RESUMEN
The use of electrochemotherapy (ECT) is a well-established technique to increase the cellular uptake of cytotoxic agents within certain cancer treatment strategies. The study of the mechanisms that take part in this complex process is of high interest to gain a deeper knowledge of it, enabling the improvement of these strategies. In this work, we present a coupled multi-physics electroporation model based on a related previous one, to describe the effect of a set of electric pulses on cisplatin transport across the plasma membrane. The model applies a system of partial differential equations that includes Poisson's equation for the electric field, Nernst-Planck's equation for species transport, Maxwell's tensor and mechanical equilibrium equation for membrane deformation and Smoluchowski's equation for pore creation dynamics. Our numerical results were compared with previous numerical and experimental published data with good qualitative and quantitative agreement. These results indicate that pore aperture is favored at the cell poles by the electric field and mechanical stress forces, giving support to the dominant hypothesis of hydrophilic pore creation as the main mechanism of drug entry during an ECT treatment.
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Antineoplásicos/administración & dosificación , Cisplatino/administración & dosificación , Electroquimioterapia , Neoplasias/tratamiento farmacológico , Antineoplásicos/farmacocinética , Cisplatino/farmacocinética , Electroquimioterapia/métodos , Análisis de Elementos Finitos , Humanos , Modelos BiológicosRESUMEN
In the present work, the preparation, characterisation, and efficiency of two different silica nanostructures as release vehicles of Cisplatin are reported. The 1-hexadeciltrimethyl-ammonium bromide templating agent was used to obtain mesoporous silica nanoparticles which were later loaded with Cisplatin. While sol-gel silica was very fast prepared using an excess of acetic acid during the hydrolysis-condensation reactions of tetraethylorthosilicate and at the same time the Cisplatin was added. Several physicochemical techniques including spectroscopies, electronic microscopy, X-ray diffraction, N2 adsorption-desorption were used to characterise the silica nanostructures. An in vitro Cisplatin release test was carried out using artificial cerebrospinal fluid. Finally, the toxicity of all silica nanostructures was tested using the C6 cancer cell line. The spectroscopic results showed the suitable stabilisation of Cisplatin into the two different silica nanostructures. A large surface area was obtained for the mesoporous silica nanoparticles, while low areas were obtained in the silica nanoparticles. Cisplatin was released faster from mesoporous silica channels than from inside of aggregates nanoparticles silica. Cisplatin alone, as well as, cisplatin released from both silica nanostructures exerted a toxic effect on cancer cells. In contrast, both silica structures without the drug did not exert any toxic effect.
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Neoplasias Encefálicas/metabolismo , Cisplatino , Portadores de Fármacos , Nanopartículas/química , Dióxido de Silicio/química , Animales , Línea Celular Tumoral , Cisplatino/química , Cisplatino/farmacocinética , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , RatasRESUMEN
With the aim improving drug delivery, liposomes have been employed as carriers for chemotherapeutics achieving promising results; their co-encapsulation with magnetic nanoparticles is evaluated in this work. The objective of this study was to examine the physicochemical characteristics, the pharmacokinetic behaviour, and the efficacy of pegylated liposomes loaded with cisplatin and magnetic nanoparticles (magnetite) (Cis-MLs). Cis-MLs were prepared by a modified reverse-phase evaporation method. To characterize their physicochemical properties, an evaluation was made of particle size, ζ-potential, phospholipid and cholesterol concentration, phase transition temperature (Tm), the encapsulation efficiency of cisplatin and magnetite, and drug release profiles. Additionally, pharmacokinetic studies were conducted on normal Wistar rats, while apoptosis and the cytotoxic effect were assessed with HeLa cells. We present a method for simultaneously encapsulating cisplatin at the core and also embedding magnetite nanoparticles on the membrane of liposomes with a mean vesicular size of 104.4 ± 11.5 nm and a ζ-potential of -40.5 ± 0.8 mV, affording a stable formulation with a safe pharmacokinetic profile. These liposomes elicited a significant effect on cell viability and triggered apoptosis in HeLa cells.
Asunto(s)
Cisplatino/farmacología , Sistemas de Liberación de Medicamentos , Nanopartículas de Magnetita/química , Neoplasias/tratamiento farmacológico , Animales , Supervivencia Celular/efectos de los fármacos , Cisplatino/química , Cisplatino/farmacocinética , Liberación de Fármacos , Células HeLa , Humanos , Liposomas/química , Liposomas/farmacología , Neoplasias/patología , Polietilenglicoles/química , Polietilenglicoles/farmacología , Ratas , Ratas WistarRESUMEN
Cisplatin (CDDP) chemotherapy associated with radiation (RT) has been used in advanced head and neck squamous cell carcinoma (HNSCC) patients, and vomiting is a common side effect during treatment. This prospective study aimed to identify the roles of GSTM1 and GSTT1 (presents or nulls), GSTP1 c.313A>G, XPC c.2815A>C, XPD c.934G>A and c.2251A>C, XPF c.2505T>C, ERCC1 c.354C>T, MLH1 c.-93G>A, MSH2 c.211 + 9C>G, MSH3 c.3133G>A, EXO1 c.1765G>A, TP53 c.215G>C, CASP3 c.-1191A>G and c.-1168G>T, CASP9 c.-1339A>G, CASP8 c.-937_-932delAGTAAG, FAS c.-1378G>A and c.-671A>G, and FASL c.-157-687C>T single nucleotide polymorphisms, involved in CDDP metabolism, in vomiting severity in 88 HNSCC patients treated with CDDP and RT. Ondansetron and dexamethasone were administered as anti-emetic therapy. Patients with GSTP1 c.313AG or GG genotype alone and combined with XPD c.934GA or AA, XPF c.2505TC or CC, and CASP9 c.-1339AG or GG genotypes had 4.28, 5.00, 5.45 and 5.38 more chances of presenting moderate/severe vomiting than patients with others genotypes. Our data suggest, for the first time, that inherited abnormality in apoptosis pathway alone or combined with inherited abnormalities in DNA repair pathway, is capable of modulating emesis in HNSCC patients under CDDP chemoradiation and may be used for selecting patients who should receive pre-emptive anti-emetic therapy.
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Antineoplásicos/efectos adversos , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/terapia , Quimioradioterapia/efectos adversos , Cisplatino/efectos adversos , Predisposición Genética a la Enfermedad/genética , Neoplasias de Cabeza y Cuello/genética , Neoplasias de Cabeza y Cuello/terapia , Vómitos/inducido químicamente , Vómitos/genética , Adulto , Anciano , Antieméticos/uso terapéutico , Antineoplásicos/farmacocinética , Carcinoma de Células Escamosas/complicaciones , Cisplatino/farmacocinética , Femenino , Estudio de Asociación del Genoma Completo , Genotipo , Neoplasias de Cabeza y Cuello/complicaciones , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo Genético/genética , Polimorfismo de Nucleótido Simple , Estudios Prospectivos , Factores de Riesgo , Carcinoma de Células Escamosas de Cabeza y Cuello , Vómitos/tratamiento farmacológicoRESUMEN
BACKGROUND: Cisplatin is a high-potency anticancer agent; however, it causes significant adverse drug reactions (ADRs). Potential pharmacokinetic markers must be studied to predict or prevent cisplatin-induced ADRs and achieve better prognosis. This study was designed to investigate the relationship between ADRs and kinetics of cisplatin excretion in the urine of patients undergoing high-dose cisplatin chemotherapy and radiotherapy for head and neck cancer. METHODS: Outpatients with head and neck cancer received a first cycle of high-dose cisplatin chemotherapy (80-100 mg/m2) concurrent to radiotherapy. ADRs (haematological, renal, and gastrointestinal reactions) were classified based on severity by National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE, version 4, grade 0-4). The kinetics of cisplatin excretion in urine was evaluated by high-performance liquid chromatography over three time periods: 0-12, 12-24, and 24-48 h after the administration of cisplatin. Spearman Correlation test and regression analysis were performed to assess the relationship between ADRs and cisplatin excretion in the urine. RESULTS: In total, 59 patients with a mean age of 55.6 ± 9.4 years were analysed; most patients were male (86.4%), white (79.7%), and with pharyngeal tumours in advanced stages (66.1%). The most frequently observed ADRs were anaemia (81.4%), lymphopenia (78%), and nausea (64.4%); mostly grades 1 and 2 of toxicity. The mean cisplatin excretion was 70.3 ± 64.4, 7.3 ± 6.3, and 5 ± 4 µg/mg creatinine at 0-12, 12-24, and 24-48 h, respectively. Statistical analysis showed that the amount of cisplatin excreted did not influence the severity of ADRs. CONCLUSIONS: The most frequent ADRs were anaemia, lymphopenia, and nausea. Grades 1 and 2 were the severities for most ADRs. The period over which the highest cisplatin excretion observed was 0-12 h after chemotherapy, and cisplatin excretion could not predict toxicity.
Asunto(s)
Antineoplásicos/efectos adversos , Cisplatino/efectos adversos , Neoplasias de Cabeza y Cuello/terapia , Anemia/inducido químicamente , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapéutico , Antineoplásicos/orina , Quimioradioterapia/métodos , Cisplatino/farmacocinética , Cisplatino/uso terapéutico , Cisplatino/orina , Femenino , Humanos , Linfopenia/inducido químicamente , Masculino , Persona de Mediana Edad , Náusea/inducido químicamente , Neoplasias Faríngeas/terapia , Estudios ProspectivosRESUMEN
Cisplatin is a drug widely used in chemotherapy that frequently causes severe renal dysfunction. Organic transporters have an important role to control the absorption and excretion of cisplatin in renal cells. Deletion and blockage of kinin B1 receptor has already been show to protect against cisplatin-induced acute kidney injury. To test whether it exerts its protective function by modulating the organic transporters in kidney, we studied kinin B1 receptor knockout mice and treatment with a receptor antagonist at basal state and in presence of cisplatin. Cisplatin administration caused downregulation of renal organic transporters; in B1 receptor knockout mice, this downregulation of organic transporters in kidney was absent; and treatment by a B1 receptor antagonist attenuated the downregulation of the transporter MATE-1. Moreover, kinin B1 receptor deletion and blockage at basal state resulted in higher renal expression of MATE-1. Moreover we observed that kinin B1 receptor deletion and blockage result in less accumulation of platinum in renal tissue. Thus, we propose that B1 receptor deletion and blockage protect the kidney from cisplatin-induced acute kidney injury by upregulating the expression of MATE-1, thereby increasing the efflux of cisplatin from renal cells.
Asunto(s)
Lesión Renal Aguda/prevención & control , Antagonistas del Receptor de Bradiquinina B1/farmacología , Cisplatino/farmacocinética , Proteínas de Transporte de Catión Orgánico/genética , Receptor de Bradiquinina B1/genética , Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/genética , Animales , Cisplatino/administración & dosificación , Cisplatino/efectos adversos , Modelos Animales de Enfermedad , Regulación de la Expresión Génica/efectos de los fármacos , Técnicas de Inactivación de Genes , Riñón/efectos de los fármacos , Riñón/metabolismo , Masculino , Ratones , Proteínas de Transporte de Catión Orgánico/metabolismo , Receptor de Bradiquinina B1/metabolismoRESUMEN
Cisplatin (Cisp) is an effective antitumor drug; however, it causes severe nephrotoxicity. Minimization of renal toxicity is essential, but the interference of nephroprotective agents, particularly antioxidants, with the antitumor activity of cisplatin is a general concern. We have recently demonstrated that the anti-hypertensive and antioxidant drug carvedilol (CV) protects against the renal damage and increases the survival of tumor-bearing mice without impairing the tumor reduction by cisplatin. So far, reports on the antioxidant mechanism of CV are controversial and there are no data on the impact of CV on the antitumor mechanisms of cisplatin. Therefore, this study addresses the effect of CV on mechanisms underlying the tumor control by cisplatin. CV did not interfere with the biodistribution or the genotoxicity of cisplatin. We also addressed the antioxidant mechanisms of CV and demonstrated that it does not neutralize free radicals, but is an efficient chelator of ferrous ions that are relevant catalyzers in cisplatin nephrotoxicity. The present data suggest that oxidative damage and genotoxicity play different roles in the toxicity of cisplatin on kidneys and tumors and therefore, some antioxidants might be safe as chemoprotectors. Altogether, our studies provide consistent evidence of the beneficial effect of CV on animals treated with cisplatin and might encourage clinical trials.
Asunto(s)
Antineoplásicos/toxicidad , Antioxidantes/uso terapéutico , Carbazoles/uso terapéutico , Cisplatino/toxicidad , Riñón/efectos de los fármacos , Propanolaminas/uso terapéutico , Sarcoma 180/tratamiento farmacológico , Animales , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Antioxidantes/farmacología , Carbazoles/farmacología , Carvedilol , Cisplatino/farmacocinética , Cisplatino/farmacología , Riñón/patología , Masculino , Propanolaminas/farmacología , Sarcoma 180/patología , Distribución TisularRESUMEN
Both types of diabetes are associated with higher incidence of some types of cancer. Treating cancer in diabetic patients without aggravating diabetes-related complications is a challenge for clinicians. Additionally, little is known about how diabetes affects the treatment of cancer. One of the most effective chemotherapeutic drugs is cisplatin, which is nephrotoxic. Studies suggest that diabetes acts as a protective factor against the nephrotoxicity of cisplatin, but the mechanisms involved have not been elucidated yet. This renal protection has been attributed to decreased accumulation of cisplatin in the kidneys, which could be associated with deficient active transport of proximal tubular cells or to pharmacokinetic alterations caused by diabetes. However, it is uncertain if diabetes also compromises the antitumor activity of cisplatin. To address this issue, we developed a mouse model bearing cisplatin-induced nephrotoxicity, Sarcoma 180 and streptozotocin-induced diabetes. Four groups of treatment were defined: (i) control, (ii) diabetic, (iii) cisplatin and (iv) diabetic treated with cisplatin. The following parameters were evaluated: renal function, oxidative stress, apoptosis, renal histopathology, tumor remission, survival rate, genotoxicity and platinum concentration in tumor and several organs. Results indicate that diabetes protects against the renal damage induced by cisplatin, while also compromises its antitumor effectiveness. This is the first study to demonstrate this effect.
Asunto(s)
Antineoplásicos/farmacocinética , Antineoplásicos/uso terapéutico , Cisplatino/farmacocinética , Cisplatino/uso terapéutico , Diabetes Mellitus Experimental/complicaciones , Enfermedades Renales/inducido químicamente , Sarcoma 180/complicaciones , Sarcoma 180/tratamiento farmacológico , Animales , Antineoplásicos/toxicidad , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Cisplatino/toxicidad , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patología , Riñón/efectos de los fármacos , Riñón/metabolismo , Riñón/patología , Enfermedades Renales/metabolismo , Enfermedades Renales/patología , Masculino , Ratones , Estrés Oxidativo/efectos de los fármacos , Sarcoma 180/metabolismo , Sarcoma 180/patología , Distribución TisularRESUMEN
Recent studies using long-circulating and pH-sensitive liposomes containing cisplatin (SpHL-CDDP) have resulted in a formulation with improved pharmacokinetic, toxicity and tumor localization properties. In this study, SpHL-CDDP were prepared in both laboratory and pilot scales. This study evaluated the possibility of using the dehydration-rehydration method, as well as using alternative organic solvents (ethyl acetate/ethanol mixtures at 2:1 and 1:1 volume ratios), for the preparation of liposomes by the reverse-phase evaporation (REV) method. The influence of different concentrations of cisplatin (CDDP) (2.0, 1.0, 0.5 and 0.25 mg/mL) on the entrapment percentage and size of SpHL-CDDP was also investigated. In addition, carbohydrates were tested as cryoprotectants in a freeze-thaw study as a pretest to screen the type to be used in the freeze-drying process. A decrease in the encapsulation percentage of CDDP and an increase in the vesicle diameter could be observed for both liposome formulations prepared with ethyl acetate:ethanol mixtures, as compared with REV liposomes prepared with ethyl ether. It is important to note that after applying either quick or slow cooling, the mean diameter of SpHL (empty liposomes) proved to be similar when in the presence of cryoprotectants. In sum, the optimal processing conditions were achieved when using a 0.5 mg/mL CDDP solution, ethyl ether and the REV method, resulting in liposomal dispersions of mean diameters and homogeneities that were deemed suitable for intravenous administration.
Asunto(s)
Cisplatino/administración & dosificación , Solventes/farmacología , Acetatos/química , Acetatos/farmacología , Química Farmacéutica/métodos , Cisplatino/farmacocinética , Crioprotectores/farmacología , Etanol/química , Etanol/farmacología , Éter/química , Éter/farmacología , Liofilización , Liposomas/síntesis química , Tamaño de la Partícula , Fosfatidiletanolaminas/administración & dosificación , Proyectos Piloto , Polietilenglicoles/administración & dosificaciónRESUMEN
The chemotherapeutic agent cisplatin (cDDP) is widely used to treat a variety of solid and hematological tumors. However, cDDP exerts severe side effects, such as nephrotoxicity, neurotoxicity, and bone-marrow suppression. The use of some dietary compounds to protect organs that are not targets in association with chemotherapy has been encouraged. This study evaluated the protective effects of chlorophyll b (CLb) on DNA damage induced by cDDP by use of single-cell gel electrophoresis (SCGE) assays. Further, this investigation also determined platinum (Pt) and magnesium (Mg) bioaccumulation in mice tissues after treatment with CLb alone and/or in association of cDDP (simultaneous treatment) by inductively coupled plasma-mass spectroscopy (ICP-MS). All parameters were studied in peripheral blood cells (PBC), kidneys, and liver of mice after administration of CLb (0.2 or 0.5 mg/kg of body weight [b.w.]), cDDP (6 mg/kg b.w.), and the combination CLb 0.2 plus cDDP or CLb 0.5 plus cDDP. Pt accumulation in liver and kidneys was higher than that found in PBC, while DNA damage was higher in kidneys and liver than in PBC. Further, treatment with CLb alone did not induce DNA damage. Evidence indicates that genotoxic effects produced by cDDP may not be related to Pt accumulation and distribution. In combined treatments, CLb decreased DNA damage in tissues, but the PT contents did not change and these treatments also showed that CLb may be an important source of Mg. Thus, our results indicate that consumption of CLb-rich foods may diminish the adverse health effects induced by cDDP exposure.
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Antimutagênicos/farmacología , Antineoplásicos/toxicidad , Clorofila/farmacología , Cisplatino/toxicidad , Daño del ADN/efectos de los fármacos , Animales , Antineoplásicos/farmacocinética , Cisplatino/farmacocinética , Ensayo Cometa , Femenino , Riñón/efectos de los fármacos , Riñón/metabolismo , Hígado/efectos de los fármacos , Hígado/metabolismo , Compuestos de Magnesio/metabolismo , Masculino , Ratones , Compuestos de Platino/metabolismoRESUMEN
Magnetic fluid hyperthermia as a cancer treatment method is an attractive alternative to other forms of hyperthermia. It is based on the heat released by magnetic nanoparticles subjected to an alternating magnetic field. Recent studies have shown that magnetic fluid hyperthermia-treated cells respond significantly better to chemotherapeutic treatment compared with cells treated with hot water hyperthermia under the same temperature conditions. We hypothesized that this synergistic effect is due to an additional stress on the cellular membrane, independent of the thermal heat dose effect that is induced by nanoparticles exposed to an alternating magnetic field. This would result in an increase in Cis-diammine-dichloroplatinum (II) (cDDP, cisplatin) uptake via passive transport. To test this hypothesis, we exposed cDDP-treated cells to extracellular copper in order to hinder the human cell copper transporter (hCTR1)-mediated active transport of cDDP. This, in turn, can increase the passive transport of the drug through the cell membrane. Our results did not show statistically significant differences in surviving fractions for cells treated concomitantly with magnetic fluid hyperthermia and cDDP, in the presence or absence of copper. Nonetheless, significant copper-dependent variations in cell survival were observed for samples treated with combined cDDP and hot water hyperthermia. These results correlated with platinum uptake studies, which showed that cells treated with magnetic fluid hyperthermia had higher platinum uptake than cells treated with hot water hyperthermia. Changes in membrane fluidity were tested through fluorescence anisotropy measurements using trimethylamine-diphenylhexatriene. Additional uptake studies were conducted with acridine orange and measured by flow cytometry. These studies indicated that magnetic fluid hyperthermia significantly increases cell membrane fluidity relative to hot water hyperthermia and untreated cells, and hence this could be a factor contributing to the increase of cDDP uptake in magnetic fluid hyperthermia-treated cells. Overall, our data provide convincing evidence that cell membrane permeability induced by magnetic fluid hyperthermia is significantly greater than that induced by hot water hyperthermia under similar temperature conditions, and is at least one of the mechanisms responsible for potentiation of cDDP by magnetic fluid hyperthermia in Caco-2 cells.
Asunto(s)
Cisplatino/farmacología , Neoplasias del Colon/terapia , Hipertermia Inducida/métodos , Nanopartículas de Magnetita/química , Fluidez de la Membrana/efectos de los fármacos , Naranja de Acridina/farmacocinética , Células CACO-2 , Membrana Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Cisplatino/química , Cisplatino/farmacocinética , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/patología , Cobre/farmacología , Humanos , Concentración 50 Inhibidora , Fluidez de la Membrana/efectos de la radiaciónRESUMEN
Liposome encapsulation of platinum (Pt) drugs has emerged as a promising strategy to overcome their toxicity and cellular Pt resistance. The aim of the present work was to examine the impact of liposome encapsulation of a novel antitumor lipophilic Pt complex, dichloro-(N-dodecyl)-propanediamine-platinum(II) complex (DDPP), on its pharmacological profile as an antitumor agent. Biological assays included acute toxicity and histopathological evaluations, pharmacokinetics, and growth inhibition of B16-F1 tumor cells in C57Bl/6 mice. Comparison was made with cisplatin and free DDPP dissolved in castor oil. DDPP encapsulated in pegylated liposomes showed reduced acute toxicity in mice following intraperitoneal administration, compared with the free complex. Free DDPP at 5 mg Pt/kg induced histopathological alterations in the liver, in contrast to liposomal DDPP and cisplatin. Interestingly, the marked loss of body weight following the treatment of mice with cisplatin was not observed after liposomal DDPP at the same Pt dose. Liposomal DDPP was found to inhibit tumor growth significantly, when administered at 5 mg Pt/kg/day for 3 days, similar to cisplatin, but in contrast to the free complex. Pharmacokinetic studies after intraperitoneal and intravenous administrations at 5 mg Pt/kg indicated greater and more prolonged Pt levels in the plasma, liver, spleen, and kidneys from liposomal DDPP, compared with free DDPP or cisplatin. The tumor concentration of Pt increased after liposomal DDPP over the 24-h period, whereas it decreased after cisplatin. In conclusion, the encapsulation of DDPP in pegylated liposomes reduced the drug toxicity and enhanced its antitumoral activity in mice, as a result of improved drug pharmacokinetics.
Asunto(s)
Antineoplásicos/administración & dosificación , Liposomas/administración & dosificación , Compuestos Organoplatinos/administración & dosificación , Animales , Antineoplásicos/química , Antineoplásicos/farmacocinética , Línea Celular Tumoral , Cisplatino/farmacocinética , Cisplatino/farmacología , Portadores de Fármacos/administración & dosificación , Portadores de Fármacos/química , Inyecciones Intraperitoneales , Liposomas/química , Masculino , Melanoma Experimental/tratamiento farmacológico , Melanoma Experimental/metabolismo , Ratones , Ratones Endogámicos C57BL , Neoplasias/tratamiento farmacológico , Compuestos Organoplatinos/química , Compuestos Organoplatinos/farmacocinética , Polietilenglicoles/administración & dosificación , Polietilenglicoles/química , Distribución TisularRESUMEN
INTRODUCTION: Cervical cancer is the third most prevalent cancer in females worldwide. When advanced, the disease requires primary radiation concurrent with chemotherapy. However, chemotherapy alone is the standard treatment for recurrent/persistent/metastatic disease. AREAS COVERED: Areas covered in this review include the treatment of advanced cervical cancer with gemcitabine as radiosensitizer, either alone or in combination with cisplatin. The use of gemcitabine for recurrent/persistent/metastatic cervical cancer is also reviewed. EXPERT OPINION: Statistically significantly better survival rates are achieved with cisplatin doublets against cisplatin alone, in the management of recurrent/persistent/metastatic cervical cancer. The choice of the cisplatin doublet with paclitaxel, vinorelbine, gemcitabine and topotecan arms should be based on physician preference, pre-existing morbidity and patient-related factors. In advanced disease, a recently reported Phase III trial establishes the novel regimen of concurrent gemcitabine plus cisplatin and external radiation, followed by brachytherapy and two adjuvant 21-day cycles of gemcitabine plus cisplatin, as significantly improving survival outcomes when compared with the current standard of care. The increased acute toxicity of this regimen is clear; however, this should not deter its incorporation into clinical practice, in that the toxicity is predictable and manageable; nevertheless, the occurrence of late toxicity and survival at longer follow-up time are reasonable concerns in this regimen.
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Desoxicitidina/análogos & derivados , Fármacos Sensibilizantes a Radiaciones/farmacocinética , Neoplasias del Cuello Uterino/tratamiento farmacológico , Antineoplásicos/administración & dosificación , Antineoplásicos/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Braquiterapia , Cisplatino/administración & dosificación , Cisplatino/farmacocinética , Ensayos Clínicos como Asunto , Desoxicitidina/administración & dosificación , Desoxicitidina/farmacocinética , Femenino , Humanos , Metástasis de la Neoplasia , Paclitaxel/administración & dosificación , Paclitaxel/farmacocinética , Fármacos Sensibilizantes a Radiaciones/administración & dosificación , Tasa de Supervivencia , Topotecan/administración & dosificación , Topotecan/farmacocinética , Vinblastina/administración & dosificación , Vinblastina/análogos & derivados , Vinblastina/farmacocinética , Vinorelbina , GemcitabinaRESUMEN
Cisplatin (CDDP) is one of the most active cytotoxic agents and has been widely used in the treatment of peritoneal carcinomatosis by the intraperitoneal (i.p.) route. However, CDDP, a low-molecular-weight compound, is rapidly absorbed by the capillaries in the i.p. serosa and transferred to the bloodstream, inducing the appearance of systemic side-effects, such as nephrotoxicity. Furthermore, the i.p. CDDP chemotherapy is limited to patients whose residual tumor nodules are less than 0.5 cm in diameter after surgical debulking. The failure of i.p. therapy is attributed to the poor penetration of CDDP into larger tumors. One strategy to improve drug delivery in the peritoneal region and reduce toxicity is the use of drug delivery systems. The objective of the present work was to evaluate the biodistribution and antitumoral effect of long-circulating and pH-sensitive liposomes containing CDDP (SpHL-CDDP), as compared with free CDDP, after their i.p. administration in Ehrlich ascitic tumor-bearing mice. After administering a 6 mg/kg single i.p. bolus injection of either free CDDP or SpHL-CDDP, ascitic fluid (AF), blood and organs (kidneys, liver, spleen and lungs) were collected and analyzed for CDDP content. The area under the CDDP concentration-time curve (AUC) obtained for AF and blood after SpHL-CDDP administration was 3.3-fold larger and 1.3-fold lower, respectively, when compared with free CDDP treatment, thus indicating its high retention within the peritoneal cavity. The determination of the ratio between AUC in each tissue and that in blood (Kp) showed a lower accumulation of CDDP in kidneys after SpHL-CDDP treatment. The SpHL-CDDP treatment demonstrated a significant uptake by the liver and spleen. SpHL-CDDP treatment led to a higher survival rate of mice with initial or disseminated peritoneal carcinomatosis than CDDP treatment. These results indicate that SpHL-CDDP may be useful for i.p. chemotherapy due to their greater concentration in the peritoneal cavity.
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Antineoplásicos/farmacología , Antineoplásicos/farmacocinética , Carcinoma de Ehrlich/tratamiento farmacológico , Cisplatino/farmacología , Cisplatino/farmacocinética , Liposomas/farmacocinética , Neoplasias Peritoneales/tratamiento farmacológico , Estructuras Animales/química , Animales , Antineoplásicos/administración & dosificación , Cisplatino/administración & dosificación , Modelos Animales de Enfermedad , Portadores de Fármacos/administración & dosificación , Portadores de Fármacos/farmacocinética , Humanos , Concentración de Iones de Hidrógeno , Liposomas/administración & dosificación , Ratones , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
Long-circulating and pH-sensitive liposomes, containing cisplatin (SpHL-CDDP), have been developed as an alternative aimed at avoiding severe side effects as well as the appearance of resistance, which can limit the use of free cisplatin. However, physical (i.e., aggregation/fusion) and chemical instabilities limit the use of these drug carriers as pharmaceutical products. The preparation of freeze-dried pharmaceuticals has proven to be a successful strategy implemented to improve the stability of these formulations. In addition, the development of an economically feasible, reproducible process of liposome production, on a large scale, has also become necessary. A pilot production process, using three stages (i.e., reverse-phase evaporation, homogenization under high pressure, and ultrafiltration), was used to prepare SpHL-CDDP. The optimization of factors related to the homonogenization under high pressure (i.e., pressure and number of cycles), ultrafiltration (i.e., number of cycles), and storage stability at 4°C were assessed by means of particle size, zeta potential, and encapsulation percentage. A 500-bar pressure and 9 cycles were adopted as measures for the production of SpHL-CDDP, which presented a mean diameter of 99.0 ± 3.9 nm and an encapsulation percentage of 12.9 ± 2.3. The use of trehalose as a cryoprotectant was investigated, regarding its effective ability to control the vesicle diameter and retain encapsulated CDDP after the freeze-drying/rehydration step. After 135 days of storage, freeze-dried or liquid SpHL-CDDP showed no significant change in mean diameter. However, the freeze-dried SpHL-CDDP proved to be more efficient, in terms of CDDP retention, than did the liposomal liquid dispersion.
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Antineoplásicos/administración & dosificación , Cisplatino/administración & dosificación , Concentración de Iones de Hidrógeno , Liposomas , Antineoplásicos/farmacocinética , Cisplatino/farmacocinética , Tamaño de la Partícula , Proyectos Piloto , Piel/metabolismoRESUMEN
Cisplatin and carboplatin are the most common platinum-based drugs used in cancer treatment. Pharmacokinetic investigations, the evaluation of the body burden during the treatment, as well as baseline levels of platinum in humans have attracted great interest. Thus, accurate analytical methods for fast and easy Pt monitoring in clinical samples become necessary. In the present study atomic absorption spectrometric methods for the determination of platinum in the forms of cisplatin and carboplatin in human urine were investigated. Platinum, in these different forms, could be determined in urine, after simple sample dilution. Regarding electrothermal atomic absorption spectrometry, the optimum parameters were defined by a central composite design optimization. Multiplicative matrix effects were overcome by using a mixture of HCl and NaCl as modifier. The limit of detection (LOD) was 0.004 mgL(-1) of platinum in the original sample. For the analysis of more concentrated samples, high resolution continuous source flame atomic absorption spectrometry was also investigated. Flame conditions were optimized by a multivariate D-optimal design, using as response the sum of the analyte addition calibration slopes and their standard deviations. Matrix matched external calibration with PtCl(2) calibration solutions, was possible, and the LOD was 0.06 mgL(-1) in the original sample. The results obtained by the proposed procedures were also in good agreement with those obtained by an independent comparative procedure.
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Antineoplásicos/orina , Carboplatino/orina , Cisplatino/orina , Espectrofotometría Atómica/métodos , Antineoplásicos/farmacocinética , Calibración , Carboplatino/farmacocinética , Cisplatino/farmacocinética , Humanos , Técnicas In Vitro , Límite de Detección , Compuestos de Platino/química , Reproducibilidad de los Resultados , Espectrofotometría Atómica/instrumentaciónRESUMEN
Cisplatin (CDDP) is a chemotherapeutic agent that produces nephrotoxicity associated with oxidative/nitrosative stress. alpha-Mangostin (alpha-M) is a xanthone extracted from mangosteen with antioxidant and anti-inflammatory properties. The purpose of this study was to evaluate the renoprotective effect of alpha-M on the CDDP-induced nephrotoxicity. alpha-M was administered (12.5 mg/kg/day, i.g.) for 10 days (7 days before and 3 days after CDDP injection). On day 7, rats were treated with a single injection of CDDP (7.5 mg/Kg, i.p.); 3 days after the rats were killed. alpha-M attenuated renal dysfunction, structural damage, oxidative/nitrosative stress, decrease in catalase expression and increase in mRNA levels of tumour necrosis factor alpha and transforming growth factor beta. In conclusion the renoprotective effect of alpha-M on CDDP-induced nephrotoxicity was associated with the attenuation in oxidative/nitrosative stress and inflammatory and fibrotic markers and preservation of catalase activity.
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Cisplatino/toxicidad , Enfermedades Renales/inducido químicamente , Enfermedades Renales/prevención & control , Xantonas/farmacología , Animales , Antineoplásicos/farmacocinética , Antineoplásicos/toxicidad , Antioxidantes/farmacología , Cisplatino/farmacocinética , Interacciones Farmacológicas , Enfermedades Renales/metabolismo , Masculino , Análisis de Secuencia por Matrices de Oligonucleótidos , Estrés Oxidativo/efectos de los fármacos , Ratas , Ratas WistarRESUMEN
We investigated the ability of mifepristone, an anti-progestin drug, to modulate the cytotoxic effect of cisplatin in two cervical cancer cell lines and in human xenograft cervical tumors. The effect of cisplatin alone or combined with mifepristone on cellular proliferation was studied with the XTT assay which use a tetrazolium dye {sodium3'-[1-(phenylamino-carbonyl)-3,4-tetrazolium],XTT}. Before and after treatment with mifepristone, the intracellular accumulation of cisplatin in cancer cells and tumors of mice was evaluated by HPLC. The expression of Bcl-2 and Bax genes was also assessed by a reverse transcriptase polymerase chain reaction (RT-PCR) and Western blotting. In addition, single agents and combination treatment in vivo studies were performed with the xenograft cervical model. Tumor measurements were carried out weekly. Analysis of the data by the isobologram method shows a synergistic antiproliferative effect produced by the combination of mifepristone with cisplatin only in the HeLa cervical cancer cell line but not in CaSki cells. The effect of mifepristone on cytotoxicity of cisplatin could be mediated, at least partially, by an increase of intracellular cisplatin accumulation, but not by changes in Bcl-2/Bax gene relation expression in these cells. In vivo studies showed that the combination of these agents has a significant antitumor activity against HeLa xenograft tumors. Our results suggest that mifepristone can improve the efficacy of the antiproliferative effect of cisplatin in vitro and in vivo. This anti-hormonal drug therapy may be a useful candidate for further evaluation in combination with other antineoplastic drugs in the treatment of cancer, particularly with cisplatin.
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Antineoplásicos/toxicidad , Cisplatino/toxicidad , Antagonistas de Hormonas/farmacología , Mifepristona/farmacología , Neoplasias del Cuello Uterino/tratamiento farmacológico , Animales , Antineoplásicos/farmacocinética , Western Blotting , Línea Celular Tumoral/efectos de los fármacos , Cisplatino/farmacocinética , Sinergismo Farmacológico , Femenino , Humanos , Técnicas In Vitro , Ratones , Ratones Desnudos , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Distribución Tisular , Neoplasias del Cuello Uterino/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto , Proteína X Asociada a bcl-2/metabolismoRESUMEN
We encapsulated cisplatin into stealth pH-sensitive liposomes and studied their stability, cytotoxicity and accumulation in a human small-cell lung carcinoma cell line (GLC4) and its resistant subline (GLC4/CDDP). Since reduced cellular drug accumulation has been shown to be the main mechanism responsible for resistance in the GLC4/CDDP subline, we evaluated the ability of this new delivery system to improve cellular uptake. The liposomes were composed of dioleoylphosphatidylethanolamine (DOPE), cholesteryl hemisuccinate (CHEMS), and distearoylphosphatidylethanolamine-polyethyleneglycol 2000 (DSPE-PEG2000) and were characterized by determining the encapsulation percentage as a function of lipid concentration. Among the different formulations, DOPE/CHEMS/DSPE-PEG liposomes (lipid concentration equal to 40 mM) encapsulated cisplatin more efficiently than other concentrations of liposomes (about 20.0%, mean diameter of 174 nm). These liposomes presented good stability in mouse plasma which was obtained using a 0.24-M EDTA solution (70% cisplatin was retained inside the liposomes after 30 min of incubation). Concerning cytotoxic effects, they are more effective (1.34-fold) than free cisplatin for growth inhibition of the human lung cancer cell line A549. The study of cytotoxicity to GLC4 and GLC4/CDDP cell lines showed similar IC50 values (approximately 1.4 microM), i.e., cisplatin-resistant cells were sensitive to this cisplatin formulation. Platinum accumulation in both sensitive and resistant cell lines followed the same pattern, i.e., approximately the same intracellular platinum concentration (4.0 x 10-17 mol/cell) yielded the same cytotoxic effect. These results indicate that long-circulating pH-sensitive liposomes, also termed as stealth pH-sensitive liposomes, may present a promising delivery system for cisplatin-based cancer treatment. This liposome system proved to be able to circumvent the cisplatin resistance, whereas it was not observed when using non-long-circulating liposomes composed of phosphatidylcholine, phosphatidylserine, and cholesterol.
Asunto(s)
Antineoplásicos/farmacología , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Cisplatino/farmacología , Liposomas/química , Neoplasias Pulmonares/tratamiento farmacológico , Antineoplásicos/farmacocinética , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , Línea Celular Tumoral , Cisplatino/farmacocinética , Sistemas de Liberación de Medicamentos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologíaRESUMEN
We encapsulated cisplatin into stealth pH-sensitive liposomes and studied their stability, cytotoxicity and accumulation in a human small-cell lung carcinoma cell line (GLC4) and its resistant subline (GLC4/CDDP). Since reduced cellular drug accumulation has been shown to be the main mechanism responsible for resistance in the GLC4/CDDP subline, we evaluated the ability of this new delivery system to improve cellular uptake. The liposomes were composed of dioleoylphosphatidylethanolamine (DOPE), cholesteryl hemisuccinate (CHEMS), and distearoylphosphatidylethanolamine-polyethyleneglycol 2000 (DSPE-PEG2000) and were characterized by determining the encapsulation percentage as a function of lipid concentration. Among the different formulations, DOPE/CHEMS/DSPE-PEG liposomes (lipid concentration equal to 40 mM) encapsulated cisplatin more efficiently than other concentrations of liposomes (about 20.0 percent, mean diameter of 174 nm). These liposomes presented good stability in mouse plasma which was obtained using a 0.24-M EDTA solution (70 percent cisplatin was retained inside the liposomes after 30 min of incubation). Concerning cytotoxic effects, they are more effective (1.34-fold) than free cisplatin for growth inhibition of the human lung cancer cell line A549. The study of cytotoxicity to GLC4 and GLC4/CDDP cell lines showed similar IC50 values (approximately 1.4 æM), i.e., cisplatin-resistant cells were sensitive to this cisplatin formulation. Platinum accumulation in both sensitive and resistant cell lines followed the same pattern, i.e., approximately the same intracellular platinum concentration (4.0 x 10-17 mol/cell) yielded the same cytotoxic effect. These results indicate that long-circulating pH-sensitive liposomes, also termed as stealth pH-sensitive liposomes, may present a promising delivery system for cisplatin-based cancer treatment. This liposome system proved to be able to circumvent the cisplatin resistance, whereas...