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1.
Crit Rev Toxicol ; 41(10): 803-21, 2011 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-21838551

RESUMEN

Cisplatin is among the most effective chemotherapeutic agents against solid tumors. Nephrotoxicity is the most common side effect of cisplatin chemotherapy, which limits the clinical use of cisplatin and seriously worsens the quality of life of cancer patients resulting in dosage reduction and discontinuation of treatment. Cisplatin involves a complex multifactorial process, as it has direct toxic effect on cells of the renal tubules, vasculature and glomeruli, and causes alterations in renal blood flow and glomerular filtration rate. Indirectly, cisplatin also induces inflammation of the renal interstitium, which contributes to the acute damage and may lead to chronic interstitial fibrosis, indicative of irreversible renal damage. This review presents an integrative view of the pathophysiological effects of cisplatin on tubular, vascular, glomerular, and interstitial function and the interplay among these actions. Moreover, it reviewed human clinical trials of the last ten years in order to evaluate the incidence and severity of the renal injury induced by cisplatin at the doses and therapeutic guidelines used in the clinical practice.


Asunto(s)
Antineoplásicos/efectos adversos , Cisplatino/efectos adversos , Necrosis Tubular Aguda/fisiopatología , Riñón/efectos de los fármacos , Enfermedad Aguda , Animales , Antineoplásicos/farmacocinética , Enfermedad Crónica , Cisplatino/farmacocinética , Ensayos Clínicos como Asunto , Daño del ADN , Modelos Animales de Enfermedad , Humanos , Riñón/fisiopatología , Glomérulos Renales/efectos de los fármacos , Necrosis Tubular Aguda/inducido químicamente , Túbulos Renales/citología , Túbulos Renales/efectos de los fármacos , Factores de Riesgo
2.
Nephrol Dial Transplant ; 26(11): 3484-95, 2011 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-21602180

RESUMEN

BACKGROUND: Nephrotoxicity is the major limitation for the clinical use of cisplatin as an anti-tumoural drug. Our aim was to investigate the protective effect of quercetin on cisplatin nephrotoxicity in a rat tumour model in vivo and to examine the mechanisms of renal protection. METHODS: Breast adenocarcinoma (13762 Mat B-III) cells were inoculated subcutaneously in male Fischer rats and 7 days later, the rats were administered daily with quercetin [50 mg/kg/day, intraperitoneally (i.p.)] or vehicle. Four days after that, the rats were given a single dose of cisplatin (4 mg/kg, i.p.) or vehicle. Tumour growth and renal function were monitored throughout the experiment. Two or 6 days after cisplatin administration, the rats were killed and the kidneys and tumours were removed to examine renal function and toxicity markers in both tissues. RESULTS: In the kidney, cisplatin treatment induced: (i) a decrease in renal blood flow and glomerular filtration rate, (ii) tubular necrosis/apoptosis, (iii) increased lipid peroxidation and decreased endogenous antioxidant systems, (iv) increased expression of inflammation markers and (v) increased activity of the apoptosis executioner caspase-3. Cisplatin effectively reduced tumour size and weight. CONCLUSIONS: Co-treatment with quercetin partially prevented all the renal effects of cisplatin, whereas it did not impair its anti-tumour activity. In conclusion, in a model of tumour-bearing rats, quercetin prevents the nephrotoxic effect of cisplatin without affecting its anti-tumour activity.


Asunto(s)
Lesión Renal Aguda/prevención & control , Adenocarcinoma/tratamiento farmacológico , Antineoplásicos/uso terapéutico , Antioxidantes/uso terapéutico , Cisplatino/uso terapéutico , Neoplasias Mamarias Experimentales/tratamiento farmacológico , Quercetina/uso terapéutico , Lesión Renal Aguda/inducido químicamente , Adenocarcinoma/complicaciones , Animales , Antineoplásicos/toxicidad , Antioxidantes/metabolismo , Apoptosis/efectos de los fármacos , Caspasa 3 , Cisplatino/toxicidad , Creatinina/orina , Quimioterapia Combinada , Femenino , Tasa de Filtración Glomerular , Inflamación/inducido químicamente , Inflamación/prevención & control , Mediadores de Inflamación/metabolismo , Pruebas de Función Renal , Peroxidación de Lípido , Neoplasias Mamarias Experimentales/complicaciones , Estrés Oxidativo/efectos de los fármacos , Ratas , Ratas Wistar
3.
Food Chem Toxicol ; 107(Pt A): 226-236, 2017 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-28669851

RESUMEN

Strategies to minimize the nephrotoxicity of platinated antineoplastics without affecting its antitumour efficacy are strongly necessary to improve the pharmacotoxicological profile of these drugs. The natural flavonoid quercetin has been shown to afford nephroprotection without affecting cisplatin antitumour effect. The purpose of the present study has been to assess the differential mechanisms of action of cisplatin and quercetin on kidney and tumour tissues that could explain these effects. Wistar rats bearing subcutaneous tumours were treated with cisplatin and quercetin (and the appropriate controls). Tumour size and renal function evolution was monitored during 6 days. Platinum and quercetin content were also determined in both tissues. All the parameters studied, including blood supply, inflammation, apoptosis, critical MAPK signaling and oxidative stress in the cisplatin-treated animals are almost normalized by quercetin in the kidneys, but unaffected in the tumours. Our results suggest that in a cancer model in vivo, the protection exerted by quercetin on cisplatin nephrotoxicity is related to its antioxidant, vascular, anti-inflammatory and antiapoptotic effects, but these properties do not affect the mechanisms responsible for the antitumour effect of cisplatin.


Asunto(s)
Antineoplásicos/toxicidad , Cisplatino/toxicidad , Neoplasias Renales/tratamiento farmacológico , Quercetina/administración & dosificación , Animales , Antineoplásicos/administración & dosificación , Antioxidantes/administración & dosificación , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Cisplatino/administración & dosificación , Humanos , Riñón/efectos de los fármacos , Riñón/metabolismo , Riñón/fisiopatología , Neoplasias Renales/metabolismo , Neoplasias Renales/fisiopatología , Masculino , Estrés Oxidativo/efectos de los fármacos , Ratas , Ratas Endogámicas F344 , Ratas Wistar
4.
Toxicol Sci ; 132(2): 493-501, 2013 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-23335628

RESUMEN

Although generally reversible, contrast media toxicity often induces contrast-induced nephropathy (CIN), which is associated with longer hospitalization time, the need for dialysis, and higher incidence of later cardiovascular events and higher mortality. Preventive cotreatments have been assayed at the preclinical and clinical levels, but recent meta-analysis has not demonstrated a beneficial effect, which supports the search for new nephroprotective strategies. We have assessed if the administration of cardiotrophin-1 (CT-1), an endogenous cytokine with protective properties on the heart and liver, might mitigate CIN in rats. We have developed a model of CIN induced by the administration of the contrast medium gastrographin iv (3.7mg/kg) in rats sensitized by previous administration of subnephrotoxic doses of gentamicin (50mg/kg/day, ip) for 6 days. The severity of CIN was assessed by the measurement of renal function; renal histological damage; urinary excretion of markers of tubular damage, including N-acetyl beta glucosaminidase (NAG), kidney injury molecule 1 (KIM-1), and plasminogen activator inhibitor 1; lipid peroxidation; and renal apoptosis. Treatment with CT-1 almost completely prevented the renal tissue damage, as evidenced by almost total prevention of tubular desepithelization and tubular obstruction, reduced caspase activation, and cell proliferation. Besides, CT-1 also prevented the increment in renal tissue levels of renal tissue injury markers NAG, KIM-1, and neutrophil gelatinase-associated lipocalin. Oxidative stress, a hallmark of CIN, was also prevented by CT-1. Administration of CT-1 also prevented the derangement in kidney function induced by CIN. Renal hemodynamics, also impaired by the contrast medium, was normal in rats cotreated with CT-1. CT-1 administration significantly prevents the alterations in renal function and structure observed in a rat model of CIN.


Asunto(s)
Medios de Contraste/toxicidad , Citocinas/administración & dosificación , Riñón/efectos de los fármacos , Animales , Masculino , Ratas , Ratas Wistar
5.
Toxicol Lett ; 203(2): 154-61, 2011 Jun 10.
Artículo en Inglés | MEDLINE | ID: mdl-21439361

RESUMEN

Iron-chelating therapy results in a significant improvement in the life expectancy of patients with transfusional iron overload. However, alterations of renal function have been observed in some patients undergoing chelation therapy. In the present study we evaluated the effect of treatment with deferasirox iron chelator on the renal function in normal Wistar rats and in mouse and human cultured tubular cell lines. Results indicate that deferasirox given daily via intraperitoneal route for 7 days induced: (1) an increased urinary protein, albumin and glucose excretion, (2) tubular necrosis/apoptosis, (3) and increased tubular damage markers, in spite of normal glomerular function. Moreover, in vitro studies revealed that: (1) mouse MCT cultures resulted more susceptible to the antiproliferative/cytotoxic effect of deferasirox, mainly at 24h after treatment, than human HK-2 cultures, (2) MCT cell content of damage molecules increased after 24h of iron chelator treatment with slight changes in their excretion into the culture medium and (3) MCT cultures showed a significant evidence of apoptotic cell death through an increased expression and activation of caspase-3 and marked DNA fragmentation. In conclusion, this renal side effect of deferasirox-chelating therapy seems to be based on direct toxic effects of deferasirox on renal tubular cells.


Asunto(s)
Benzoatos/toxicidad , Quelantes del Hierro/toxicidad , Enfermedades Renales/inducido químicamente , Triazoles/toxicidad , Acetilglucosaminidasa/orina , Animales , Apoptosis/efectos de los fármacos , Moléculas de Adhesión Celular/orina , Línea Celular , Embrión de Pollo , Clusterina/orina , Cistatina C/orina , Deferasirox , Células Epiteliales/efectos de los fármacos , Células Epiteliales/patología , Tasa de Filtración Glomerular/efectos de los fármacos , Histocitoquímica , Riñón/efectos de los fármacos , Riñón/patología , Enfermedades Renales/patología , Enfermedades Renales/orina , Lipocalinas/orina , Masculino , Ratas , Ratas Wistar
6.
Toxicol Appl Pharmacol ; 210(1-2): 128-35, 2006 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-16226777

RESUMEN

Inflammation can play a key role in Cd-induced dysfunctions. Quercetin is a potent oxygen free radical scavenger and a metal chelator. Our aim was to study the effect of quercetin on Cd-induced kidney damage and metallothionein expression. The study was performed in Wistar rats that were administered during 9 weeks with either cadmium (1.2 mg Cd/kg/day, s.c.), quercetin (50 mg/kg/day, i.p.) or cadmium + quercetin. Renal toxicity was evaluated by measuring blood urea nitrogen concentration and urinary excretion of enzymes marker of tubular damage. Endothelial nitric oxide synthase (eNOS), inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) renal expression were assessed by Western blot. Renal expression of metallothionein 1 and 2 (MT-1, MT-2) and eNOS mRNA was assessed by Northern blot. Our data demonstrated that Cd-induced renal toxicity was markedly reduced in rats that also received quercetin. MT-1 and MT-2 mRNA levels in kidney were substantially increased during treatment with Cd, being even higher when the animals received Cd and quercetin. Renal eNOS expression was significantly higher in rats receiving Cd and quercetin than in animals receiving Cd alone or in control rats. In the group that received Cd, COX-2 and iNOS expression was markedly higher than in control rats. In the group Cd+quercetin, no changes in COX-2 and iNOS expression were observed compared with the control group. Our results demonstrate that quercetin treatment prevents Cd-induced overexpression of iNOS and COX-2, and increases MT expression. These effects can explain the protection by quercetin of Cd-induced nephrotoxicity.


Asunto(s)
Compuestos de Cadmio/toxicidad , Ciclooxigenasa 2/biosíntesis , Enfermedades Renales/inducido químicamente , Metalotioneína/biosíntesis , Óxido Nítrico Sintasa/biosíntesis , Sustancias Protectoras/uso terapéutico , Quercetina/uso terapéutico , Animales , Enfermedad Crónica , Modelos Animales de Enfermedad , Inducción Enzimática , Enfermedades Renales/enzimología , Enfermedades Renales/metabolismo , Enfermedades Renales/prevención & control , Masculino , Ratas , Ratas Wistar
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