RESUMEN
Inflammation and oxidative stress play important roles in the progression of renal damage. The natural polyphenol naringenin is known to exert potent antioxidant and anti-inflammatory effects. In this study, we have investigated the effect of naringenin on kidney dysfunction, fibrosis, endoplasmic reticulum (ER) stress, angiotensin II type I receptor (AT1R) expression and inflammation in daunorubicin (DNR) induced nephrotoxicity model. Nephrotoxicity was induced in rats by intravenous injection of DNR at a cumulative dose of 9 mg/kg. After 1 week, naringenin (20mg/kg/day. p.o) was administered daily for 6 weeks. Biochemical studies were performed to evaluate renal function. Western blotting was performed to measure the protein levels of AT1R, endothelin (ET)1, ET receptor type A (ETAR), extracellular signal-regulated kinase (ERK)1/2, nuclear factor (NF)κB p65, peroxisome proliferator activated receptor (PPAR)γ, oxidative/ER stress, apoptosis, and inflammatory markers in the kidney of DNR treated rats. Histopathological analysis was done using hemotoxylin eosin and Masson trichrome stained renal sections to investigate the structural abnormalities and fibrosis. DNR treated rats suffered from nephrotoxicity as evidenced by worsened renal function, increased blood urea nitrogen, serum creatinine levels in renal tissues and histopathogical abnormalities. Treatment with naringenin mitigated these changes. Furthermore, naringenin up regulated PPARγ and down regulated AT1R, ET1, ETAR, p-ERK1/2, p-NFκB p65, ER stress, apoptosis, and inflammatory markers. Our results suggest that naringenin has an ability to improve renal function and attenuates AT1R, ERK1/2-NFκB p65 signaling pathway in DNR induced nephrotoxicity in rats.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Antibióticos Antineoplásicos/toxicidad , Daunorrubicina/antagonistas & inhibidores , Daunorrubicina/toxicidad , Flavanonas/farmacología , Enfermedades Renales/inducido químicamente , Enfermedades Renales/prevención & control , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Receptor de Angiotensina Tipo 1/efectos de los fármacos , Fármacos Renales/farmacología , Factor de Transcripción ReIA/efectos de los fármacos , Animales , Apoptosis/efectos de los fármacos , Estrés del Retículo Endoplásmico/efectos de los fármacos , Fibrosis , Inflamación/tratamiento farmacológico , Inflamación/fisiopatología , Inyecciones Intravenosas , Enfermedades Renales/patología , Masculino , PPAR gamma/biosíntesis , Ratas , Ratas Sprague-DawleyRESUMEN
The effect of ABCB1 (P-gp, (P-glycoprotein), MDR1) and ABCG2 (BCRP1, (breast cancer resistance protein 1)) expressions on cell resistance to daunorubicin (DRN), imatinib, and nilotinib was studied in human leukemia cells. We used a set of cells derived from a parental K562 cell line, expressing various levels of ABCB1 and ABCG2, respectively. The function of ABCB1 and ABCG2 was confirmed using calcein AM and pheophorbide A accumulation assays, respectively. These assays indicated distinct differences in activities of ABCB1 and ABCG2 which corresponded to their expression levels. We observed that the resistance to DRN and imatinib was proportional to the expression level of ABCB1. Similarly, the resistance to nilotinib and imatinib was proportional to the expression level of ABCG2. Importantly, K562/DoxDR05 and K562/ABCG2-Z cells with the lowest expressions of ABCB1 and ABCG2, respectively, failed to reduce the intracellular levels of imatinib to provide a significant resistance to this drug. However, the K562/DoxDR05 and K562/ABCG2-Z cells significantly decreased the intracellular levels of DRN and nilotinib, respectively, thereby mediating significant resistances to these drugs. Only cells which expression of ABCB1 or ABCG2 exceeded a certain level exhibited a significantly decreased intracellular level of imatinib, and this effect was accompanied by a significantly increased resistance to this drug. Our results clearly indicated that resistance to anticancer drugs mediated by main ABC transporters, ABCB1 and ABCG2, strongly depends on their expressions at protein levels. Importantly, resistance for one drug might be maintained while resistance for other ones might become undetectable at low transporter expression levels.
Asunto(s)
Transportadoras de Casetes de Unión a ATP/metabolismo , Benzamidas/farmacología , Daunorrubicina/farmacología , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Proteínas de Neoplasias/metabolismo , Piperazinas/farmacología , Pirimidinas/farmacología , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2 , Transportadoras de Casetes de Unión a ATP/genética , Benzamidas/antagonistas & inhibidores , Benzamidas/uso terapéutico , Western Blotting , Supervivencia Celular/efectos de los fármacos , Daunorrubicina/antagonistas & inhibidores , Daunorrubicina/uso terapéutico , Resistencia a Antineoplásicos/fisiología , Humanos , Mesilato de Imatinib , Células K562 , Proteínas de Neoplasias/genética , Piperazinas/antagonistas & inhibidores , Piperazinas/uso terapéutico , Pirimidinas/antagonistas & inhibidores , Pirimidinas/uso terapéuticoRESUMEN
Daunorubicin (DNR) is a widely used chemotherapeutic agent; however, its clinical use is limited because of its cardiotoxicity. This study was aimed to investigate the protective effect of sodium ferulate (SF), an effective component from traditional Chinese herbs, against DNR-induced cardiotoxicity in juvenile rats. DNR was administered intraperitoneally to rats at the dosage of 2.5 mg·kg(-1)·wk(-1) for 5 consecutive weeks (cumulative dose of 12.5 mg/kg) or in combination with intraperitoneal injection of SF at 50 mg·kg(-1)·d(-1) over a period of 30 days. The animals were killed 6 days after the last injection of DNR. SF significantly ameliorated the DNR-induced cardiac dysfunction, structural damage of the myocardium, and release of lactate dehydrogenase and creatine kinase. Treatment with SF also reversed DNR-induced oxidative stress as evidenced by a decrease in malondialdehyde levels with a concomitant increase in myocardical superoxide dismutase activities. Furthermore, SF afforded significant cardioprotection against DNR-induced apoptosis in vivo and effectively suppressed the complex mitochondrion-dependent apoptotic signaling triggered by DNR. This study indicates that SF may improve cardiac function by inhibition of oxidative stress and apoptosis, thus providing a beneficial effect on the prevention of DNR-induced cardiotoxicity.
Asunto(s)
Antiinflamatorios no Esteroideos/uso terapéutico , Antibióticos Antineoplásicos/antagonistas & inhibidores , Antibióticos Antineoplásicos/toxicidad , Apoptosis/efectos de los fármacos , Ácidos Cumáricos/uso terapéutico , Daunorrubicina/antagonistas & inhibidores , Daunorrubicina/toxicidad , Cardiopatías/inducido químicamente , Cardiopatías/prevención & control , Mitocondrias/efectos de los fármacos , Animales , Cardiopatías/patología , Hemodinámica , Masculino , Miocardio/metabolismo , Estrés Oxidativo/efectos de los fármacos , Ratas , Ratas Sprague-DawleyRESUMEN
Anthracycline cardiotoxicity ranks among the most severe complications of cancer chemotherapy. Although its pathogenesis is only incompletely understood, "reactive oxygen species (ROS) and iron" hypothesis has gained the widest acceptance. Besides dexrazoxane, novel oral iron chelator deferiprone has been recently reported to afford significant cardioprotection in both in vitro and ex vivo conditions. Therefore, the aim of this study was to assess whether deferiprone 1) has any effect on the anticancer action of daunorubicin and 2) whether it can overcome or significantly reduce the chronic anthracycline cardiotoxicity in the in vivo rabbit model (daunorubicin, 3 mg/kg i.v., weekly for 10 weeks). First, using the leukemic cell line, deferiprone (1-300 microM) was shown not to blunt the antiproliferative effect of daunorubicin. Instead, in clinically relevant concentrations (>10 microM), deferiprone augmented the antiproliferative action of daunorubicin. However, deferiprone (10 or 50 mg/kg administered p.o. before each daunorubicin dose) failed to afford significant protection against daunorubicin-induced mortality, left ventricular lipoperoxidation, cardiac dysfunction, and morphological cardiac deteriorations, as well as an increase in plasma cardiac troponin T. Hence, this first in vivo study changes the current view on deferiprone as a potential cardioprotectant against anthracycline cardiotoxicity. In addition, these results, together with our previous findings, further suggest that the role of iron and its chelation in anthracycline cardiotoxicity is not as trivial as originally believed and/or other mechanisms unrelated to iron-catalyzed ROS production are involved.
Asunto(s)
Antraciclinas/administración & dosificación , Antraciclinas/toxicidad , Cardiopatías/inducido químicamente , Piridonas/uso terapéutico , Animales , Antraciclinas/antagonistas & inhibidores , Antineoplásicos/uso terapéutico , Antineoplásicos/toxicidad , Cardiotónicos/uso terapéutico , Cardiotónicos/toxicidad , Proliferación Celular/efectos de los fármacos , Daunorrubicina/antagonistas & inhibidores , Deferiprona , Células HL-60 , Cardiopatías/mortalidad , Cardiopatías/patología , Humanos , Masculino , ConejosRESUMEN
Nebivolol is a cardioselective beta-blocker (BB) currently used for the treatment of hypertension. It has mild vasodilating properties attributed to its interaction with the L-arginine/nitric oxide pathway, a property not shared by other BBs. Carvedilol is a nonselective ss-adrenergic receptor antagonist that also blocks alpha1-adrenergic receptors and is a potent antioxidant. Anthracyclines (ANTs), daunorubicin and doxorubicin, are commonly used in the treatment of several tumours, but their cardiac toxicity prevents their use at maximum myelotoxic doses, representing an important problem. In this study, we have evaluated the role of these BBs administered in combination with ANTs (daunorubicin and doxorubicin) on a reduction in cardiac toxicity. The combination of BB and ANTs has reduced the release of GSSG and GSH; in particular, co-treatment with nebivolol to ANTs has shown a significant reduction. The total integrated creatine kinase and troponin T activities were improved by BB and ANTs co-treatment. A significant reduction of their release was observed when hearts were treated with nebivolol. Cardiac tissue activity of gluthatione reductase was not significant and similar among experimental groups. In contrast, gluthatione peroxidise, Mn-superoxide dismutase and nitrite/nitrate release were increased after co-treatment with nebivolol. Finally, three parameters have been used to evaluate the cardiac toxicity of ANTs: the left ventricular pressure developed under a constant perfusion pressure (LVDP), the rate of variation of this parameter during systole (contractility) (LV/dt)max and during diastole (relaxation) (LV(dP/dt)min. Combination with BB has shown a reduction in cardiac toxicity; in particular, nebivolol has exerted the most significant cardioprotective effect.
Asunto(s)
Antagonistas Adrenérgicos beta/administración & dosificación , Antibióticos Antineoplásicos/antagonistas & inhibidores , Benzopiranos/administración & dosificación , Daunorrubicina/antagonistas & inhibidores , Etanolaminas/administración & dosificación , Cardiopatías/prevención & control , Análisis de Varianza , Animales , Antibióticos Antineoplásicos/toxicidad , Carbazoles/administración & dosificación , Carvedilol , Daunorrubicina/toxicidad , Relación Dosis-Respuesta a Droga , Combinación de Medicamentos , Evaluación Preclínica de Medicamentos , Glutatión/metabolismo , Cardiopatías/inducido químicamente , Masculino , Nebivolol , Nitratos/metabolismo , Estrés Oxidativo , Propanolaminas/administración & dosificación , Ratas , Ratas Sprague-DawleyRESUMEN
PURPOSE: Anthracyclines, such as doxorubicin and daunorubicin, continue to be widely used in the treatment of cancer, although they share the adverse effect of chronic, cumulative dose-related cardiotoxicity. The only approved treatment in prevention of anthracycline cardiotoxicity is dexrazoxane, a putative iron chelator. Previous in vitro studies have shown that disorders of iron metabolism, including altered IRP1-IRE binding, may be an important mechanism of anthracycline cardiotoxicity. METHODS: This study examined the role of IRP1-IRE binding ex vivo in a chronic model of daunorubicin cardiotoxicity in the Fischer 344 rat and whether dexrazoxane could prevent any daunorubicin-induced changes in IRP1 binding. Young adult (5-6 months) Fischer 344 rats received daunorubicin (2.5 mg/kg iv once per week for 6 weeks) with and without pretreatment with dexrazoxane (50 mg/kg ip). Other groups received saline (controls) or dexrazoxane alone. Rats were killed either 4 h or 2 weeks after the last dose of daunorubicin to assess IRP1-IRE binding. RESULTS: Contractility (dF/dt) of atrial tissue, obtained from rats 2 weeks after the last dose of daunorubicin, was significantly reduced in daunorubicin-treated compared to control rats. Dexrazoxane pretreatment protected against the daunorubicin-induced decrease in atrial dF/dt. However, left ventricular IRP1/IRE binding was not affected by daunorubicin treatment either 4 h or 2 weeks after the last dose of daunorubicin. CONCLUSIONS: IRP1 binding may not be altered in the rat model of chronic anthracycline cardiotoxicity.
Asunto(s)
Antibióticos Antineoplásicos/toxicidad , Quelantes/uso terapéutico , Daunorrubicina/toxicidad , Cardiopatías/inducido químicamente , Proteína 1 Reguladora de Hierro/metabolismo , Proteínas Reguladoras del Hierro/metabolismo , Razoxano/uso terapéutico , Animales , Antibióticos Antineoplásicos/antagonistas & inhibidores , Daunorrubicina/antagonistas & inhibidores , Cardiopatías/prevención & control , Masculino , Ratas , Ratas Endogámicas F344RESUMEN
Melampodium divaricatum is a member of the Asteraceae and in Brazil is known as false-calendula, its flowers being used in anti-inflammatory preparations, substituting the true calendula or marigold (Calendula officinalis L.). The flower extract was investigated for mutagenic and antimutagenic effect in the Salmonella/microsome assay. The tested extract was not mutagenic in the strains TA100, TA98, TA97a and TA102 and decreased the mutagenicity of aflatoxin B1, benzo(a)pyrene and daunomycin. Chlorophyll and triterpenes were detected in the extract, and they might have contributed to the observed effect. Our data suggest that these medicinal plants possess cancer chemopreventive properties.
Asunto(s)
Antimutagênicos/farmacología , Asteraceae/química , Mutágenos/toxicidad , Salmonella typhimurium/efectos de los fármacos , Salmonella typhimurium/genética , Aflatoxina B1/antagonistas & inhibidores , Aflatoxina B1/toxicidad , Animales , Antibacterianos/antagonistas & inhibidores , Antibacterianos/toxicidad , Benzo(a)pireno/antagonistas & inhibidores , Benzo(a)pireno/toxicidad , Clorofila/toxicidad , Cromatografía en Capa Delgada , Daño del ADN/efectos de los fármacos , Daunorrubicina/antagonistas & inhibidores , Daunorrubicina/toxicidad , Relación Dosis-Respuesta a Droga , Flores/química , Pruebas de Mutagenicidad , Mutación/efectos de los fármacos , Mutación/genética , Extractos Vegetales/farmacología , Extractos Vegetales/toxicidad , Ratas , Triterpenos/toxicidadRESUMEN
In the present study we have developed a simple method to elucidate the melanin binding ability of different chemotherapeutic agents. The anthracyclines, doxorubicin and daunorubicin, or the alkylating agent cisplatin were preincubated with melanin (Sepia). Melanin and free drug was then separated through centrifugation and the cytotoxic effects of corresponding drug were evaluated in a MTT (3-(4,5-dimetyltiazol-2-yl)-2,5-difenyl-tetrazoliumbromide) assay using MOLT-4 cells. Our results show that melanin pretreatment shifted the IC50 value for doxorubicin from 0.06 to 0.97 microM and for daunorubicin from 0.04 to 0.80 microM. In contrast, the IC50 values of cisplatin was not influenced by melanin pre-treatment indicating that cisplatin does not bind to melanin. By comparing equi-active concentrations from concentration-response curves with or without melanin pretreatment an approximate binding capacity of melanin could be estimated. Our results show that melanin binds about 900 nmol/mg doxorubicin and 760 nmol/mg daunorubicin. Chloroquine, which is known to bind to melanin with high affinity, was found to inhibit melanin binding of both daunorubicin and doxorubicin, thereby leading to an increased sensitivity of the anthracyclines. The clinical implications of melanin binding regarding unwanted accumulation of anthracyclines in the skin as well as chemoprotective effects against chemotherapy are discussed.
Asunto(s)
Antineoplásicos/antagonistas & inhibidores , Daunorrubicina/antagonistas & inhibidores , Doxorrubicina/antagonistas & inhibidores , Melaninas/farmacología , Antineoplásicos/metabolismo , Antineoplásicos/toxicidad , Línea Celular Tumoral , Cloroquina/metabolismo , Daunorrubicina/metabolismo , Daunorrubicina/toxicidad , Relación Dosis-Respuesta a Droga , Doxorrubicina/metabolismo , Doxorrubicina/toxicidad , Humanos , Melaninas/metabolismo , Unión ProteicaRESUMEN
The ubiquitous NF-kappaB transcription factor has been reported to inhibit apoptosis and to induce drug resistance in cancer cells. Drug resistance is the major reason for cancer therapy failure and neoplastic cells often develop multiple mechanisms of drug resistance during tumor progression. We observed that NF-kappaB or P-glycoprotein inhibition in the HCT15 colon cancer cells led to increased apoptotic cell death in response to daunomycin treatment. Interestingly, NF-kappaB inhibition through transfection of a plasmid coding for a mutated IkappaB-alpha inhibitor increased daunomycin cell uptake. Indeed, the inhibition of NF-kappaB reduced mdr1 mRNA and P-glycoprotein expression in HCT15 cells. We identified a consensus NF-kappaB binding site in the first intron of the human mdr1 gene and demonstrated that NF-kappaB complexes could bind with this intronic site. Moreover, NF-kappaB transactivates an mdr1 promoter luciferase construct. Our data thus demonstrate a role for NF-kappaB in the regulation of the mdr1 gene expression in cancer cells and in drug resistance.
Asunto(s)
Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/genética , Neoplasias del Colon/genética , Resistencia a Antineoplásicos/fisiología , FN-kappa B/fisiología , Antineoplásicos/farmacología , Secuencia de Bases , Neoplasias del Colon/patología , Cartilla de ADN , Daunorrubicina/antagonistas & inhibidores , Daunorrubicina/farmacocinética , Ensayo de Cambio de Movilidad Electroforética , Regulación Neoplásica de la Expresión Génica/fisiología , Humanos , Intrones , Plásmidos , Regiones Promotoras Genéticas , Activación Transcripcional/fisiología , Células Tumorales CultivadasRESUMEN
Induction of apoptosis by chemotherapeutic drugs involves the sphingomyelin-ceramide (SM-CER) pathway. This signaling is critically dependent on reactive oxygen species (ROS) generation and p53/p56 Lyn activation. In this study, we have investigated the influence of protein kinase C (PKC) zeta overexpression on the SM-CER pathway in U937 human leukemia cell line. We show that PKCzeta overexpression resulted in delayed apoptosis and significant resistance to both 1-beta-D-arabinofuranosylcytosine (ara-C) and daunorubicin (DNR), but there was no significant protection against cell-permeant C(6)-CER. Moreover, PKCzeta overexpression abrogated drug-induced neutral sphingomyelinase stimulation and CER generation by inhibiting ROS production. We further investigated p53/p56 Lyn activation in PKCzeta-overexpressing U937 cells treated with ara-C or DNR. We demonstrate that PKCzeta inhibited p53/p56 Lyn phosphorylation and stimulation in drug- or H(2)O(2)-treated cells, suggesting that p53/p56 Lyn redox regulation is altered in PKCzeta-overexpressing cells. Finally, we show that PKCzeta-overexpressing U937 cells displayed accelerated H(2)O(2) detoxification. Altogether, our study provides evidence for the role of PKCzeta in the negative regulation of drug-induced SM-CER pathway.
Asunto(s)
Antineoplásicos/antagonistas & inhibidores , Sustancias Protectoras/farmacología , Proteína Quinasa C/farmacología , Esfingomielina Fosfodiesterasa/antagonistas & inhibidores , Supervivencia Celular/efectos de los fármacos , Ceramidas/farmacología , Citarabina/antagonistas & inhibidores , Citarabina/farmacología , Daunorrubicina/antagonistas & inhibidores , Daunorrubicina/farmacología , Humanos , Peróxido de Hidrógeno/antagonistas & inhibidores , Peróxido de Hidrógeno/farmacología , Inactivación Metabólica , Oxidación-Reducción , Fosforilación , Proteína Quinasa C/biosíntesis , Proteína Quinasa C/genética , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal/fisiología , Esfingomielina Fosfodiesterasa/metabolismo , Transfección , Proteína p53 Supresora de Tumor/metabolismo , Células U937 , Familia-src Quinasas/metabolismoRESUMEN
Different preparations of chamomile (Matricaria chamomilla) are used to treat various diseases, including inflammation and cancer; however, no studies on the plant's antigenotoxic capacity have been made. The aim of the present work was to determine the inhibitory effect of the chamomile essential oil (CO), on the sister chromatid exchanges (SCEs) produced by daunorubicin and methyl methanesulfonate (MMS) in mouse bone marrow cells. CO was analyzed and was found to contain 13 compounds, mainly bisabolol and its oxides, chamazulene, farnesene, germacrene and other sesquiterpenes. Initially, a toxic and a genotoxic analysis of CO were made; both showed negative results. To determine whether CO can inhibit the mutagenic effects induced by daunorubicin, one group of mice was administered corn oil, another group was treated with the mutagen (10 mg/kg), a third group was treated with 500 mg/kg of CO; three other groups were treated first with CO (5, 50 and 500 mg/kg) and then with 10 mg/kg of daunorubicin. In the case of MMS, the experimental groups consisted of the following: the negative control group which was administered corn oil, a group treated with 25 mg/kg of MMS, a group treated with 1000 mg/kg of CO, and three groups treated first with CO (250, 500 and 1000 mg/kg) and then with MMS (25 mg/kg). The results indicated a dose-dependent inhibitory effect on the SCEs formed by both mutagens. In the case of daunorubicin, a statistically significant result was observed in the three tested doses: from the lowest to the highest dose, the inhibitory values corresponded to 25.7, 63.1 and 75.5%. No alterations were found with respect to the cellular proliferation kinetics, but a reduction in the mitotic index was detected. As regards MMS, the inhibitory values were 24.8, 45.8 and 60.6%; no alterations were found in either the cellular proliferation kinetics or in the mitotic indices. Our results suggest that CO may be an effective antimutagen that could be considered for further study.
Asunto(s)
Antibióticos Antineoplásicos/efectos adversos , Antineoplásicos Alquilantes/efectos adversos , Células de la Médula Ósea/efectos de los fármacos , Manzanilla , Daunorrubicina/efectos adversos , Metilmetanosulfonato/efectos adversos , Intercambio de Cromátides Hermanas/efectos de los fármacos , Animales , Antibióticos Antineoplásicos/antagonistas & inhibidores , Antineoplásicos Alquilantes/antagonistas & inhibidores , Células de la Médula Ósea/fisiología , División Celular/efectos de los fármacos , Daunorrubicina/antagonistas & inhibidores , Dosificación Letal Mediana , Masculino , Metilmetanosulfonato/antagonistas & inhibidores , Ratones , Índice MitóticoRESUMEN
The syntheses and SAR studies of various quinazolinone compounds are described for the dual inhibition of Pgp and MRP1 in multidrug resistance.
Asunto(s)
Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/antagonistas & inhibidores , Resistencia a Múltiples Medicamentos , Quinazolinas/síntesis química , Antibióticos Antineoplásicos/antagonistas & inhibidores , Antibióticos Antineoplásicos/farmacocinética , Antineoplásicos/antagonistas & inhibidores , Antineoplásicos/farmacocinética , Daunorrubicina/antagonistas & inhibidores , Daunorrubicina/farmacocinética , Doxorrubicina/antagonistas & inhibidores , Doxorrubicina/farmacocinética , Interacciones Farmacológicas , Humanos , Concentración 50 Inhibidora , Quinazolinas/química , Quinazolinas/farmacología , Relación Estructura-Actividad , Células Tumorales CultivadasRESUMEN
Fluphenazine, an antipsychotic drug that belongs to the phenothiazine family, reduced the genotoxicity of direct- and indirect-acting mutagens in the Ames test, both in the presence and in the absence of promutagen-activating S9 fraction. In short-term tests on human lymphocytes, the inhibitory effect of fluphenazine on the genotoxicity of standard mutagens was strongest in the cytokinesis-blocked micronucleus assay and in the thioguanine resistance test, and weakest in the sister chromatid exchange test. Fluphenazine also considerably reduced the level of free radicals estimated in in vitro samples of human granulocytes. The results suggest that, in the range of the tested concentrations, fluphenazine could be considered for use to prevent the genotoxicity of daunorubicin, methyl methanesulfonate, benzo[a]pyrene, and mitomycin C. Reduction in the level of free radicals appears to be an important mechanism of the antimutagenic action of fluphenazine.
Asunto(s)
Antimutagênicos/farmacología , Flufenazina/farmacología , Pruebas de Mutagenicidad/métodos , Adulto , Benzo(a)pireno/antagonistas & inhibidores , Benzo(a)pireno/toxicidad , Células Cultivadas , Daunorrubicina/antagonistas & inhibidores , Daunorrubicina/toxicidad , Humanos , Linfocitos/efectos de los fármacos , Masculino , Metilmetanosulfonato/antagonistas & inhibidores , Metilmetanosulfonato/toxicidad , Pruebas de Micronúcleos , Persona de Mediana Edad , Mitomicina/antagonistas & inhibidores , Mitomicina/toxicidad , Mutágenos/toxicidad , Intercambio de Cromátides Hermanas/efectos de los fármacosRESUMEN
Accidental extravasation of anthracyclines is a feared complication. Present treatment consists of local cooling and extensive surgical debridement, which often results in severe morbidity. All clinically important anthracyclines are topoisomerase II poisons that are antagonized by topoisomerase II catalytic inhibitors such as dexrazoxane. Therefore, we investigated whether dexrazoxane protects against extravasation lesions caused by anthracyclines. B6D2F1 mice received s.c. daunorubicin, doxorubicin, or idarubicin followed by systemic treatment with dexrazoxane or saline. One single systemic dose of dexrazoxane immediately after s.c. administration of doxorubicin, daunorubicin, or idarubicin reduced the tissue lesions (expressed as area under the curve of wound size times duration) by 96% (P < 0.0001), 70% (P < 0.0001), and 87% (P = 0.0004), respectively. Moreover, the treatment resulted in a statistically significant reduction in the fraction of mice with wounds as well as the duration of wounds. The induction of wounds was dose-dependent, as was the degree of protection by dexrazoxane. Dexrazoxane could be administered up to 3 h after the anthracycline without loss of protection. Triple-dosage of dexrazoxane tended to be more effective than a single injection. Dexrazoxane had no effect on lesions induced by hydrogen peroxide. This is the first report of use of a topoisomerase II catalytic inhibitor such as dexrazoxane in the treatment of anthracycline extravasation injuries. These convincing preclinical data represent a novel nontoxic approach that can easily be implemented into the clinical handling of accidental extravasation of anthracyclines.
Asunto(s)
Antibióticos Antineoplásicos/toxicidad , Extravasación de Materiales Terapéuticos y Diagnósticos/tratamiento farmacológico , Razoxano/farmacología , Animales , Antibióticos Antineoplásicos/antagonistas & inhibidores , Daunorrubicina/antagonistas & inhibidores , Daunorrubicina/toxicidad , Relación Dosis-Respuesta a Droga , Doxorrubicina/antagonistas & inhibidores , Doxorrubicina/toxicidad , Inhibidores Enzimáticos/farmacología , Extravasación de Materiales Terapéuticos y Diagnósticos/complicaciones , Extravasación de Materiales Terapéuticos y Diagnósticos/etiología , Femenino , Idarrubicina/antagonistas & inhibidores , Idarrubicina/toxicidad , Ratones , Enfermedades de la Piel/inducido químicamente , Enfermedades de la Piel/prevención & control , Inhibidores de Topoisomerasa IIRESUMEN
P-glycoprotein (Pgp)-mediated drug efflux is a major factor contributing to the variance of absorption and distribution of many drugs. A simple and reliable in vitro method to identify inhibitors of Pgp helps to prevent the potential of drug interactions. Using daunorubicin as a fluorescent marker and vanadate as a positive control compound, a functional flow cytometry method for assessing the ability of a drug to inhibit Pgp-mediated drug efflux from CR1R12 multidrug-resistant cells has been evaluated. Quantitation of the relative fluorescence was used to compare potency of individual inhibitors. Known Pgp inhibitors, such as cyclosporin A, nicardipine, verapamil, quinidine, terfenadine, tamoxifen, and vinblastine were demonstrated to inhibit the Pgp-mediated efflux of daunorubicin. Cyclosporin A and terfenadine were the most potent inhibitors among the compounds tested. Tetraphenylphosphonium and alpha-tocopherol had little inhibitory effect. Progesterone produced significant inhibition at relatively high concentrations. This study demonstrated that this in vitro flow cytometry method is a simple, sensitive, and quantitative tool to assess the capacity of a drug to inhibit Pgp transporters, and is useful for screening or identifying inhibitors of Pgp as well as evaluation of potential for drug interactions.
Asunto(s)
Subfamilia B de Transportador de Casetes de Unión a ATP/antagonistas & inhibidores , Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Antibióticos Antineoplásicos/antagonistas & inhibidores , Antibióticos Antineoplásicos/farmacología , Bloqueadores de los Canales de Calcio/farmacología , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Daunorrubicina/antagonistas & inhibidores , Daunorrubicina/farmacología , Resistencia a Múltiples Medicamentos , Resistencia a Antineoplásicos , Citometría de Flujo , Humanos , Microscopía Fluorescente , Células Tumorales Cultivadas , Vanadatos/farmacología , Verapamilo/farmacologíaRESUMEN
Anthracyclines serve as a valuable tool in chemotherapy, but their usefulness is often limited by the occurrence of resistance mechanisms in tumor cells. Resistance of tumor cells is a multifactorial event, where several mechanisms act concurrently, including drug efflux and enzymatic drug inactivation. Liposomal encapsulation of anthracyclines has been discussed as a successful regimen to overcome drug resistance. Our investigations were carried out on a daunorubicin (DRC) sensitive breast cancer cell line and two DRC resistant sublines generated thereof. In all three cell lines, the extent of DRC detoxification via carbonyl reduction to daunorubicinol (DRCOL) was determined. In addition, rutin, the most effective inhibitor of carbonyl reducing enzymes, was tested to affect DRCOL formation. DRC IC(50) values were determined in relation to several combinations of DRC administration, (a) liposomal encapsulated DRC, (b) addition of verapamil (inhibitor of drug efflux), (c) addition of rutin (inhibitor of DRC carbonyl reduction). We could show that DRC sensitive and resistant breast cancer cell lines are able to catalyze DRC detoxification via carbonyl reduction to DRCOL. Rutin was shown to inhibit this reaction, but could not serve as an enhancer of DRC toxicity in MTT tests. Verapamil was effective only in resistant cells due to the overexpression of P-glycoprotein 170. Liposomal encapsulation of DRC did not show the expected increase in DRC toxicity in the present tumor cell model.
Asunto(s)
Antibióticos Antineoplásicos/toxicidad , Daunorrubicina/toxicidad , Antibióticos Antineoplásicos/administración & dosificación , Antibióticos Antineoplásicos/antagonistas & inhibidores , Neoplasias de la Mama/patología , Daunorrubicina/administración & dosificación , Daunorrubicina/antagonistas & inhibidores , Portadores de Fármacos , Composición de Medicamentos , Resistencia a Antineoplásicos , Humanos , Liposomas , Rutina/farmacología , Sales de Tetrazolio , Tiazoles , Células Tumorales CultivadasRESUMEN
The mechanisms of the smooth muscle contractile action of daunorubicin were investigated using guinea-pig aortae, and the involvement of the Ca2+ entry mechanism was compared among different smooth-muscle preparations. In the aorta, daunorubicin showed a concentration-dependent contractile action at concentrations of 10-200 microM. The contractile response to daunorubicin was completely dependent on extracellular Ca2+, but only slightly sensitive to verapamil or nifedipine. Trifluoperazine abolished the contraction by daunorubicin, but no significant effect was noted with amiloride, phentolamine, indomethacin or staurosporine. The order of potency (sensitivity) for daunorubicin-induced smooth muscle contraction was oesophagus = gall bladder = iliac artery > bronchus = aorta, while that of maximum reactivity was iliac artery = aorta > bronchus = oesophagus = gall bladder. In the portal vein, daunorubicin showed no contractile action. Although the smooth muscle contraction induced by daunorubicin was strongly dependent on extracellular Ca2+ in the aorta, iliac artery, bronchus, oesophagus and gall bladder, its sensitivity to verapamil varied among the different smooth muscle preparations, with the sensitivity being iliac artery = gall bladder > bronchus = oesophagus > aorta. These results suggest that daunorubicin has contractile action on various kinds of smooth muscle, mainly via the transplasmalemmal Ca2+ entry mechanism, but the degree of involvement of the voltage-dependent Ca2+ channel differs among the different smooth muscle preparations.
Asunto(s)
Antibióticos Antineoplásicos/farmacología , Calcio/fisiología , Daunorrubicina/farmacología , Contracción Muscular/efectos de los fármacos , Músculo Liso/fisiología , Animales , Bloqueadores de los Canales de Calcio/farmacología , Daunorrubicina/antagonistas & inhibidores , Cobayas , Técnicas In Vitro , Masculino , Músculo Liso/efectos de los fármacos , Músculo Liso Vascular/efectos de los fármacos , Músculo Liso Vascular/fisiología , Cloruro de Potasio/farmacología , Trifluoperazina/farmacología , Verapamilo/farmacologíaRESUMEN
The purpose of this study was to characterize the transport mechanisms involved in the renal tubular secretion of quinolones. The contribution of P-glycoprotein to the transport of quinolones was elucidated using a kidney epithelial cell line, LLC-PK1, and its transfectant derivative cell line, LLC-GA5-COL150, which expresses human P-glycoprotein on the apical membrane. The transcellular transport of levofloxacin, a quinolone antibacterial drug, from the basolateral to apical side was increased in LLC-GA5-COL150 compared with that in LLC-PK1 monolayers. The apparent Michaelis constant and maximum velocity values for the saturable transcellular transport of levofloxacin from the basolateral to apical side in LLC-GA5-COL150 monolayers were 3.0 mM and 45 nmol/mg protein per 15 min, respectively. The increased basolateral-to-apical transport in LLC-GA5-COL150 monolayers was completely inhibited by cyclosporin A and quinidine to the level observed in LLC-PK1 monolayers. In addition, 3 mM levofloxacin inhibited the basolateral-to-apical transport of daunorubicin in LLC-GA5-COL150 monolayers. The basolateral-to-apical transport of another quinolone antibacterial drug, DU-6859a, in LLC-GA5-COL150 monolayers greatly exceeded than that in LLC-PK1 monolayers, and was inhibited by levofloxacin. These findings suggest that quinolone antibacterial drugs are transported by P-glycoprotein, and that P-glycoprotein may contribute at least in part to the renal tubular secretion of quinolones.
Asunto(s)
Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Antiinfecciosos/farmacocinética , Fluoroquinolonas , Riñón/metabolismo , Levofloxacino , Ofloxacino/farmacocinética , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/genética , Animales , Transporte Biológico , Daunorrubicina/antagonistas & inhibidores , Daunorrubicina/farmacocinética , Células Epiteliales , Epitelio/metabolismo , Humanos , Riñón/citología , Células LLC-PK1 , Quinolonas/farmacocinética , PorcinosRESUMEN
The clinical use of anthracyclines and related antitumor agents is limited by their cumulative dose-related cardiac toxicity. Cardioxane (ICRF-187) is an agent that has been recommended to block selectively this toxicity which e.g. limits the use of daunorubicin (DNR) in doses higher than 550-700 mg/m2. We decided to use cardioxane in patients with relapsed acute myeloid leukemias (AML) who have previously been treated with DNR doses above 500 mg/m2. Seven patients with relapsed AML received cardioxane 30 min before DNR or mitozantrone (MTZ) in doses 8-13x higher than DNR or 40-60x higher than MTZ. Two patients received anthracyclines cumulative doses corresponding to more than 1300 mg/m2 and 1000 mg/m2 of DNR, respectively, without any signs of cardiac toxicity. The other 5AML patients in relapse received 1-3 chemotherapy cycles with cardioxane. Their total cumulative doses of DNR were 550-750 mg/m2 and their left ventricular ejection fraction remained above 50% as were their pretreatment values. Cardioxane seems to be a useful cardioprotective agent in relapsed AML which enables further treatment with anthracyclines.
Asunto(s)
Antibióticos Antineoplásicos/antagonistas & inhibidores , Antineoplásicos/farmacología , Fármacos Cardiovasculares/farmacología , Daunorrubicina/antagonistas & inhibidores , Corazón/efectos de los fármacos , Leucemia Mieloide/tratamiento farmacológico , Razoxano/farmacología , Enfermedad Aguda , Antibióticos Antineoplásicos/efectos adversos , Citarabina/uso terapéutico , Daunorrubicina/efectos adversos , Femenino , Humanos , Masculino , Persona de Mediana Edad , RecurrenciaRESUMEN
Daunomycin (DM) is one of the most important antitumor agents. However, the cardiotoxicity of DM limits it's clinical use. We have made an ionic complex with heparin to decrease the cardiotoxicity. Cardiotoxicities of DM and DM-heparin complex were compared in hamsters. On the electrocardiogram (ECG), two of the four hamsters given DM showed the serious abnormality, bidirectional ventricular premature contraction, while the hamsters given DM-heparin or saline had no abnormalities. On pathological examination, cardiac tissue in hamsters given DM showed deposition of basophilic materials, mild eosinophilic change of myofibrils and microvascuolization, whereas no change was observed in hamsters given DM-heparin complex or saline. Acute toxic effects on survival rates and body weights were more profound in DM-infused mice than in DM-heparin-infused mice. DM and DM-heparin complex showed similar anticancer activity both in vivo and in vitro. Thus, the present study suggests that the DM-heparin complex may attenuate the cardiotoxicity of DM without affecting it's antitumor effect in humans.