RESUMEN
Insulin resistance (IR), accompanied by an impaired cellular glucose uptake, characterizes diverse pathologies that include, but are not limited to, metabolic disease, prediabetes and type 2 diabetes. Chronic inflammation associated with deranged cellular signaling is thought to contribute to IR. The key molecular players in IR are plasma membrane proteins, including the insulin receptor and glucose transporter 4. Certain natural products, such as lipids, phenols, terpenes, antibiotics and alkaloids have beneficial effects on IR, yet their mode of action remains obscured. We hypothesized that these products belong to a novel class of bioactive molecules that we have named membrane-active immunomodulators (MAIMs). A representative MAIM, the naturally occurring medium chain fatty acid ester diethyl azelate (DEA), has been shown to increase the fluidity of cell plasma membranes with subsequent downstream effects on cellular signaling. DEA has also been shown to improve markers of IR, including blood glucose, insulin and lipid levels, in humans. The literature supports the notion that DEA and other natural MAIMs share similar mechanisms of action in improving IR. These findings shed a new light on the mechanism of IR mitigation using natural products, and may facilitate the discovery of other compounds with similar activities.
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BACKGROUND/AIM: Mycobacterium ulcerans causes the necrotizing skin disease Buruli ulcer (BU), characterized by the formation of subcutaneous lesions and immunosuppression thought to be mediated by the virulence factor mycolactone. Since early BU lesions are typically painless, patients often seek standard oral antibiotic therapy at the advanced stages when the treatment is less effective. Given that currently there is no curative topical treatment for BU, our objective was to evaluate a plasma membrane fluidizer, diethyl azelate (DEA), as a potential novel topical therapy for BU. MATERIALS AND METHODS: We evaluated the effects of DEA against bacterial extracts and live strains of M. ulcerans ATCC 35840 (mycolactone positive; M+) and ATCC 19423 (mycolactone negative; M-) by measuring cytokine levels in cultured cells and tissue extracts using multiplexed immunoassays and numbers of skin lesions as the endpoints. RESULTS: In vitro, DEA counteracted immunosuppression induced by extract from the M+ strain in the 3-D human skin model (EpiDerm) and in human dendritic cells. In vivo, topical DEA reduced immunosuppressive activities of M+ and M- strains at all stages of BU, including advanced ulcers. DEA also diminished lesion formation and ulceration, accelerated healing of skin lesions and preserved normal immune responsiveness to pathogen-associated molecular pattern receptor agonists in blood of infected animals. CONCLUSION: The efficacy of DEA in BU models is linked to overcoming the immunosuppressive activity of virulence factors produced by M. ulcerans. Thanks to its pluripotent activity, DEA is a promising novel treatment for BU and possibly other pathogenic mycobacteria.
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Úlcera de Buruli , Mycobacterium ulcerans , Animales , Humanos , Úlcera de Buruli/tratamiento farmacológico , Úlcera de Buruli/microbiología , Mycobacterium ulcerans/metabolismo , Macrólidos/metabolismo , Inmunosupresores , Adyuvantes InmunológicosRESUMEN
BACKGROUND/AIM: Brown recluse spider bite releases hemolytic and cytotoxic phospholipase D to the wound that may cause necrosis or even death. We examined diethyl azelate (DEA), a plasma membrane fluidizer with a broad range of immunomodulatory activities, as a potential treatment for the brown recluse spider bite. MATERIALS AND METHODS: Topical DEA was used in emergency to treat brown recluse spider bites in a human subject. We subsequently evaluated the effects of DEA on hemolysis induced by the brown recluse spider venom, recluse recombinant phospholipase D (rPLD), and venoms from honey bee and moccasin snake, and on phospholipase A2 activity in the bee and snake venoms and in human urine. RESULTS: Topical DEA resolved the consequences of human brown recluse spider envenomation in two weeks. In vitro, DEA inhibited hemolysis caused by the brown recluse spider venom and rPLD and suppressed phospholipase A2 activity in a dose-dependent manner. CONCLUSION: DEA is a promising novel therapy for the brown recluse spider bite and perhaps even unrelated envenomations involving PLDs.
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Araña Reclusa Parda , Picaduras de Arañas , Animales , Ácidos Dicarboxílicos , Hemólisis , Necrosis , Picaduras de Arañas/tratamiento farmacológicoRESUMEN
BACKGROUND/AIM: Alterations of plasma membrane fluidity are characteristic of many diseases but the intentional modulation of membrane fluidity with drugs has been less studied. We examined the therapeutic potential of the membrane fluidizer diethyl azelate (DEA) and related azelates. MATERIALS AND METHODS: The effects of azelates on plasma membrane fluidity and cell signaling were examined in primary human and murine cells and in vivo. Endpoints were queried using single target and multiplexed immunoassays. RESULTS: Unique membrane-fluidizing properties and biomarker signatures suggest that azelates are not prodrugs. DEA decreased cytokine signaling from pattern recognition receptors in human dendritic cells, disabled membrane attack of cholera toxin in vitro, and prevented immunosuppression by anthrax lethal toxin in vitro and in vivo. In the murine sepsis model, DEA increased survival and reduced organ damage. CONCLUSION: Azelates represent a new class of drugs, membrane active immunomodulators, which target an innate homeostatic mechanism, adaptive membrane fluidity modulation.
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Fluidez de la Membrana , Transducción de Señal , Animales , Membrana Celular , Retroalimentación , Homeostasis , Humanos , RatonesRESUMEN
The structure of the plasma membrane affects its function. Changes in membrane fluidity with concomitant effects on membrane protein activities and cellular communication often accompany the transition from a healthy to a diseased state. Although deliberate modulation of membrane fluidity with drugs has not been exploited to date, the latest data suggest the "druggability" of the membrane. Azelaic acid esters (azelates) modulate plasma membrane fluidity and exhibit a broad range of immunomodulatory effects in vitro and in vivo. Azelates represent a new class of drugs, membrane active immunomodulators (MAIMs), which use the entire plasma membrane as the target, altering the dynamics of an innate feedback regulated homeostatic system, adaptive membrane fluidity modulation (AMFM). A review of the literature data spanning >200 years supports the notion that molecules in the MAIMs category including known drugs do exert immunomodulatory effects that have been either neglected or dismissed as off-target effects.
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Fluidez de la Membrana , Proteínas de la Membrana , Membrana Celular , Retroalimentación , HomeostasisRESUMEN
BACKGROUND/AIM: Insulin resistance (IR) is linked to increased risk of cardiovascular disease and cancer. We examined safety and efficacy of the natural product diethyl azelate (DEA) in overweight males with a varying degree of IR. PATIENTS AND METHODS: Seventeen subjects [age 18-42, hemoglobin A1c (A1c) of 5.2-6.2%] received orally 1 mg/kg DEA daily for 21 days. Blood plasma glucose, insulin and lipid levels were assessed before and after treatment. RESULTS: DEA was well tolerated without hypoglycemia or adverse effects except transient diarrhea (n=1). DEA significantly reduced fasting glucose by 6.06 mg/dl (n=8) and insulin by 37.8% (n=8) in subjects with IR and/or A1c ≥5.6%. Furthermore, it improved cholesterol/HDL, LDL/HDL, and non-cholesterol HDL/HDL by 5.4, 6.5, and 6.6%, respectively in all subjects, and by 8.0, 9.8, and 9.8%, respectively in 9 subjects with A1c ≥5.6%. CONCLUSION: DEA efficacy correlates with the degree of IR. DEA holds promise as a novel treatment for the management of IR.
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Biomarcadores , Ácidos Dicarboxílicos/administración & dosificación , Resistencia a la Insulina , Sobrepeso/metabolismo , Administración Oral , Glucemia , Ácidos Dicarboxílicos/química , Ésteres , Cromatografía de Gases y Espectrometría de Masas , Humanos , Insulina/sangre , Metabolismo de los Lípidos , Masculino , Sobrepeso/sangre , Sobrepeso/tratamiento farmacológico , Sobrepeso/etiología , Factores SexualesRESUMEN
PNT100 is a 24-base, chemically unmodified DNA oligonucleotide sequence that is complementary to a region upstream of the BCL-2 gene. Exposure of tumor cells to PNT100 results in suppression of proliferation and cell death by a process called DNA interference. PNT2258 is PNT100 that is encapsulated in protective amphoteric liposomes developed to efficiently encapsulate the PNT100 oligonucleotide, provide enhanced serum stability, optimized pharmacokinetic properties and antitumor activity of the nanoparticle both in vivo and in vitro. PNT2258 demonstrates broad antitumor activity against BCL-2-driven WSU-DLCL2 lymphoma, highly resistant A375 melanoma, PC-3 prostate, and Daudi-Burkitt's lymphoma xenografts. The sequence specificity of PNT100 was demonstrated against three control sequences (scrambled, mismatched, and reverse complement) all encapsulated in a lipid formulation with identical particle characteristics, and control sequences did not demonstrate antiproliferative activity in vivo or in vitro. PNT2258 is currently undergoing clinical testing to evaluate safety and antitumor activity in patients with recurrent or refractory non-Hodgkin's lymphoma and additional studies are planned.
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Antineoplásicos/uso terapéutico , ADN sin Sentido/uso terapéutico , ADN de Cadena Simple/uso terapéutico , Silenciador del Gen/efectos de los fármacos , Neoplasias/tratamiento farmacológico , Proteínas Proto-Oncogénicas c-bcl-2/antagonistas & inhibidores , Región de Flanqueo 5'/efectos de los fármacos , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , ADN sin Sentido/administración & dosificación , ADN sin Sentido/farmacocinética , ADN sin Sentido/farmacología , ADN de Cadena Simple/administración & dosificación , ADN de Cadena Simple/farmacocinética , ADN de Cadena Simple/farmacología , Composición de Medicamentos , Estabilidad de Medicamentos , Femenino , Liposomas , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Ratones SCID , Neoplasias/sangre , Oligodesoxirribonucleótidos/química , Oligodesoxirribonucleótidos/farmacocinética , Oligodesoxirribonucleótidos/farmacología , Oligodesoxirribonucleótidos/uso terapéutico , Vehículos Farmacéuticos , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Distribución Aleatoria , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: Lung cancer (LC) is the leading cause of deaths caused by cancer worldwide. A diagnostic test for LC is needed for monitoring high-risk populations. PATIENTS AND METHODS: Fifty-seven markers were measured using multiplex immunoassays of plasma of patients with non-small cell lung cancer (NSCLC); (245 men, 114 women, 1 unknown), asthma (67 men, 111 women, 2 unknown) and of healthy controls (165 men, 122 women, 1 unknown). Mass spectrometry was used for biomarker discovery. A support vector machine (SVM) was used for data analysis. RESULTS: When all biomarkers and both genders were co-analyzed, SVM classified NSCLC and asthma with an accuracy of 0.94. Restricting to NSCLC versus healthy using best subsets of variables (males: epidermal growth factor (EGF), interleukin-8 (IL-8), soluble Fas (sFas), matrix metalloproteinase-9 (MMP-9), plasminogen activator inhibitor-1 (PAI-1); females: EGF, soluble cluster of differentiation 40 (sCD40) ligand, IL-8) yielded sensitivity and specificity of 1. Expression of eleven mass spectrometric biomarkers differed between pathologies. CONCLUSION: Significant inter-pathology and gender differences between biomarkers may improve diagnosis of LC.
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Asma/sangre , Asma/diagnóstico , Biomarcadores/sangre , Carcinoma de Pulmón de Células no Pequeñas/sangre , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico , Neoplasias Pulmonares/sangre , Neoplasias Pulmonares/diagnóstico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/sangre , Minería de Datos/métodos , Femenino , Humanos , Inmunoensayo/métodos , Masculino , Espectrometría de Masas , Persona de Mediana Edad , Proteómica/métodos , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Factores Sexuales , Adulto JovenRESUMEN
AIM: To examine changes in biomarkers expressed in breast tumors in response to patient treatment with the polyamine synthesis inhibitor alpha-difluoromethylornithine (DFMO). PATIENTS AND METHODS: The expression of Ki-67 (MIB-1), matrix metalloproteinases (MMP) 2 and 9, urokinase-type plasminogen activator (uPA) were examined by immunohistochemistry in breast tissue specimens (controls: n=15, 13 evaluable, and DFMO group; n=27, 21 evaluable). Apoptosis was evaluated by terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL). RESULTS: Significant increases in apoptosis, MMP-9 and uPA (tumor) were observed in 7 patients >or=50 years who received DFMO for >or=14 days relative to patients <50 years and/or who received <14 days of treatment (n=11). No other measured characteristics, including tumor estrogen and progesterone receptor status, hormone replacement therapy history, histopathological characteristics or tumor grade were correlated with these biomarker changes. CONCLUSION: Unexpected correlation of proapoptotic DFMO activity in postmenopausal women with breast cancer warrants further study.
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Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Biomarcadores de Tumor/análisis , Neoplasias de la Mama/tratamiento farmacológico , Carcinoma Intraductal no Infiltrante/tratamiento farmacológico , Eflornitina/farmacología , Neoplasias de la Mama/patología , Carcinoma Intraductal no Infiltrante/patología , Proliferación Celular/efectos de los fármacos , Femenino , Humanos , Etiquetado Corte-Fin in Situ , Antígeno Ki-67/análisis , Metaloproteinasa 2 de la Matriz/análisis , Metaloproteinasa 9 de la Matriz/análisis , Persona de Mediana Edad , Invasividad NeoplásicaRESUMEN
BACKGROUND: A maximum entropy approach is proposed to predict the cytotoxic effects of a panel of colchicine derivatives in several human cancer cell lines. Data was obtained from cytotoxicity assays performed with 21 drug molecules from the same family of colchicine compounds and correlate these results with independent tubulin isoform expression measurements for several cancer cell lines. The maximum entropy method is then used in conjunction with computed relative binding energy values for each of the drug molecules against tubulin isotypes to which these compounds bind with different affinities. RESULTS: We have found by using our analysis that alphabetaI and alphabetaIII tubulin isoforms are the most important isoforms in establishing predictive response of cancer cell sensitivity to colchicine derivatives. However, since alphabetaI tubulin is widely distributed in the human body, targeting it would lead to severe adverse side effects. Consequently, we have identified tubulin isotype alphabetaIII as the most important molecular target for inhibition of microtubule polymerization and hence cancer cell cytotoxicity. Tubulin isotypes alphabetaI and alphabetaII are concluded to be secondary targets. CONCLUSIONS: The benefit of being able to correlate expression levels of specific tubulin isotypes and the resultant cell death effect is that it will enable us to better understand the origin of drug resistance and hence design optimal structures for the elimination of cancer cells. The conclusion of the study described herein identifies tubulin isotype alphabetaIII as a target for optimized chemotherapy drug design.
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Antineoplásicos/farmacología , Colchicina/farmacología , Resistencia a Antineoplásicos/genética , Ensayos de Selección de Medicamentos Antitumorales/métodos , Neoplasias/tratamiento farmacológico , Tubulina (Proteína)/biosíntesis , Línea Celular Tumoral , Diseño de Fármacos , Humanos , Neoplasias/genética , Neoplasias/metabolismo , Isoformas de Proteínas/biosíntesis , Isoformas de Proteínas/química , Isoformas de Proteínas/genética , Tubulina (Proteína)/química , Tubulina (Proteína)/genética , Moduladores de Tubulina/farmacologíaRESUMEN
BACKGROUND: This report and a companion report describe a validation of the ability of serum proteomic profiling via SELDI-TOF mass spectrometry to detect prostatic cancer. Details of this 3-stage process have been described. This report describes the development of the algorithm and results of the blinded test for stage 1. METHODS: We derived the decision algorithm used in this study from the analysis of serum samples from patients with prostate cancer (n = 181) and benign prostatic hyperplasia (BPH) (n = 143) and normal controls (n = 220). We also derived a validation test set from a separate, geographically diverse set of serum samples from 42 prostate cancer patients and 42 controls without prostate cancer. Aliquots were subjected to randomization and blinded analysis, and data from each laboratory site were subjected to the decision algorithm and decoded. RESULTS: Using the data collected from the validation test set, the decision algorithm was unsuccessful in separating cancer from controls with any predictive utility. Analysis of the experimental data revealed potential sources of bias. CONCLUSION: The ability of the decision algorithm to successfully differentiate between prostate cancer, BPH, and control samples using data derived from serum protein profiling was compromised by bias.
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Biomarcadores de Tumor/sangre , Recolección de Muestras de Sangre , Neoplasias de la Próstata/diagnóstico , Algoritmos , Sesgo , Técnicas de Apoyo para la Decisión , Humanos , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Hiperplasia Prostática/diagnóstico , Hiperplasia Prostática/metabolismo , Neoplasias de la Próstata/metabolismo , Proteómica , Curva ROC , Espectrometría de Masa por Láser de Matriz Asistida de Ionización DesorciónRESUMEN
PURPOSE: This phase II study evaluated the combination of semaxanib, a small molecule tyrosine kinase inhibitor of vascular endothelial growth factor (VEGF) receptor-2, and thalidomide in patients with metastatic melanoma to assess the efficacy, tolerability, pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of the combination. PATIENTS AND METHODS: Patients with metastatic melanoma, who had failed at least one prior biologic and/or chemotherapeutic regimen, were treated with escalating doses of thalidomide combined with a fixed dose of semaxanib. RESULTS: Twelve patients were enrolled and received 44 courses of semaxanib at the fixed dose of 145 mg/m2 intravenously twice-weekly in combination with thalidomide, commencing at 200 mg daily with intrapatient dose escalation as tolerated. Treatment with semaxanib was initiated 1 day before thalidomide in the first course, permitting the assessment of the PKs of semaxanib alone (course 1) and in combination with thalidomide (course 2). The principal toxicities included deep venous thrombosis, headache, and lower extremity edema. Of ten patients evaluable for response, one complete response lasting 20 months and one partial response lasting 12 months were observed. Additionally, four patients had stable disease lasting from 2 to 10 months. The PKs of semaxanib were characterized by drug exposure parameters comparable to those observed in single-agent phase II studies, indicating the absence of major drug-drug interactions. Maximum semaximib plasma concentration values were 1.2-3.8 microg/ml in course 1 and 1.1-3.9 microg/ml in course 2. The mean terminal half-life was 1.3 ( +/- 0.31) h. Biological studies revealed increasing serum VEGF concentrations following treatment in patients remaining on study for more than 4 months. CONCLUSION: The combination of semaxanib and thalidomide was feasible and demonstrated anti-tumor activity in patients with metastatic melanoma who had failed prior therapy. Further evaluations of therapeutic strategies that target multiple angiogenesis pathways may be warranted in patients with advanced melanoma and other malignancies.
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Indoles/farmacocinética , Melanoma/tratamiento farmacológico , Pirroles/farmacocinética , Talidomida/farmacocinética , Adulto , Anciano , Inhibidores de la Angiogénesis/efectos adversos , Inhibidores de la Angiogénesis/farmacocinética , Inhibidores de la Angiogénesis/uso terapéutico , Área Bajo la Curva , Astenia/inducido químicamente , Relación Dosis-Respuesta a Droga , Edema/inducido químicamente , Femenino , Semivida , Cefalea/inducido químicamente , Humanos , Indoles/efectos adversos , Indoles/uso terapéutico , Masculino , Melanoma/patología , Persona de Mediana Edad , Metástasis de la Neoplasia , Enfermedades del Sistema Nervioso Periférico/inducido químicamente , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/farmacocinética , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirroles/efectos adversos , Pirroles/uso terapéutico , Talidomida/efectos adversos , Factor de Necrosis Tumoral alfa/sangre , Factor de Necrosis Tumoral alfa/orina , Factor A de Crecimiento Endotelial Vascular/sangre , Factor A de Crecimiento Endotelial Vascular/orina , Trombosis de la Vena/inducido químicamenteRESUMEN
BACKGROUND/PURPOSE: Genetic heterogeneity of neuroblastic tumors leads to biochemical changes that manifest themselves in different symptoms and clinical courses, which may vary from spontaneous regression and remission to progression with fatal outcome. METHODS: To test the hypothesis that ratios of dopamine (DA) to noradrenaline and of DA to vanillylmandelic acid reflect the composition of adrenergic clones and tumor heterogeneity, we determined urinary DA/noradrenaline and DA/vanillylmandelic acid ratios that presumably reflect DA-beta-hydroxylase (DBH) activity and the prognostic values thereof. RESULTS: Based on catecholamine metabolism, 4 model situations were defined: (a) complete block of DBH in all cells; (b) block of DBH in some cells; (c) a different enzymatic block; and (d) normal DBH activity in the population of tumor-forming cells. Normal DBH activity was encountered most frequently in children younger than 2 years and in tumors representing favorable prognostic stages (I, II, and IVS). Surviving children with stage IV neuroblastoma presented with tumors composed primarily of cells without the DBH block. Further stratification of 2 prognostically poor groups (stages IV and III + IV) was possible with respect to DBH activity. CONCLUSIONS: Differential production of neurotransmitters in a population of tumor cells may be explained in terms of tumor heterogeneity.
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Catecolaminas/orina , Neoplasias del Sistema Nervioso/genética , Neuroblastoma/genética , Catecolaminas/genética , Células Clonales/metabolismo , Dopamina/orina , Ganglioneuroma/genética , Ganglioneuroma/orina , Neoplasias del Sistema Nervioso/orina , Neuroblastoma/orina , Norepinefrina/orina , Valor Predictivo de las Pruebas , Pronóstico , Ácido Vanilmandélico/orinaRESUMEN
BACKGROUND: The differential sensitivity of some tumors to paclitaxel and docetaxel raises questions regarding the specific mechanisms responsible for the discrepant sensitivity to these taxanes. MATERIALS AND METHODS: Docetaxel and paclitaxel were evaluated and compared at maximum tolerated doses (MTD) and 0.5 MTDs against the human pediatric tumor xenograft models SK-N-MC and IMR32 (neuroblastoma), RH1 and RH30 (rhabdomyosarcoma) and KHOS/NP (osteosarcoma), with 8-10 animals per group. The drug effects on the expression of the beta-tubulin isotypes, Bcl-2, Bax, Bcl-XL and proteomic profiles were evaluated by immunobloting and SELDI mass spectrometry in tumor xenografts dosed at 0.5 MTDs. RESULTS: At MTDs, docetaxel was superior in neuroblastoma and osteosarcoma, while paclitaxel was more active in the rhabdomyosarcoma models. Docetaxel showed remarkable efficacy in KHOS/NP even at 0.5 MTD. The drugs had significantly different, yet highly heterogeneous effects on the tumor levels of betaI-tubulin (RH30), betaIII-tubulin (IMR32, KHOS/NP, RH]), Bax (IMR32, SK-N-MC) and Bcl-XL (KHOS/NP). In contrast, six protein species identified by proteomic profiling were consistently and differentially regulated by docetaxel and paclitaxel in all KHOS/NP xenografts. CONCLUSION: Anticancer activity showed no apparent correlation with drug effects on beta-tubulin isotypes and apoptotic markers. The mass spectrometry approach has potential for the discovery of proteomic biomarkers for drug sensitivity.
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Biomarcadores de Tumor/metabolismo , Neoplasias Óseas/tratamiento farmacológico , Neuroblastoma/tratamiento farmacológico , Osteosarcoma/tratamiento farmacológico , Paclitaxel/farmacología , Rabdomiosarcoma/tratamiento farmacológico , Taxoides/farmacología , Animales , Neoplasias Óseas/metabolismo , Niño , Docetaxel , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Humanos , Ratones , Ratones Desnudos , Neuroblastoma/metabolismo , Osteosarcoma/metabolismo , Proteómica , Rabdomiosarcoma/metabolismo , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: The antineoplastic activity of AZD3409 was evaluated in relation to paclitaxel in human breast (MDA-MB-231, BT-474) and ovarian (A2780, A2780cp) cancer cell lines. Biomarkers of apoptosis, protein prenylation, survival, angiogenesis and cellular growth were determined. MATERIALS AND METHODS: Cytotoxicity was evaluated by MTS assay, and apoptosis was evaluated by TUNEL. Biomarkers were measured by Western blots and ELISA. RESULTS: The IC50 concentrations of AZD3409 in MDA-MB-231, BT-474, A2780 and A2780cp were 19.16, 5.69, 3.19, and 8.86 microM, respectively. The corresponding apoptogenic EC50 concentrations were 6.81, 4.15, 1.54 and 4.59 microM. CONCLUSION: Famesylation of HDJ-2 was inhibited in all cell lines. Secretion of VEGF, bFGF and MMP-1 were inhibited in the breast lines but augmented in the ovarian lines. AZD3409 increased Akt activation in breast lines and decreased it in ovarian lines, without effect on MEK or ERK activation. AZD3409 cytotoxicity is mediated in part by inhibition of farnesylation.
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Antineoplásicos/farmacología , Transducción de Señal/efectos de los fármacos , Apoptosis/efectos de los fármacos , Western Blotting , Relación Dosis-Respuesta a Droga , Ensayo de Inmunoadsorción Enzimática , Etiquetado Corte-Fin in SituRESUMEN
Neuroblastoma, the most common extracranial solid tumor in children, has a highly heterogeneous clinical presentation and course. Current risk-based therapy is usually effective in patients who have intermediate risk features, however, intensive treatment of advanced neuroblastoma in children over two years of age is far from satisfactory. Current therapeutic approaches include the optimization of pharmacokinetic and pharmacodynamic properties of conventional agents, as well as the development of novel targeted drugs, such as signal transduction and angiogenesis inhibitors, apoptosis/differentiation stimulators and immunotherapeutics. This review provides an overview of current treatment options and future perspectives for the therapy and prevention of neuroblastoma.
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Inhibidores de la Angiogénesis/administración & dosificación , Antineoplásicos/administración & dosificación , Vacunas contra el Cáncer/administración & dosificación , Sistemas de Liberación de Medicamentos , Neuroblastoma/tratamiento farmacológico , Administración Oral , Inhibidores de la Angiogénesis/uso terapéutico , Antineoplásicos/uso terapéutico , Apoptosis/efectos de los fármacos , Diferenciación Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Combinación de Medicamentos , Diseño de Fármacos , Resistencia a Antineoplásicos , Quimioterapia Combinada , Humanos , Inmunoterapia , Proteína Proto-Oncogénica N-Myc , Neuroblastoma/genética , Neuroblastoma/inmunología , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Proteínas Oncogénicas/genética , Proteínas Oncogénicas/metabolismo , Ensayos Clínicos Controlados Aleatorios como Asunto , Transducción de Señal/efectos de los fármacosRESUMEN
BACKGROUND: Farnesyltransferase inhibitor R115777 (Tipifamib, Zarnestra) is active in breast cancer, but its efficacy in drug combinations has not been extensively investigated. MATERIALS AND METHODS: The activity of R115777 and paclitaxel, alone and in combination, was studied in the human breast cancer cell lines, BT-474 (overexpressed HER2/neu) and MDA-MB-231 (low HER2/neu), with cell viability and biomarkers for farnesylation (HDJ-2, Rho B), tumor growth (Raf/MEK/ERK), survival (PI3K/Akt) and angiogenesis (VEGF, FGF-2, MMP-1, MMP-2, MMP-9) as the endpoints. RESULTS: The drug combination resulted in additive cytotoxicity. R115777 +/- paclitaxel inhibited HDJ-2 farnesylation, up-regulated RhoB, transiently lowered (P)ERK/ERK and (P)Akt/Akt, reduced Raf-1 and MEK and inhibited secretion of VEGF and MMP-1. CONCLUSION: The effect of R115777 on prenylation biomarkers is consistent with its mechanism of action. The drug interfered with tumor growth, survival and angiogenesis pathways in breast cancer models with low or overexpressed HER2/neu receptor. The combination of R115777 with paclitaxel might offer clinical advantage over monotherapies.
Asunto(s)
Transferasas Alquil y Aril/antagonistas & inhibidores , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Quinolonas/farmacología , Neoplasias de la Mama/irrigación sanguínea , Neoplasias de la Mama/enzimología , Proteínas Portadoras/metabolismo , Procesos de Crecimiento Celular/efectos de los fármacos , Procesos de Crecimiento Celular/fisiología , Línea Celular Tumoral , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/farmacología , Farnesiltransferasa , Proteínas del Choque Térmico HSP40 , Proteínas de Choque Térmico/metabolismo , Humanos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Neovascularización Patológica/metabolismo , Paclitaxel/administración & dosificación , Paclitaxel/farmacología , Prenilación de Proteína/efectos de los fármacos , Quinolonas/administración & dosificación , Receptor ErbB-2/biosíntesis , Proteína de Unión al GTP rhoB/metabolismoRESUMEN
PURPOSE: To determine the antitumor activity and safety of oblimersen sodium, a phosphorothioate antisense oligonucleotide directed to the bcl-2 mRNA, with docetaxel in patients with hormone-refractory prostate cancer (HRPC) and to determine if relevant pharmacokinetic and pharmacodynamic variables of oblimersen or docetaxel influence response to this therapy. EXPERIMENTAL DESIGN: Patients with HRPC were treated with oblimersen sodium by continuous i.v. infusion on days 1 to 8 with docetaxel given i.v. over 1 hour on day 6 every 3 weeks. Plasma samples were analyzed to characterize the pharmacokinetic variables of both oblimersen and docetaxel, and paired collections of peripheral blood mononuclear cells were collected to determine Bcl-2 protein expression pretreatment and post-treatment. RESULTS: Twenty-eight patients received 173 courses of oblimersen (7 mg/kg/d continuous i.v. infusion on days 1-8) and docetaxel (75 mg/m(2) i.v. on day 6). Prostate-specific antigen responses were observed in 14 of 27 (52%) patients, whereas 4 of 12 (33%) patients with bidimensionally measurable disease had objective responses. The mean oblimersen steady-state concentration (C(ss)) was a significant determinant of antitumor activity; mean C(ss) values were higher in responders compared with nonresponders (6.24 +/- 1.68 versus 4.27 +/- 1.22; P = 0.008). The median survival of all patients was 19.8 months. Bcl-2 protein expression decreased a median of 49.9% in peripheral blood mononuclear cells post-treatment, but the individual incremental change did not correlate with either oblimersen C(ss) or response. CONCLUSIONS: Oblimersen combined with docetaxel is an active combination in HRPC patients demonstrating both an encouraging response rate and an overall median survival. The absence of severe toxicities at this recommended dose, evidence of Bcl-2 protein inhibition, and encouraging antitumor activity in HPRC patients warrant further clinical evaluation of this combination, including studies to optimize oblimersen C(ss).
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Próstata/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos Hormonales/farmacología , Docetaxel , Resistencia a Antineoplásicos , Humanos , Masculino , Persona de Mediana Edad , Oligonucleótidos Antisentido , Neoplasias de la Próstata/patología , Proteínas Proto-Oncogénicas c-bcl-2/biosíntesis , Análisis de Supervivencia , Taxoides/administración & dosificación , Taxoides/farmacocinética , Tionucleótidos/administración & dosificación , Tionucleótidos/farmacocinética , Resultado del TratamientoRESUMEN
BACKGROUND: Paclitaxel and docetaxel affect microtubule polymerization, yet surprising differences in tumor sensitivity to the taxanes have been observed. Docetaxel was superior to paclitaxel in inhibiting in vivo growth of human lung and prostate but not breast cancer models. MATERIALS AND METHODS: We compared drug cytotoxicity, effects on ß-tubulin isoforms, markers of apoptosis and proteomic profiles in human prostate (LNCaP), lung (SK-MES, MV-522) and breast (MCF-7, MDA-231) cancer cell lines in vitro. RESULTS: Cytotoxicity followed the order SK-MES