10 microM PD132301-2, but did block cytotoxicity of 100 microM o,p'-DDD. In adrenocortical mitochondrial preparations, inhibition of respiration by PD132301-2 was site II-specific. Both state 3 and state 4 respiration were inhibited 50-75% at 1-30 microM PD132301-2. Thus, ATP depletion resulting from direct inhibition of mitochondrial respiration is a critical early event in adrenocortical cytotoxicity of PD132301-2.
Assuntos
Trifosfato de Adenosina/análise , Córtex Suprarrenal/efeitos dos fármacos , Compostos de Fenilureia/toxicidade , Difosfato de Adenosina/análise , Trifosfato de Adenosina/biossíntese , Córtex Suprarrenal/metabolismo , Córtex Suprarrenal/ultraestrutura , Hormônio Adrenocorticotrópico/farmacologia , Animais , Células Cultivadas , Frutose/farmacologia , Cobaias , Masculino , Metirapona/farmacologia , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Consumo de Oxigênio/efeitos dos fármacosRESUMO
A study of the toxic properties of sonet in chronic experiment on white rats established the threshold and non-acting dose of the insecticide. The accumulation of the insecticide in the potato tubers during the entire vegetation period as well as its effect on the potato quality were investigated. The author recommends 0.05 mg/g of sonet per 1 g of potato as a maximum permissible level.