RESUMEN
BACKGROUND: Increasing evidence suggests that diabetes increases the risk of developing different types of cancer. Hyperinsulinemia, hyperglycemia and chronic inflammation, characteristic of diabetes, could represent possible mechanisms involved in cancer development in diabetic patients. At the same time, cancer increases the risk of developing new-onset diabetes, mainly caused by the use of specific anticancer therapies. Of note, diabetes has been associated with a â¼10% increase in mortality for all cancers in comparison with subjects who did not have diabetes. Diabetes is associated with a worse prognosis in patients with cancer, and more recent findings suggest a key role for poor glycemic control in this regard. Nevertheless, the association between glycemic control and cancer outcomes in oncologic patients with diabetes remains unsettled and poorly debated. PURPOSE: The current review seeks to summarize the available evidence on the effect of glycemic control on cancer outcomes, as well as on the possibility that timely treatment of hyperglycemia and improved glycemic control in patients with cancer and diabetes may favorably affect cancer outcomes.
RESUMEN
Increasing evidence suggests that patients with diabetes, particularly type 2 diabetes (T2D), are characterized by an increased risk of developing different types of cancer, so cancer could be proposed as a new T2D-related complication. On the other hand, cancer may also increase the risk of developing new-onset diabetes, mainly caused by anticancer therapies. Hyperinsulinemia, hyperglycemia, and chronic inflammation typical of T2D could represent possible mechanisms involved in cancer development in diabetic patients. MicroRNAs (miRNAs) are a subset of non-coding RNAs, â22 nucleotides in length, which control the post-transcriptional regulation of gene expression through both translational repression and messenger RNA degradation. Of note, miRNAs have multiple target genes and alteration of their expression has been reported in multiple diseases, including T2D and cancer. Accordingly, specific miRNA-regulated pathways are involved in the pathogenesis of both conditions. In this review, a panel of experts from the Italian Association of Medical Oncology (AIOM), Italian Association of Medical Diabetologists (AMD), Italian Society of Diabetology (SID), Italian Society of Endocrinology (SIE), and Italian Society of Pharmacology (SIF) provide a critical view of the evidence about the involvement of miRNAs in the pathophysiology of both T2D and cancer, trying to identify the shared miRNA signature and pathways able to explain the strong correlation between the two conditions, as well as to envision new common pharmacological approaches.
Asunto(s)
Diabetes Mellitus Tipo 2 , MicroARNs , Neoplasias , Humanos , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/fisiopatología , Diabetes Mellitus Tipo 2/terapia , Neoplasias/complicaciones , Neoplasias/genética , Neoplasias/terapia , MicroARNs/genética , MicroARNs/metabolismo , Células Secretoras de Insulina/patología , Resistencia a la Insulina/genética , Terapia Molecular Dirigida/tendenciasRESUMEN
Cancer management has significantly evolved in recent years, focusing on a multidisciplinary team approach to provide the best possible patient care and address the various comorbidities, toxicities, and complications that may arise during the patient's treatment journey. The co-occurrence of diabetes and cancer presents a significant challenge for health care professionals worldwide. Management of these conditions requires a holistic approach to improve patients' overall health, treatment outcomes, and quality of life, preventing diabetes complications and cancer treatment side-effects. In this article, a multidisciplinary panel of experts from different Italian scientific societies provide a critical overview of the co-management of cancer and diabetes, with an increasing focus on identifying a novel specialty field, 'diabeto-oncology', and suggest new co-management models of cancer patients with diabetes to improve their care. To better support cancer patients with diabetes and ensure high levels of coordinated care between oncologists and diabetologists, 'diabeto-oncology' could represent a new specialized field that combines specific expertise, skills, and training.
Asunto(s)
Diabetes Mellitus , Neoplasias , Humanos , Calidad de Vida , Consenso , Neoplasias/complicaciones , Neoplasias/epidemiología , Neoplasias/terapia , Oncología Médica , Diabetes Mellitus/epidemiología , Diabetes Mellitus/terapia , Italia/epidemiologíaRESUMEN
BACKGROUND: Proton-pump-inhibitors (PPIs) are frequently prescribed for the management of anticancer drug-related gastrointestinal symptoms. Palbociclib is a weak base with pH-dependent solubility and potential drug-drug interaction at the absorption level may affect clinical pharmacokinetics. The current study was aimed at investigating the effect of co-administration of PPIs and palbociclib on progression-free survival (PFS) in metastatic breast cancer (mBC) patients. PATIENTS AND METHODS: Patients affected by estrogen receptor-positive, human epidermal growth factor receptor 2-negative mBC, who were candidates for first-line treatment with palbociclib, were enrolled in this retrospective observational study. Patients were defined as 'no concomitant PPIs' if no PPIs were administered during palbociclib treatment, and as 'concomitant PPIs' if the administration of PPIs covered the entire or not less than two-thirds of treatment with palbociclib. All clinical interventions were made according to clinical practice. RESULTS: A total of 112 patients were enrolled in the study; 56 belonged to the 'no concomitant PPIs' group and 56 to the 'concomitant PPIs' group. Seventy-one patients were endocrine-sensitive and received palbociclib and letrozole, and 43 were endocrine-resistant and were treated with palbociclib and fulvestrant. The most prescribed PPI was lansoprazole. Patients taking PPIs had a shorter PFS than those taking palbociclib and endocrine therapy alone (14.0 versus 37.9 months, P < 0.0001). Multivariate analysis confirmed concomitant PPIs as the only independent predictive factor for shorter PFS (P = 0.0002). PFS was significantly longer in estrogen-sensitive mBC with no concomitant PPIs compared with patients taking PPIs or estrogen-resistant patients, with and without PPIs (P < 0.0001). No correlation with adverse events was found when considering grade >2 hematological toxicities [Common Terminology Criteria for Adverse Events (CTCAE) scale]. CONCLUSIONS: The present study demonstrates that concomitant use of PPIs in mBC patients treated with palbociclib has a detrimental effect on PFS. Therefore, it is recommended to prescribe PPIs with caution in these patients, strictly adhering to the indications in the summary of product characteristics (RCP).
Asunto(s)
Neoplasias de la Mama , Preparaciones Farmacéuticas , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias de la Mama/tratamiento farmacológico , Interacciones Farmacológicas , Femenino , Humanos , Piperazinas , Inhibidores de la Bomba de Protones/uso terapéutico , Piridinas , Receptores de Estrógenos/uso terapéuticoRESUMEN
The therapeutic landscape of cancer is changing rapidly due to the growing number of approved drugs capable of targeting specific genetic alterations. This aspect, together with the development of noninvasive methods for the assessment of somatic mutations in the peripheral blood of patients, generated a growing interest toward a new tumor-agnostic classification system based on 'predictive' biomarkers. The current review article discusses this emerging alternative approach to the classification of cancer and its implications for the selection of treatments. It is suggested that different types of cancers sharing the same molecular profiles could benefit from the same targeted drugs. Although recent clinical trials have demonstrated that this approach cannot be generalized, there are also specific examples that demonstrate the clinical utility of this alternative vision. In this rapidly evolving scenario, a multidisciplinary approach managed by institutional Molecular Tumor Boards is fundamental to interpret the biological and clinical relevance of genetic alterations and the complexity of their relationship with treatment response.
Asunto(s)
Terapia Molecular Dirigida , Neoplasias , Carcinogénesis , Humanos , Mutación , Neoplasias/tratamiento farmacológico , Neoplasias/genética , OncogenesRESUMEN
Echinacea is one of the most widely used alternative medicine in the world. Intake of Echinacea preparations is common among patients with advanced malignancies enrolled onto phase I chemotherapy trials; however, to our knowledge, no data are available regarding the possible direct effect of Echinacea species on human cancer cells. The purpose of the present study was to investigate potential in vitro cytotoxic and pro-apoptotic properties of hexanic root extract of the three medicinal Echinacea (Asteraceae) species (Echinacea pallida (Nutt.) Nutt., Echinacea angustifolia DC. var. angustifolia, Echinacea purpurea (L.) Moench.) on the human pancreatic cancer MIA PaCa-2 and colon cancer COLO320 cell lines. We demonstrated, for the first time, that all the three species reduced cell viability in a concentration- and time-dependent manner; Echinacea pallida was the most active species with IC(50)s of 46.41+/-0.87 and 10.55+/-0.70 microg/ml in MIA PaCa-2 and COLO320 cells, respectively. Echinacea pallida extract was able to induce apoptosis by increasing significantly caspase 3/7 activity and promoting nuclear DNA fragmentation. These results represent the starting point to establish viable scientific evidence on the possible role of Echinacea species in medical oncology.
Asunto(s)
AntiinfecciososAsunto(s)
Neoplasias de la Mama , Inhibidores de la Bomba de Protones , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Interacciones Farmacológicas , Femenino , Humanos , Piperazinas , Inhibidores de la Bomba de Protones/farmacología , Inhibidores de la Bomba de Protones/uso terapéutico , Piridinas/farmacología , Piridinas/uso terapéuticoRESUMEN
Cellular responses to anti-cancer agents result from the interaction between drugs, cellular targets and mechanisms of damage repair. Despite the pharmacological advances in the treatment of cancer, the clinical efficacy of chemotherapy is unpredictable in most patients. However, new information on the genetics of cancer delineates strategies by which the genetic background of tumour cells and patients might be profiled to select anti-cancer agents with improved efficacy and tolerability. This article focuses on the application of pharmacogenetics in the characterization of differences in the pharmacokinetics and pharmacodynamics of anti-cancer agents among individuals to define the likelihood of response and reduce the incidence of adverse effects.
Asunto(s)
Antineoplásicos , Neoplasias/genética , Farmacogenética , Antineoplásicos/efectos adversos , Antineoplásicos/metabolismo , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapéutico , Humanos , Neoplasias/tratamiento farmacológico , Polimorfismo GenéticoRESUMEN
The purpose of this study was to determine the response rate of the gemcitabine/epirubicin/paclitaxel combination (GET) and its feasibility as induction chemotherapy before high-dose consolidation treatment in patients with metastatic breast cancer. Patients received gemcitabine 1,000 mg/m2 on days I and 4, epirubicin 90 mg/m2 on day 1, and paclitaxel 175 mg/m2 on day I every 3 weeks for up to eight courses. After six courses of GET, responding patients or those with stable disease entered a high-dose chemotherapy program. All 36 enrolled patients were evaluated for toxicity and response. The GET combination was well tolerated, with myelosuppression the being most common toxicity; grade 4 neutropenia was reported in 56% of patients. The overall response rate was 89% (95% confidence interval, 73.4% to 96.9%), with a 28% complete response rate. The high-dose chemotherapy program resulted in a response rate of 92% and a complete response rate of 44%. As a result of the promising activity demonstrated in this phase II study with GET and following high-dose chemotherapy, three related studies are planned: an in vitro study evaluating the possible synergism of paclitaxel and gemcitabine, a phase III study comparing GET with epirubicin/paclitaxel in metastatic breast cancer, and a phase II trial evaluating GET in patients with operable breast cancer.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Adulto , Neoplasias de la Mama/patología , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacocinética , Epirrubicina/administración & dosificación , Epirrubicina/farmacocinética , Femenino , Trasplante de Células Madre Hematopoyéticas , Humanos , Persona de Mediana Edad , Metástasis de la Neoplasia , Paclitaxel/administración & dosificación , Paclitaxel/farmacocinética , Análisis de Supervivencia , Tomografía Computarizada de Emisión , GemcitabinaRESUMEN
A deficiency in apoptosis is one of the key events in the proliferation and resistance of malignant cells to antitumor agents; for these reasons, the search for apoptosis-inducing drugs represents a valuable approach for the development of novel anticancer therapies. In this study we report the first example of conformationally restrained analogues of ceramide (compounds 1-4), where the polar portion of the molecule has been replaced by a thiouracil (1, 3) or uracil (2, 4) ring. The evaluation of their biologic activity on CCRF-CEM human leukemia cells demonstrated that the most active was compound 1 followed by compound 2 (mean 50% inhibition of cell proliferation [IC(50)] 1.7 and 7.9 microM, respectively), while compounds 3 and 4 were inactive, as were uracil, thiouracil, and 5,6-dimethyluracil, the pyrimidine moieties of compounds 1-4. For comparison, the IC(50) of the reference substance, the cell-permeable C2-ceramide, was 31.6 microM. Compounds 1 and 2 and C2-ceramide were able to trigger apoptosis, as shown by the occurrence of DNA and nuclear fragmentation, and to release cytochrome c from treated cells. The treatment of female CD-1 nu/nu athymic mice bearing a WiDr human colon xenograft with the most active compound 1 at 2, 10, 50, and 200 mg/kg ip daily for 10 days resulted in an antitumor effect that was equivalent at 50 mg/kg or superior (200 mg/kg) to that of cyclophosphamide, 20 mg/kg ip daily, delivered on the same schedule, with markedly lower systemic toxicity. In conclusion, the present study demonstrates that the new ceramide analogues 1 and 2 are characterized by in vitro and in vivo antitumor activity and low toxicity.
Asunto(s)
Antineoplásicos/síntesis química , Ceramidas/síntesis química , Tiouracilo/análogos & derivados , Tiouracilo/síntesis química , Uracilo/análogos & derivados , Uracilo/síntesis química , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Apoptosis , Caspasa 3 , Caspasas/metabolismo , División Celular/efectos de los fármacos , Ceramidas/química , Ceramidas/farmacología , Grupo Citocromo c/metabolismo , Ensayos de Selección de Medicamentos Antitumorales , Activación Enzimática , Femenino , Humanos , Immunoblotting , Espectroscopía de Resonancia Magnética , Ratones , Ratones Desnudos , Relación Estructura-Actividad , Tiouracilo/química , Tiouracilo/farmacología , Trasplante Heterólogo , Células Tumorales Cultivadas , Uracilo/química , Uracilo/farmacologíaRESUMEN
Preliminary randomized studies have failed to show a survival benefit of high-dose chemotherapy with alkylators in advanced breast cancer. Idarubicin is an active agent in breast cancer and is suitable for dose escalation. We designed a dose finding study with escalating high-dose idarubicin (HD-Ida) followed by fixed high-dose thiotepa+melphalan (HD-TM) with peripheral blood progenitor cells (PBPC) in MBC patients with stable disease or in partial response after six courses of induction chemotherapy with gemcitabine 1000 mg/m(2) days 1 and 4, epirubicin 90 mg/m(2) day 1, taxol 175 mg/m(2) day 1 (GET). Aims of the study were to identify the maximum tolerated dose (MTD) of idarubicin, to evaluate the cardiac safety and activity of HD-Ida and HD-TM after GET and to study the pharmacokinetic profile of idarubicin and idarubicinol. A total of 14 patients were treated. Idarubicin was administered as a 48 h continuous i.v. infusion at the following dose levels: 40 mg/m(2) (three patients), 50 mg/m(2) (three patients), 60 mg/m(2) (five patients) and 70 mg/m(2) (three patients). Mucositis was the dose-limiting toxicity and the MTD was 60 mg/m(2). C(max) of Idarubicin and idarubicinol were 7.7+/-2.0 and 26.3+/-9.7 ng/ml at 40 mg/m(2) and increased to 14.8+3.0 and 47.4+12.6 ng/ml at 70 mg/m(2). AUCt(0-264) of idarubicin and idarubicinol increased from 423.2+/-111.6 and 2581+/-606 hng/ml at 40 mg/m(2) to 732.8+/-140.2 and 4590+/-1258 hng/ml at 70 mg/m(2). Conversion rates after HD-Ida and HD-TM were 28.6 and 38.5%, respectively. No episodes of cardiac toxicity were observed. We conclude that HD-Ida followed by HD-TM is feasible and devoid of cardiac toxicity. Moreover, the activity of HD-Ida after a epirubicin-containing regimen suggests incomplete cross-resistance between the two drugs.
Asunto(s)
Antineoplásicos Alquilantes/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/terapia , Daunorrubicina/análogos & derivados , Idarrubicina/uso terapéutico , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Daunorrubicina/líquido cefalorraquídeo , Daunorrubicina/farmacocinética , Daunorrubicina/uso terapéutico , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Relación Dosis-Respuesta a Droga , Epirrubicina/administración & dosificación , Femenino , Humanos , Idarrubicina/líquido cefalorraquídeo , Idarrubicina/farmacocinética , Melfalán/administración & dosificación , Persona de Mediana Edad , Metástasis de la Neoplasia , Paclitaxel/administración & dosificación , Inducción de Remisión , Taxoides , Tiotepa/administración & dosificación , Factores de Tiempo , Acondicionamiento Pretrasplante/métodos , Resultado del TratamientoRESUMEN
The aim of the present study was to test the ability of the chemotherapeutic agent suramin to inhibit angiogenesis in experimental models in vitro and in vivo. In the culture of rat aortic rings on fibronectin, suramin dose-dependently inhibited vascular cell growth, achieving the maximal effect (mean - 88% versus controls, P < 0.05) at 400 microg/ml. Image analysis showed that suramin could inhibit microvessel sprouting in fibrin from rat aortic rings as evaluated by the ratio between the cellular area and the mean gray value of the sample (sprouting index); suramin at 50 microg/ml significantly reduced the sprouting index from the control value of 0.35+/-0.04 to 0.14+/-0.02 mm2/gray level (P < 0.05). Likewise, the area occupied by cells was 19.2+/-1.8 mm2 as compared with 41.8+/-4.2 mm2 in controls (P < 0.05). In the rat model of neovascularization induced in the cornea by chemical injury, suramin at 1.6 mg/eye per day reduced the length of blood vessels (0.7+/-0.1 mm as compared with 1.5+/-0.1 mm in controls, P < 0.05). In the same model the ratio between the area of blood vessels and the total area of the cornea (area fraction score) was decreased by suramin from 0.19+/-0.02 in controls to 0.03+/-0.003 (P < 0.05). Suramin given i.p. at 30 mg/ kg per day markedly inhibited the neovascularization induced in the rat mesentery by compound 48/80 or conditioned medium from cells secreting the angiogenic protein fibroblast growth factor-3 (FGF-3). The area fraction score in control rats treated with compound 48/80 was 0.31+/-0.03, and this was reduced to 0.07+/-0.01 by suramin (P < 0.05). After i.p. administration of FGF-3 the area fraction score was reduced by suramin from 0.29+/-0.03 to 0.05+/-0.01 (P < 0.05). These results provide evidence that suramin exerts inhibitory effects on angiogenesis in both in vitro and in vivo models.
Asunto(s)
Antineoplásicos/farmacología , Neovascularización Fisiológica/efectos de los fármacos , Suramina/farmacología , Animales , Aorta Torácica/efectos de los fármacos , Aorta Torácica/fisiología , Células Cultivadas , Córnea/irrigación sanguínea , Córnea/efectos de los fármacos , Medios de Cultivo Condicionados , Depresión Química , Relación Dosis-Respuesta a Droga , Femenino , Procesamiento de Imagen Asistido por Computador , Mesenterio/irrigación sanguínea , Mesenterio/efectos de los fármacos , Técnicas de Cultivo de Órganos , Ratas , Ratas Wistar , p-Metoxi-N-metilfenetilamina/farmacologíaRESUMEN
PURPOSE: To describe the metabolism of 6-mercaptopurine (6-MP) in erythrocytes and tissues of rats after repeated administration of 6-MP at two dose levels and to provide evidence that in vivo modulation of 6-MP anabolism can be obtained by simultaneous treatment with ribavirin or hydroxyurea, two inhibitors of enzymes involved in the bioactivation of 6-MP to the active 6-thioguanine nucleotides (6-TGN). METHODS: Rats were treated i.p. with 6-MP at 12.5 and 25 mg/kg daily for 12 days and erythrocyte, liver, and kidney levels of 6-mercaptopurine nucleotides (6-MPN) and 6-TGN were investigated during the accumulation phase and for 50 days after the end of treatment. In combination studies, ribavirin at 75 and 100 mg/kg per day (for 6-MP, 25 and 12.5 mg/kg per day) or hydroxyurea at 200 mg/kg per day were given i.p. for 12 days. The measurements of thionucleotide levels in rat samples were performed by high-pressure liquid chromatography (HPLC). RESULTS: The maximal concentration (Cmax) and the area under the concentration versus time curve (AUC) of 6-MPN and 6-TGN in erythrocytes and tissues increased significantly after the administration of 6-MP at 25 mg/kg per day as compared with 12.5 mg/kg per day. In particular, the Cmax and AUC of 6-TGN in erythrocytes of rats treated with 6-MP at 25 mg/kg per day were approximately 5-fold higher than the 6-TGN values observed following treatment at 12.5 mg/kg per day. Moreover, 6-TGN levels in erythrocytes were significantly higher than those of 6-MPN (910.9+/-53.1 and 286.8+/-23.4 pmol/8 x 10(8) cells for 6-TGN and 6-MPN, respectively, P < 0.05) after treatment with 6-MP at 25 mg/kg per day. The administration of ribavirin, an inhibitor of inosine monophosphate dehydrogenase, in association with 6-MP increased the amount of 6-MPN detected in erythrocytes and tissues while reducing 6-TGN levels in samples. The production and accumulation of 6-MPN and 6-TGN were increased in erythrocytes and tissues by hydroxyurea, an inhibitor of ribonucleotide reductase. Finally, a significant correlation between thionucleotide concentrations and erythrocyte counts was observed. CONCLUSION: The overall results demonstrate that 6-MP is actively metabolized in rats and that its biotransformation can be modulated by agents acting on enzymes of the purine metabolism, resulting in significant changes in erythrocyte and tissue levels of 6-MPN and 6-TGN. These findings provide evidence that the rat is a suitable model for investigation of the metabolism of 6-MP and its possible pharmacologic modulation.
Asunto(s)
Antimetabolitos Antineoplásicos/administración & dosificación , Antimetabolitos Antineoplásicos/farmacocinética , Eritrocitos/metabolismo , Riñón/metabolismo , Hígado/metabolismo , Mercaptopurina/administración & dosificación , Mercaptopurina/farmacocinética , Animales , Antimetabolitos/farmacología , Área Bajo la Curva , Biotransformación , Cromatografía Líquida de Alta Presión , Inhibidores Enzimáticos/farmacología , Femenino , Hidroxiurea/farmacología , Ratas , Ratas Wistar , Análisis de Regresión , Ribavirina/farmacologíaRESUMEN
In the present study, the ability of suramin 18 mg/kg i.p. twice a week to induce chronic neurotoxicity in rats was investigated. After 20 weeks of suramin treatment, morphological analysis of nerve fibers demonstrated that 57.7+/-3.2% of them presented vesicular disruption of myelin sheaths; their thickness was 0.23+/-0.07 microm in suramin-treated rats with respect to 0.43+/-0.07 microm of controls (P<0.05). To investigate the interaction between suramin and nerve tissue, the binding of the drug to partially purified myelin P0 protein obtained from sciatic nerves was analysed. The percentage of suramin bound to rat myelin P0 protein was 94.0+/-9.5%; this value was decreased to 55.0+/-7.6% when heparan sulfate was added to the myelin protein suspension before suramin. The analysis of tissue drug concentrations at 5, 10 and 20 weeks of treatment showed that suramin accumulated into the sciatic nerve in a time-dependent fashion (130.8+/-18.1, 219.7+/-17.1 and 449.3+/-15.6 microg/g of tissue, respectively). In conclusion, suramin induces a chronic peripheral neurotoxicity in rats characterized by myelin damage and high tissue levels of the drug. The high affinity of suramin for partially purified myelin P0 protein suggests a possible mechanism for drug-induced toxicity.
Asunto(s)
Fibras Nerviosas Mielínicas/patología , Neurotoxinas , Nervio Ciático/patología , Suramina/farmacocinética , Suramina/toxicidad , Potenciales de Acción/efectos de los fármacos , Animales , Esquema de Medicación , Estimulación Eléctrica , Femenino , Músculo Esquelético/inervación , Proteína P0 de la Mielina/metabolismo , Fibras Nerviosas Mielínicas/efectos de los fármacos , Fibras Nerviosas Mielínicas/fisiología , Unión Proteica , Ratas , Ratas Wistar , Nervio Ciático/efectos de los fármacos , Nervio Ciático/fisiología , Suramina/administración & dosificaciónRESUMEN
A comparative field study was carried out at two sites (a healthy site and a declining site) in a brackish wetland in northern Italy, with the objective to investigate the symptoms and the possible causes leading to reed (Phragmites australis) decline in this area. The declining reed plants presented many of the symptoms (clumping habit, smaller size, weaker culms, abnormal rhizome and root anatomy, low starch levels in rhizomes) comprised within the so-called reed die-back syndrome, frequently observed in central European wetlands but never recorded previously in (Sub)Mediterranean regions. Soil nutrient levels did not differ much between the two sites, with nitrate concentrations in the soil being even higher at the healthy site (1.54 microg g(-1); die-back site 0.76 microg g(-1)). Hence, eutrophication did not seem to represent a major cause in determining reed decline in this area. High sulphate concentrations in saltwater associated with low soil redox potentials (-215 mV) due to waterlogging resulted in high soil sulphide concentrations. Concentrations of organic acids, especially acetic acid, did not differ remarkably between sites. High sulphide levels presumably accounted for abnormal anatomical formations (callus blocking aerenchyma channels), lower rates of net CO2 exchange and reduced reserve storage, observed at the die-back site. This was associated with a lower mechanical resistance of reed culms which accelerated reed mortality in the die-back areas. We concluded that high sulpihde levels in permanently waterlogged soils may result in die-back of reed stands in Mediterranean wetlands.
Asunto(s)
Ecosistema , Poaceae/crecimiento & desarrollo , Contaminantes del Suelo/análisis , Sulfuros/análisis , Contaminantes del Agua/análisis , Monitoreo del Ambiente/métodos , Eutrofización , Italia , Poaceae/metabolismo , Poaceae/fisiología , Cloruro de Sodio/análisisRESUMEN
BACKGROUND AND PURPOSE: An important objective in asthma therapy is to prevent the accelerated growth of airway smooth muscle cells which leads to hyperplasia and bronchial hyperreactivity. We investigated the effect of combination of salbutamol and PPARγ agonists on growth factor-stimulated human bronchial smooth muscle cell (BSMC) proliferation. EXPERIMENTAL APPROACH: Synergism was quantified by the combination index-isobologram method. Assays used here included analyses of growth inhibition, cell viability, DNA fragmentation, gene transcription, cell cycle and protein expression. KEY RESULTS: The PPARγ gene was highly expressed in BSMC and the protein was identified in cell nuclei. Single-agent salbutamol or PPARγ agonists prevented growth factor-induced human BSMC proliferation within a micromolar range of concentrations through their specific receptor subtypes. Sub-micromolar levels of combined salbutamol-PPARγ agonist inhibited growth by 50% at concentrations from â¼2 to 12-fold lower than those required for each drug alone, without induction of apoptosis or necrosis. Combination treatments also promoted cell cycle arrest at the G1/S transition phase and inhibition of ERK phosphorylation. CONCLUSIONS AND IMPLICATIONS: The synergistic interaction between PPARγ agonists and ß(2) -adrenoceptor agonists on airway smooth muscle cell proliferation highlights the anti-remodelling potential of this combination in chronic lung diseases.
Asunto(s)
Albuterol/farmacología , Bronquios/efectos de los fármacos , Miocitos del Músculo Liso/citología , Miocitos del Músculo Liso/efectos de los fármacos , Receptores Activados del Proliferador del Peroxisoma/farmacología , Tiazolidinedionas/farmacología , Remodelación de las Vías Aéreas (Respiratorias)/efectos de los fármacos , Bronquios/citología , Bronquios/metabolismo , Ciclo Celular/efectos de los fármacos , División Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Sinergismo Farmacológico , Humanos , Miocitos del Músculo Liso/metabolismo , RosiglitazonaRESUMEN
BACKGROUND: The objectives of this study were to investigate the disposition of gemcitabine, epirubicin, paclitaxel, 2',2'-difluorodeoxyuridine and epirubicinol, and characterize the pharmacokinetic and pharmacodynamic profile of treatment in patients with breast cancer. PATIENTS AND METHODS: The drug dispostion in 15 patients who received gemcitabine 1000 mg/m2, epirubicin 90 mg/m2 and paclitaxel 175 mg/m2 (GEP) on day 1 of a 21-day cycle, was compared with that of patients treated with epirubicin 90 mg/m2 and paclitaxel 175 mg/m2 (EP, n = 6) and epirubicin 90 mg/m2 alone (n = 6). Drug and metabolite levels in plasma and urine were assessed by high-performance liquid chromatography and parameters of drug exposure were related to hematological toxicity by a sigmoid-maximum effect (Emax) model. RESULTS: Paclitaxel administration significantly increased the epirubicinol area under the concentration-time curve, from 357+/-146 (epirubicin) to 603+/-107 (EP) and 640+/-81 h x ng/ml (GEP), and reduced the renal clearance of epirubicin and epirubicinol by 38 and 52.2% and 34.5 and 53% in GEP- and EP-treated patients, respectively, compared with epirubicin alone. Gemcitabine had no apparent effect on paclitaxel and epirubicin pharmacokinetics, and renal clearance of epirubicin and epirubicinol. The only pharmacokinetic/pharmacodynamic relationship observed was between neutropenia and the time spent above the threshold plasma level of 0.1 micromol/l (tC0.1) of paclitaxel, with the time required to obtain a 50% decrease in neutrophil count (Et50) of GEP being 7.8 h, similar to that of EP. CONCLUSIONS: Paclitaxel and/or its vehicle, Cremophor EL, interferes with the disposition and renal excretion of epirubicin and epirubicinol; gemcitabine has no affect on epirubicin and paclitaxel plasma pharmacokinetics and renal excretion of epirubicin, while neutropenia is not enhanced by gemcitabine.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Neoplasias de la Mama/tratamiento farmacológico , Desoxicitidina/análogos & derivados , Adulto , Análisis de Varianza , Biopsia con Aguja , Neoplasias de la Mama/patología , Desoxicitidina/administración & dosificación , Desoxicitidina/farmacocinética , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Interacciones Farmacológicas , Epirrubicina/administración & dosificación , Epirrubicina/farmacocinética , Femenino , Humanos , Persona de Mediana Edad , Estadificación de Neoplasias , Paclitaxel/administración & dosificación , Paclitaxel/farmacocinética , Probabilidad , Pronóstico , Resultado del Tratamiento , GemcitabinaRESUMEN
BACKGROUND: Gemcitabine and paclitaxel are two of the most active agents in non-small-cell lung cancer (NSCLC), and pharmacologic investigation of the combination regimens including these drugs may offer a valuable opportunity in treatment optimization. The present study investigates the pharmacokinetics and pharmacodynamics of paclitaxel and gemcitabine in chemotherapy-naive patients with advanced NSCLC within a phase I study. PATIENTS AND METHODS: Patients were given i.v. paclitaxel 100 mg/m2 by one-hour infusion followed by gemcitabine 1,500, 1,750 and 2,000 mg/m2 by 30-min administration. Plasma levels of paclitaxel, gemcitabine and its metabolite 2',2'-difluorodeoxyuridine (dFdU) were determined by high-performance liquid chromatography (HPLC). Concentration-time curves were modeled by compartmental and non-compartmental methods and pharmacokinetic/pharmacodynamic (PK/PD) relationships were fitted according to a sigmoid maximum effect (Emax) model. RESULTS: Paclitaxel pharmacokinetics did not change as a result of dosage escalation of gemcitabine from 1,500 to 2,000 mg/m2. A nonproportional increase in gemcitabine peak plasma levels (Cmax, from 18.56 +/- 4.94 to 40.85 +/- 14.85 microg/ml) and area under the plasma concentration-time curve (AUC, from 9.99 +/- 2.75 to 25.01 +/- 9.87 h x microg/ml) at 1,500 and 2,000 mg/m, respectively, was observed, suggesting the occurrence of saturation kinetics at higher doses. A significant relationship between neutropenia and time of paclitaxel plasma levels > or = 0.05 micromol/l was observed, with a predicted time of 10.4 h to decrease cell count by 50%. A correlation was also observed between percentage reduction of platelet count and gemcitabine Cmax, with a predicted effective concentration to induce a 50% decrease of 14.3 microg/ml. CONCLUSION: This study demonstrates the lack of interaction between drugs, the nonproportional pharmacokinetics of gemcitabine at higher doses and the Emax relationship of paclitaxel and gemcitabine with neutrophil and platelet counts, respectively. In addition, gemcitabine 1,500 mg/m2 is the recommended dosage in combination with paclitaxel 100 mg/m2 for future phase II studies, due to its predictable kinetic behaviour and less severe thrombocytopenia than expected.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Desoxicitidina/análogos & derivados , Neoplasias Pulmonares/metabolismo , Adolescente , Adulto , Anciano , Área Bajo la Curva , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/patología , Cromatografía Líquida de Alta Presión , Desoxicitidina/farmacocinética , Desoxicitidina/farmacología , Relación Dosis-Respuesta a Droga , Humanos , Infusiones Intravenosas , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Persona de Mediana Edad , Paclitaxel/farmacocinética , Paclitaxel/farmacología , GemcitabinaRESUMEN
A single high-performance liquid chromatography (HPLC) method, suitable for the analysis of daunorubicin, idarubicin, doxorubicin, epirubicin, and their 13-dihydro metabolites is validated in the present study. Preparation of plasma samples was performed by a first extraction of analytes with a chloroform/1-heptanol mixture (9:1) and reextraction with ortophosphoric acid 0.1 M. The chromatographic analysis was carried out by reversed-phase isocratic elution of anthracyclines with a Supelcosil LC-CN 5 mm column (25 cm x 4.6 mm internal diameter; Supelco) and detection was accomplished by spectrofluorimetry at excitation and emission wavelengths of 480 and 560 nm, respectively. All anthracyclines eluted within 15 minutes of injection and the method appeared to be specific, because the chromatographic assay did not show interferences at the retention time of analytes. The linearity, evaluated over a concentration range of 0.4-10,000 ng/mL, gave regression coefficients better than 0.999, with recoveries of doxorubicin-doxorubicinol and epirubicin-epirubicinol of 67%-109% and 61%-109% respectively, and 93%-109% for the other compounds. The limits of detection and quantification were 0.4 ng/mL in a 50-mL sample (40 pg/injection) for all anthracyclines tested. The method proved to be precise and accurate, as the within-day and between-day coefficients of variation were less than 10% and the accuracy of the assay was in the range of 91%-107%. Overall results indicate that it is feasible to analyze all the anthracyclines used in clinical practice and their major metabolites with a single optimized method, thereby simplifying their monitoring in chemotherapeutic regimens of cancer patients.
Asunto(s)
Antibióticos Antineoplásicos/sangre , Cromatografía Líquida de Alta Presión/métodos , Monitoreo de Drogas/métodos , Daunorrubicina/sangre , Doxorrubicina/sangre , Epirrubicina/sangre , Humanos , Idarrubicina/sangre , Modelos Lineales , Estructura Molecular , Valores de Referencia , Reproducibilidad de los Resultados , Sensibilidad y EspecificidadRESUMEN
PURPOSE: To investigate the activity of the combination of gemcitabine (G) plus epirubicin (E) and taxol (T), (GET), in metastatic breast cancer, to evaluate the feasibility of this regimen as induction before high dose chemotherapy and to study the pharmacokinetic interactions of these three drugs. PATIENTS AND METHODS: Metastatic breast cancer patients, with bidimensionally measurable disease were eligible. Treatment consisted of G 1000 mg/sqm days 1 and 4 plus E 90 mg/sqm day 1 plus T 175 mg/sqm/3 h day 1, every 21 days. After six courses of GET, patients aged less than 60 years, in complete or partial remission or stable disease entered a programme of high dose chemotherapy (HDCT), as consolidation treatment. RESULTS: Thirtysix patients were included in this study. Grade 4 neutropenia was observed in 64% of the patients, with four episodes of febrile neutropenia; 39% of the patients experienced mild to moderate peripheral neuropathy; grade 2 and 3 mucositis occurred respectively in 9 (25%) and 6 (17%) patients. The overall response rate to GET was 92% (95% CI, 77.53%-98.25%); CR 31% and PR 61%. After six courses of GET, 25 patients received HDCT, leading to an overall response rate of 96% with 58% CR. At a median follow up of 25 months (range 8-39), 13 out of 36 patients are progression free and 26 alive. Median progression free survival is 21 months, while median overall survival has not yet been reached. The pharmacokinetic data show that G does not influence the interactions between E and T, while gemcitabine kinetics remains unchanged. CONCLUSIONS: The results of the present study indicate that the addition of G to E plus T as front line treatment for advanced breast cancer is well tolerated with an ORR of 92%. On the basis of the high activity and interesting progression free and overall survival rates, the GET combination deserves further evaluation in randomized trials.