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1.
Recent Pat Anticancer Drug Discov ; 13(4): 428-444, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30027855

RESUMO

BACKGROUND: The pharmaceutical development of endocrine disruptors could not achieve appropriate advances in the field of anticancer fight. OBJECTIVE: Considerations on the principles of currently used endocrine therapies. METHODS: Comparison of the results of genetic studies being performed on breast cancer cells treated with estrogens, synthetic estrogens and antiestrogens. RESULTS: In breast cancer cells, increased estrogen concentrations amplify ER-signaling via a synergistic upregulation of both liganded and unliganded ER-activations and increased aromatase expression. The higher the upregulation of ER-signaling, the stronger is the tumor response. Low doses of synthetic estrogens exert an inhibition on the ligand-independent AF1-domain in breast cancer cells, while provoke compensatory activation on the superior, ligand-dependent AF2-domain of ERs and estrogen synthesis. Conversely, high doses of synthetic estrogens induce uncompensated genome-wide disruption in ER-regulated genes leading to toxic symptoms and unpredictable tumor responses. Treatment with antiestrogens, either ER-blockers or aromatase inhibitors, obstructs the crucial AF2-domain of ERs strongly deteriorating the activation of genomic machinery. Tumor responses to antiestrogen treatment depend on the compensatory activation of ER-signaling and the restoration of genomic stability. Recent patents provide methods for the conversion of ER-negative cancers to ER-positive ones improving the possibility of successful treatment. CONCLUSION: In tumor cells, the stabilization of genomic machinery and self-directed death may be achieved via a balanced activation of the AF1 and AF2 domains of ERs by natural estrogen treatment. In contrast, the blockade of either AF1 or AF2 domain by endocrine disruptors leads to toxic symptoms and unforeseeable tumor responses.


Assuntos
Neoplasias da Mama/metabolismo , Disruptores Endócrinos/metabolismo , Receptor Cross-Talk/fisiologia , Receptores Estrogênicos/metabolismo , Receptores de Fatores de Crescimento/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Neoplasias da Mama/tratamento farmacológico , Disruptores Endócrinos/farmacologia , Disruptores Endócrinos/uso terapêutico , Antagonistas de Estrogênios/metabolismo , Antagonistas de Estrogênios/farmacologia , Antagonistas de Estrogênios/uso terapêutico , Estrogênios/metabolismo , Feminino , Humanos , Ligação Proteica/efeitos dos fármacos , Ligação Proteica/fisiologia , Receptor Cross-Talk/efeitos dos fármacos , Receptores Estrogênicos/antagonistas & inibidores , Receptores de Fatores de Crescimento/antagonistas & inibidores , Transdução de Sinais/fisiologia
2.
Expert Opin Emerg Drugs ; 23(1): 1-16, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29528256

RESUMO

INTRODUCTION: Epithelial Ovarian Cancer (EOC) is the most lethal gynecological malignancy. EOC outcomes remain unsatisfactory despite aggressive surgical approach, disease chemo-sensitivity and recent introduction of agents targeting angiogenesis and tumour genome instability. Advances in EOC research have allowed for a tailored treatment approach and accelerated development of novel treatments strategies from bench to bed side, anticipated to improve patient outcomes. Areas covered: Comprehensive review of growth factor receptor antagonists for EOC treatment currently in different stages of development was performed. English peer-reviewed articles and abstracts were searched in MEDLINE, PubMed, Embase and major conferences. We focused on agents that antagonize growth factors promoting sustained proliferative signaling, angiogenesis and evasion of immune destruction blocking the receptor or its stimulating factors. Expert opinion: Receptor signaling has been well characterized for most cancer generating pathways. Growth receptor antagonists are represented by both high receptor affinity monoclonal antibodies as well as tyrosine kinase inhibitors; both are especially effective when a related predictive biomarker of response is identified. Therefore, along with the promising development of novel receptor antagonists or modulators in EOC treatment, targeting essential growth pathways in the tumour and associated microenvironment, is fundamental for biomarker discovery and towards achieving significant improvements in response.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Epiteliais e Glandulares/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Receptores de Fatores de Crescimento/antagonistas & inibidores , Animais , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/farmacologia , Carcinoma Epitelial do Ovário , Desenho de Drogas , Feminino , Humanos , Neoplasias Epiteliais e Glandulares/patologia , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/patologia , Neoplasias Ovarianas/patologia , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico
3.
Expert Opin Emerg Drugs ; 22(2): 165-174, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28562096

RESUMO

INTRODUCTION: Therapy for metastatic melanoma has undergone a rapid transformation over the past 5-10 years. Advances in immunotherapy with checkpoint inhibitors, including both anti-CTLA-4 and anti-PD-1/PD-L1, have led to durable responses in up to 50% of patients. As our understanding of the processes driving the transformation of melanocytes has improved, progress in targeted therapies has also continued. Areas covered: Angiogenesis and the tumor's dependence on an expanded vascular supply has been a target for novel therapies since the 1970's, as this tissue is derived from endothelial cells that are genetically stable in adults. A phase II trial studying combined therapy with bevacizumab (an inhibitor of angiogenesis) and ipilimumab found promising results. Other agents such as sorafenib have not been as successful, failing to extend progression free or overall survival in clinical trials. In this paper other targeted growth factor inhibitors will also be discussed. Expert opinion: Ultimately, melanoma may not be vulnerable solely to chemotherapy or targeted therapy, but may be efficaciously treated with immunotherapy due to its high mutational rate resulting in the expression of numerous neo-antigens. Therapies with combinations of agents including growth factor receptor and either other targeted therapies or immunotherapy may be a promising complimentary approach.


Assuntos
Antineoplásicos/farmacologia , Melanoma/tratamento farmacológico , Neovascularização Patológica/tratamento farmacológico , Adulto , Inibidores da Angiogênese/farmacologia , Desenho de Drogas , Humanos , Imunoterapia/métodos , Melanoma/irrigação sanguínea , Melanoma/patologia , Terapia de Alvo Molecular , Metástase Neoplásica , Neovascularização Patológica/patologia , Receptores de Fatores de Crescimento/antagonistas & inibidores , Taxa de Sobrevida
4.
Expert Opin Emerg Drugs ; 22(2): 191-200, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28506080

RESUMO

INTRODUCTION: Hepatocellular carcinoma (HCC) is a leading cause of death worldwide. Over the last decade, sorafenib has been the only available therapeutic option for advanced HCC, although regorafenib recently showed a survival benefit compared with placebo in a second-line setting. Areas covered: This review discusses key published and ongoing studies with targeted agents in HCC, molecular targets of HCC, the mechanism of resistance to sorafenib, and the role of biomarker-enriched clinical trials. Expert opinion: The multiplicity of drivers and the existence of substantial molecular heterogeneity limit the benefits of targeted therapies in HCC. Based on molecular biology developments, a few biomarker-enriched clinical trials that target candidate driver genes are ongoing, and the outcomes of these are highly anticipated. Poor availability of tumor tissue and tumor heterogeneity in patients with HCC make liquid biopsy a very attractive option, although this technique remains to be validated.


Assuntos
Antineoplásicos/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Biomarcadores Tumorais/metabolismo , Carcinoma Hepatocelular/patologia , Desenho de Drogas , Resistencia a Medicamentos Antineoplásicos , Humanos , Neoplasias Hepáticas/patologia , Terapia de Alvo Molecular , Niacinamida/análogos & derivados , Niacinamida/farmacologia , Niacinamida/uso terapêutico , Compostos de Fenilureia/farmacologia , Compostos de Fenilureia/uso terapêutico , Receptores de Fatores de Crescimento/antagonistas & inibidores , Sorafenibe , Taxa de Sobrevida
5.
Expert Opin Emerg Drugs ; 21(4): 431-440, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27690664

RESUMO

INTRODUCTION: The landscape of systemic treatment for metastatic renal cell carcinoma (RCC) has dramatically changed with the introduction of targeted agents including vascular endothelial growth factor (VEGF) inhibitors. Recently, multiple new agents including growth factor receptor antagonists and a checkpoint inhibitor were approved for the treatment of refractory metastatic RCC based on encouraging benefit shown in clinical trials. Areas covered: The background and biological rationale of existing treatment options including a brief discussion of clinical trials which led to their approval, is presented. This is followed by reviewing the limitations of these therapeutic options, medical need to develop new treatments and major goals of ongoing research. We then discuss two recently approved growth factor receptor antagonists i.e. cabozantinib and lenvatinib, and a recently approved checkpoint inhibitor, nivolumab, and issues pertaining to drug development, and future directions in treatment of metastatic RCC. Expert opinion: Recently approved growth factor receptor antagonists have shown encouraging survival benefit but associated drug toxicity is a major issue. Nivolumab, a programmed death 1 (PD-1) checkpoint inhibitor, has similarly shown survival benefit and is well tolerated. With multiple options now available in this patient population, the right sequence of these agents remains to be determined.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Anilidas/efeitos adversos , Anilidas/farmacologia , Anilidas/uso terapêutico , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacologia , Carcinoma de Células Renais/patologia , Aprovação de Drogas , Desenho de Drogas , Humanos , Neoplasias Renais/patologia , Metástase Neoplásica , Nivolumabe , Compostos de Fenilureia/efeitos adversos , Compostos de Fenilureia/farmacologia , Compostos de Fenilureia/uso terapêutico , Piridinas/efeitos adversos , Piridinas/farmacologia , Piridinas/uso terapêutico , Quinolinas/efeitos adversos , Quinolinas/farmacologia , Quinolinas/uso terapêutico , Receptores de Fatores de Crescimento/antagonistas & inibidores
6.
Am J Physiol Heart Circ Physiol ; 310(5): H608-18, 2016 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-26747500

RESUMO

We showed previously that vascular smooth muscle cells (VSMCs) from spontaneously hypertensive rats (SHRs) exhibit overexpression of Gqα/PLCß1 proteins, which contribute to increased protein synthesis through the activation of MAP kinase signaling. Because oxidative stress has been shown to be increased in hypertension, the present study was undertaken to examine the role of oxidative stress and underlying mechanisms in enhanced expression of Gqα/PLCß1 proteins and VSMC hypertrophy. Protein expression was determined by Western blotting, whereas protein synthesis and cell volume, markers for VSMC hypertrophy, were determined by [(3)H]-leucine incorporation and three-dimensional confocal imaging, respectively. The increased expression of Gqα/PLCß1 proteins, increased protein synthesis, and augmented cell volume exhibited by VSMCs from SHRs were significantly attenuated by antioxidants N-acetyl-cysteine (NAC), a scavenger of superoxide anion, DPI, an inhibitor of NAD(P)H oxidase. In addition, PP2, AG1024, AG1478, and AG1295, inhibitors of c-Src, insulin-like growth factor receptor (IGFR), epidermal growth factor receptor (EGFR), and platelet-derived growth factor receptor (PDGFR), respectively, also attenuated the enhanced expression of Gqα/PLCß1 proteins and enhanced protein synthesis in VSMCs from SHRs toward control levels. Furthermore, the levels of IGF-1R and EGFR proteins and not of PDGFR were also enhanced in VSMCs from SHRs, which were attenuated significantly by NAC, DPI, and PP2. In addition, NAC, DPI, and PP2 also attenuated the enhanced phosphorylation of IGF-1R, PDGFR, EGFR, c-Src, and EKR1/2 in VSMCs from SHRs. These data suggest that enhanced oxidative stress in VSMCs from SHRs activates c-Src, which through the transactivation of growth factor receptors and MAPK signaling contributes to enhanced expression of Gqα/PLCß1 proteins and resultant VSMC hypertrophy.


Assuntos
Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/metabolismo , Hipertensão/enzimologia , Músculo Liso Vascular/enzimologia , Miócitos de Músculo Liso/enzimologia , Estresse Oxidativo , Fosfolipase C beta/metabolismo , Receptores de Fatores de Crescimento/metabolismo , Animais , Antioxidantes/farmacologia , Tamanho Celular , Células Cultivadas , Modelos Animais de Doenças , Receptores ErbB/metabolismo , Hipertensão/genética , Hipertensão/patologia , Hipertrofia , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/patologia , Estresse Oxidativo/efeitos dos fármacos , Fosforilação , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas pp60(c-src)/antagonistas & inibidores , Proteínas Proto-Oncogênicas pp60(c-src)/metabolismo , Interferência de RNA , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Receptor IGF Tipo 1/metabolismo , Receptores de Fatores de Crescimento/antagonistas & inibidores , Receptores de Fatores de Crescimento/genética , Receptores do Fator de Crescimento Derivado de Plaquetas/metabolismo , Transdução de Sinais , Transfecção , Regulação para Cima
7.
Cancer Treat Rev ; 42: 47-55, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26678514

RESUMO

Despite recent breakthroughs in treatment of advanced thyroid cancers, prognoses remain poor. Treatment of advanced, progressive disease remains challenging, with limited treatment options. Small-molecule tyrosine kinase inhibitors, including vandetanib, cabozantinib, sorafenib, and lenvatinib, which are now FDA-approved for thyroid cancer, have shown clinical benefit in advanced thyroid cancer. Lenvatinib is approved for treatment of locally recurrent or metastatic, progressive, radioactive iodine (RAI)-refractory differentiated thyroid cancer (DTC). It has been studied in phase II and III trials for treatment of advanced RAI-refractory DTC, and in a phase II trial for medullary thyroid cancer (MTC). Lenvatinib targets vascular endothelial growth factor receptors 1-3 (VEGFR1-3), fibroblast growth factor receptors 1-4 (FGFR-1-4), RET, c-kit, and platelet-derived growth factor receptor α (PDGFRα). Its antitumor activity may be due to antiangiogenic properties and direct antitumor effects. Lenvatinib has demonstrated antitumor activity in a variety of solid tumors, including MTC, in phase I and II clinical trials. In a phase II study in advanced RAI-refractory DTC, lenvatinib-treated patients achieved a 50% response rate (RR), with median progression-free survival (PFS) of 12.6 months. In a phase III trial in RAI-refractory DTC, median PFS in lenvatinib-treated patients was 18.3 months, with a 65% overall RR, versus 3.6 months in placebo-treated patients, with a 2% RR. Adverse events occurring in >50% of patients included hypertension, diarrhea, fatigue/asthenia, and decreased appetite. Lenvatinib is a promising new agent for treatment of patients with advanced thyroid cancer.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma/tratamento farmacológico , Terapia de Alvo Molecular , Proteínas de Neoplasias/antagonistas & inibidores , Compostos de Fenilureia/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Quinolinas/uso terapêutico , Neoplasias da Glândula Tireoide/tratamento farmacológico , Animais , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carboplatina/administração & dosagem , Carcinoma/enzimologia , Carcinoma/terapia , Ensaios Clínicos como Assunto , Terapia Combinada , Everolimo/administração & dosagem , Humanos , Lactente , Radioisótopos do Iodo/uso terapêutico , Camundongos , Estudos Multicêntricos como Assunto , Neoplasias/tratamento farmacológico , Neoplasias/enzimologia , Paclitaxel/administração & dosagem , Compostos de Fenilureia/administração & dosagem , Compostos de Fenilureia/efeitos adversos , Compostos de Fenilureia/farmacologia , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/farmacologia , Quinolinas/administração & dosagem , Quinolinas/efeitos adversos , Quinolinas/farmacologia , Receptores de Fatores de Crescimento/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Neoplasias da Glândula Tireoide/enzimologia , Neoplasias da Glândula Tireoide/terapia , Tireoidectomia , Ensaios Antitumorais Modelo de Xenoenxerto
8.
Biomed Res Int ; 2013: 964743, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23936861

RESUMO

To date, lung cancer is the leading cause of cancer-related death worldwide, among which nonsmall cell lung cancer (NSCLC) comprises about 85%. Taking into account the side effects of surgery, radiation, platinum-based doublet chemotherapy, and the growth self-sufficiency characteristic of cancer cells, drugs have been discovered toward growth factor receptor (GFR) to treat NSCLC. As expected, these drugs provide a greater benefit. To increase the efficacy of such growth factor receptor tyrosine kinase inhibitors (RTKIs), coinhibition of GFR signaling pathways and combination of inhibitors along with radiation or chemotherapy have drew intense insight. Although clinical trials about single-agent RTKIs or their combination strategies suggest their increase potency against cancer, they are not beyond adverse effects, and sometimes the effects are more deadly than chemotherapy. Nevertheless the hope for RTKIs may be proved true by further researches and digging deep into cancer therapeutics.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Terapia de Alvo Molecular , Inibidores de Proteínas Quinases/uso terapêutico , Receptores de Fatores de Crescimento/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Ensaios Clínicos como Assunto , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Receptores Proteína Tirosina Quinases/uso terapêutico , Receptores de Fatores de Crescimento/antagonistas & inibidores , Bibliotecas de Moléculas Pequenas
9.
J Steroid Biochem Mol Biol ; 138: 248-56, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23792785

RESUMO

Prostate cancer is a leading cause of cancer death in men in developed countries. Once the tumor has achieved a castration-refractory metastatic stage, treatment options are limited with the average survival of patients ranging from two to three years only. Recently, new drugs for treatment of castration-resistant prostate cancer (CRPC) have been approved, and others are in an advanced stage of clinical testing. In this review we provide an overview of the new therapeutic agents that arrived in the clinical praxis or are tested in clinical studies and their mode of action including hormone synthesis inhibitors, new androgen receptor blockers, bone targeting and antiangiogenic agents, endothelin receptor antagonists, growth factor inhibitors, novel radiotherapeutics and taxanes, and immunotherapeutic approaches. Results and limitations from clinical studies as well as future needs for improvement of CRPC treatments are critically discussed.


Assuntos
Castração , Neoplasias da Próstata/tratamento farmacológico , Humanos , Imunoterapia , Masculino , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/cirurgia , Neoplasias da Próstata/terapia , Receptores Androgênicos/metabolismo , Receptores de Fatores de Crescimento/antagonistas & inibidores
10.
Curr Med Chem ; 19(28): 4742-58, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22873663

RESUMO

Receptor-targeted optical imaging of cancer is emerging as an attractive strategy for early cancer diagnosis and surgical guidance. The success of such strategy depends largely upon the development of receptor-targeted fluorescent probes with high specificity and binding affinity to the target receptors. Recently, a host of such probes have been reported to target cancer-specific receptors, such as somatostatin receptors (SSTRs), integrin receptors, cholecystokinin-2 (CCK(2)) receptor, gastrin-releasing peptide (GRP) receptor, endothelin A (ET(A)) receptor, translocator protein (TSPO) receptor, epidermal growth factor (EGF) receptor, human epidermal growth factor receptor 2 (HER2), vascular endothelial growth factor (VEGF) receptor, folate receptor (FR), transferrin receptor (TFR), low-density lipoprotein (LDL) receptors, type I insulin-like growth factor receptor (IGF1R), vasoactive intestinal peptide (VIP) receptors, urokinase plasminogen activator (uPA) and estrogen receptor (ER). This review will describe the recent advances in synthetic targeting optical imaging probes and demonstrate their in vivo imaging potentials. Moreover, current status of near infrared (NIR) fluorescent dyes, targeting moieties and coupling reactions, as well as strategies for designing targeted probes, will also be discussed.


Assuntos
Corantes Fluorescentes/química , Imagem Óptica , Animais , Antagonistas dos Receptores de Endotelina , Receptores de Folato com Âncoras de GPI/antagonistas & inibidores , Receptores de Folato com Âncoras de GPI/metabolismo , Humanos , Neoplasias/diagnóstico , Neoplasias/metabolismo , Receptores da Bombesina/antagonistas & inibidores , Receptores da Bombesina/metabolismo , Receptores da Colecistocinina/antagonistas & inibidores , Receptores da Colecistocinina/metabolismo , Receptores de Endotelina/metabolismo , Receptores de Fatores de Crescimento/antagonistas & inibidores , Receptores de Fatores de Crescimento/metabolismo , Receptores de Somatostatina/antagonistas & inibidores , Receptores de Somatostatina/metabolismo , Receptores da Transferrina/antagonistas & inibidores , Receptores da Transferrina/metabolismo
11.
J Midwifery Womens Health ; 57(3): 241-7, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22587581

RESUMO

Uterine leiomyomas are the most common benign gynecologic tumors. While the true etiology of leiomyomas remains unknown, their origin is thought to be multifactorial including genetic, hormonal, and tissue growth factor variations. Leiomyomas are predominantly found in women of reproductive age and are the leading indication for hysterectomy worldwide. Menstrual irregularities, pain, and fertility difficulties may arise from leiomyoma presence, although many women remain asymptomatic. Diagnosis can be made via ultrasound or magnetic resonance imaging, when precise mapping of the tissue is needed. Many treatment options are available ranging from surgical to medical and should be chosen depending on symptom severity, number and size of leiomyomas, patient age, fertility desires, and patient preferences. The objective of this article is to present a practical clinical perspective on uterine leiomyomas and an overview of contemporary treatment options.


Assuntos
Leiomioma/diagnóstico , Leiomioma/terapia , Saúde Reprodutiva , Neoplasias Uterinas/diagnóstico , Neoplasias Uterinas/terapia , Fatores Etários , Antineoplásicos/uso terapêutico , Feminino , Inibidores do Crescimento/uso terapêutico , Humanos , Histerectomia , Leiomioma/etiologia , Prognóstico , Receptores de Fatores de Crescimento/antagonistas & inibidores , Fatores de Risco , Resultado do Tratamento , Neoplasias Uterinas/etiologia
12.
Crit Rev Oncol Hematol ; 83(1): 130-44, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22280915

RESUMO

Non-small cell lung cancer is the leading cause of cancer death in the United States. Efforts to improve outcomes have led to a greater understanding of the predictive and prognostic value of histologic and molecular characteristics of individual tumors. In standard practice, biopsy specimens are examined first on a histologic level, then on a molecular level with the recognition that both histologic subtype and gene expression profile can guide treatment decisions and have a profound effect on clinical outcomes. Epidermal growth factor activation mutations were among the first biomarkers shown to have therapeutic implications, and levels of gene expression for an array of other biomarkers are being evaluated in clinical trials. Ongoing studies underscore the need to implement molecular and histologic screening as part of routine clinical practice. To achieve an integration of clinical, histologic, and molecular parameters when making treatment decisions, collaboration between oncologists and pathologists is essential.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Medicina de Precisão/métodos , Antineoplásicos/administração & dosagem , Biomarcadores Tumorais/antagonistas & inibidores , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Ensaios Clínicos como Assunto , Perfilação da Expressão Gênica , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidade , Mutação , Medicina de Precisão/tendências , Prognóstico , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Receptores de Fatores de Crescimento/antagonistas & inibidores , Receptores de Fatores de Crescimento/genética , Receptores de Fatores de Crescimento/metabolismo , Taxa de Sobrevida
13.
Am J Physiol Heart Circ Physiol ; 302(8): H1591-602, 2012 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-22268112

RESUMO

Oxidative stress has been shown to increase the expression of G(i)α proteins in vascular smooth muscle cells (VSMC) from spontaneously hypertensive rats. The present study was undertaken to examine if H(2)O(2), which induces oxidative stress, could also enhance the expression of G(i)α proteins in VSMC and to further explore the underlying signaling pathways responsible for this response. Treatment of VSMC with H(2)O(2) increased the expression of G(i)α proteins and not of G(s)α protein in a concentration- and time-dependent manner. A maximal increase of ∼40-50% was observed at 100 µM and 1 h and was restored to control levels by AG1295 and AG1478, inhibitors of epidermal growth factor receptor (EGF-R) and platelet-derived growth factor receptor (PDGF-R), respectively, and PD98059 and U126, inhibitors of extracellular signal-regulated kinase (ERK1/2), and wortmannin and AKT inhibitor VIII, inhibitors of PKB/AKT, respectively. In addition, H(2)O(2) also increased the phosphorylation of EGF-R, PDGF-R, ERK1/2, and AKT, which was attenuated by the respective inhibitors, whereas the inhibitors of EGF-R and PDGE-R also inhibited the enhanced phosphorylation of ERK1/2 and AKT. Furthermore, transfection of cells with short interfering RNA of EGF-R and PDGF-R restored the H(2)O(2)-induced enhanced expression of G(i)α proteins to control levels. The increased expression of G(i)α proteins was reflected in enhanced G(i) functions as demonstrated by enhanced inhibition of adenylyl cyclase by inhibitory hormones and forskolin-stimulated adenylyl cyclase activity by a low concentration of GTPγS, whereas G(s)α-mediated stimulations of AC were significantly decreased. Furthermore, H(2)O(2)-induced enhanced proliferation of VSMC was attenuated by dibutyryl-cAMP. These results suggest that H(2)O(2) increases the expression of G(i)α proteins in VSMC through the transactivation of EGF-R/PDGF-R and ERK1/2 and phosphatidylinositol-3 kinase signaling pathways.


Assuntos
Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/biossíntese , Peróxido de Hidrogênio/farmacologia , Miócitos de Músculo Liso/fisiologia , Oxidantes/farmacologia , Receptores do Fator de Crescimento Derivado de Plaquetas/fisiologia , Adenilil Ciclases/metabolismo , Animais , Western Blotting , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , AMP Cíclico/biossíntese , AMP Cíclico/fisiologia , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/genética , Subunidades alfa Gs de Proteínas de Ligação ao GTP/biossíntese , Subunidades alfa Gs de Proteínas de Ligação ao GTP/genética , Proteínas Quinases Ativadas por Mitógeno/fisiologia , Proteína Oncogênica v-akt/biossíntese , Proteína Oncogênica v-akt/genética , Fosfatidilinositol 3-Quinases/fisiologia , Fosforilação , RNA Interferente Pequeno/farmacologia , Ratos , Receptores de Fatores de Crescimento/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Ativação Transcricional/fisiologia
14.
Invest New Drugs ; 30(6): 2148-60, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22197904

RESUMO

Biliary tract cancer (BTC) is associated with poor survival and unresponsiveness to chemotherapy. Targeted therapies for BTC have been studied, and HER family members are promising therapeutic targets in BTC. In this study, we evaluated the efficacy of PF00299804, an irreversible pan-HER inhibitor, in eight BTC cell lines alone or combined with gemcitabine. PF00299804 potently inhibited the growth of two cell lines (SNU308 and SNU478) out of the eight BTC cell lines as a single agent. PF00299804 blocked HER family and downstream signaling pathways, inducing G1 arrest or apoptosis. Moreover, PF00299804 exerted synergistic effects with gemcitabine in seven of the eight BTC cell lines, possibly through the regulation of the genes involved in the response to gemcitabine, such as TS (thymidylate synthase), RRM1 (ribonucleotide reductase), and MAGEH1, which is negatively correlated with gemcitabine sensitivity. Our results support the need for further study of PF00299804 alone or combined with gemcitabine for the treatment of BTC.


Assuntos
Antineoplásicos/administração & dosagem , Desoxicitidina/análogos & derivados , Quinazolinonas/administração & dosagem , Receptores de Fatores de Crescimento/antagonistas & inibidores , Neoplasias do Sistema Biliar/tratamento farmacológico , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Desoxicitidina/administração & dosagem , Sinergismo Farmacológico , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Inibidores de Proteínas Quinases/administração & dosagem , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Fator de Transcrição STAT3/antagonistas & inibidores
15.
Nutr Cancer ; 64(2): 173-97, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22149093

RESUMO

Extensive research within the last half a century has revealed that cancer is caused by dysregulation of as many as 500 different gene products. Most natural products target multiple gene products and thus are ideally suited for prevention and treatment of various chronic diseases, including cancer. Dietary agents such as spices have been used extensively in the Eastern world for a variety of ailments for millennia, and five centuries ago they took a golden journey to the Western world. Various spice-derived nutraceuticals, including 1'-acetoxychavicol acetate, anethole, capsaicin, cardamonin, curcumin, dibenzoylmethane, diosgenin, eugenol, gambogic acid, gingerol, thymoquinone, ursolic acid, xanthohumol, and zerumbone derived from galangal, anise, red chili, black cardamom, turmeric, licorice, fenugreek, clove, kokum, ginger, black cumin, rosemary, hop, and pinecone ginger, respectively, are the focus of this review. The modulation of various transcription factors, growth factors, protein kinases, and inflammatory mediators by these spice-derived nutraceuticals are described. The anticancer potential through the modulation of various targets is also the subject of this review. Although they have always been used to improve taste and color and as a preservative, they are now also used for prevention and treatment of a wide variety of chronic inflammatory diseases, including cancer.


Assuntos
Suplementos Nutricionais , Neoplasias/tratamento farmacológico , Fitoterapia , Transdução de Sinais/efeitos dos fármacos , Especiarias , Animais , Antineoplásicos Fitogênicos/uso terapêutico , Linhagem Celular Tumoral , Humanos , Mediadores da Inflamação , Peptídeos e Proteínas de Sinalização Intercelular , NF-kappa B/antagonistas & inibidores , Neoplasias/metabolismo , Neoplasias/prevenção & controle , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Quinases/efeitos dos fármacos , Receptores de Fatores de Crescimento/antagonistas & inibidores , Fatores de Transcrição/antagonistas & inibidores , Fatores de Transcrição/efeitos dos fármacos
17.
J Neurosci ; 31(32): 11437-42, 2011 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-21832174

RESUMO

Autism spectrum disorder (ASD) is a highly heritable, behaviorally defined, heterogeneous disorder of unknown pathogenesis. Several genetic risk genes have been identified, including the gene encoding the receptor tyrosine kinase MET, which regulates neuronal differentiation and growth. An ASD-associated polymorphism disrupts MET gene transcription, and there are reduced levels of MET protein expression in the mature temporal cortex of subjects with ASD. To address the possible neurodevelopmental contribution of MET to ASD pathogenesis, we examined the expression and transcriptional regulation of MET by a transcription factor, FOXP2, which is implicated in regulation of cognition and language, two functions altered in ASD. MET mRNA expression in the midgestation human fetal cerebral cortex is strikingly restricted, localized to portions of the temporal and occipital lobes. Within the cortical plate of the temporal lobe, the pattern of MET expression is highly complementary to the expression pattern of FOXP2, suggesting the latter may play a role in repression of gene expression. Consistent with this, MET and FOXP2 also are reciprocally expressed by differentiating normal human neuronal progenitor cells (NHNPs) in vitro, leading us to assess whether FOXP2 transcriptionally regulates MET. Indeed, FOXP2 binds directly to the 5' regulatory region of MET, and overexpression of FOXP2 results in transcriptional repression of MET. The expression of MET in restricted human neocortical regions, and its regulation in part by FOXP2, is consistent with genetic evidence for MET contributing to ASD risk.


Assuntos
Transtorno Autístico/genética , Transtornos Cognitivos/genética , Transtornos Cognitivos/metabolismo , Fatores de Transcrição Forkhead/genética , Regulação da Expressão Gênica no Desenvolvimento , Proteínas Proto-Oncogênicas c-met/biossíntese , Receptores de Fatores de Crescimento/biossíntese , Regiões 5' não Traduzidas/genética , Transtorno Autístico/metabolismo , Transtorno Autístico/patologia , Transtornos Globais do Desenvolvimento Infantil/genética , Transtornos Globais do Desenvolvimento Infantil/metabolismo , Transtornos Globais do Desenvolvimento Infantil/patologia , Transtornos Cognitivos/patologia , Feminino , Fatores de Transcrição Forkhead/biossíntese , Fatores de Transcrição Forkhead/metabolismo , Humanos , Recém-Nascido , Masculino , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-met/genética , Receptores de Fatores de Crescimento/antagonistas & inibidores , Receptores de Fatores de Crescimento/genética , Fatores de Risco
18.
Cancer Sci ; 102(11): 1949-57, 2011 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-21812860

RESUMO

Sunitinib is an orally-administered, multitargeted tyrosine kinase inhibitor. The main targets are vascular endothelial growth factor receptor (VEGFR)-1, VEGFR-2, VEGFR-3, platelet-derived growth factor receptor (PDGFR)-α, and PDGFR-ß. Among therapeutic targeting agents, it is the best available in the USA for patients with metastatic renal cell cancer (RCC). Well-constructed clinical trials have led to the worldwide approval of various agents for RCC. However, in clinical practice, it remains difficult to determine the best treatment strategy with these agents. Therefore, the identification of biomarkers to predict response and side-effects and to select optimal dosages is urgently needed. Potential mechanisms of action and resistance need to be understood in order to make accurate predictions. This article briefly reviews candidate biomarkers of sunitinib therapy in terms of clinical variables, genetic factors, and circulating proteins and endothelial cells. Although further validation and implementation is necessary, if validated, biomarkers will help measure the therapeutic response in individual patients and establish treatment strategies for metastatic RCC.


Assuntos
Antineoplásicos/uso terapêutico , Biomarcadores/sangue , Carcinoma de Células Renais/tratamento farmacológico , Monitoramento de Medicamentos/métodos , Indóis/uso terapêutico , Neoplasias Renais/tratamento farmacológico , Proteínas de Membrana/sangue , Proteínas de Neoplasias/sangue , Inibidores de Proteínas Quinases/uso terapêutico , Pirróis/uso terapêutico , Receptores de Fatores de Crescimento/sangue , Fator A de Crescimento do Endotélio Vascular/sangue , Inibidores da Angiogênese/farmacocinética , Inibidores da Angiogênese/uso terapêutico , Antineoplásicos/farmacocinética , Biotransformação/genética , Carcinoma de Células Renais/sangue , Carcinoma de Células Renais/enzimologia , Carcinoma de Células Renais/patologia , Hipóxia Celular/genética , Hipóxia Celular/fisiologia , Ensaios Clínicos como Assunto , Resistencia a Medicamentos Antineoplásicos , Humanos , Indóis/farmacocinética , Neoplasias Renais/sangue , Neoplasias Renais/enzimologia , Neoplasias Renais/patologia , Estudos Multicêntricos como Assunto , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/genética , Neovascularização Patológica/fisiopatologia , Prognóstico , Modelos de Riscos Proporcionais , Inibidores de Proteínas Quinases/farmacocinética , Pirróis/farmacocinética , Receptores de Fatores de Crescimento/antagonistas & inibidores , Estudos Retrospectivos , Fatores de Risco , Índice de Gravidade de Doença , Sunitinibe
19.
Curr Med Chem ; 18(28): 4375-88, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21861817

RESUMO

Hepatocellular carcinoma (HCC) is a major cause of cancer mortality worldwide. Unresectable or metastatic HCC has a poor prognosis, and systemic cytotoxic chemotherapy has failed to show a substantial benefit for patients with HCC. However, there has been increasing interest in developing novel molecularly targeted agents in HCC due to the accumulation of knowledge of cell signaling and molecular carcinogenesis. Furthermore, some of these agents have proven to be efficacious in other traditionally challenging carcinomas, such as renal cell carcinoma. Recently, a phase III, randomized, placebo-controlled trial demonstrated that sorafenib, an oral multikinase inhibitor of the vascular endothelial growth factor receptor and Ras kinase, improves overall survival (OS) in patients with advanced HCC. This seminal study described the first agent to improve OS in HCC and began a new era of molecule-targeted cancer therapies. Currently, many novel molecularly targeted agents are under evaluation in clinical trials. In this review, we comprehensively summarize the molecular pathogenesis, targets, and signal transduction pathways involved in HCC. We also detail the current status of molecularly targeted agents that are under clinical development in advanced HCC, including the mechanisms of action of these agents.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/mortalidade , Ensaios Clínicos como Assunto , Avaliação Pré-Clínica de Medicamentos , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/mortalidade , Receptores de Fatores de Crescimento/antagonistas & inibidores , Receptores de Fatores de Crescimento/metabolismo , Transdução de Sinais/efeitos dos fármacos
20.
J Thorac Oncol ; 6(5): 864-74, 2011 May.
Artigo em Inglês | MEDLINE | ID: mdl-21774103

RESUMO

INTRODUCTION: To identify new therapeutic approaches in malignant mesothelioma (MM), we examined the expression and activation of receptor tyrosine kinases (RTKs) and the effects of specific RTK inhibitors and the mammalian target of rapamycin (mTOR) inhibitor rapamycin; the latter being of special interest in MM given the recent linkage between NF2 loss and mTOR activation. METHODS: We performed a screen for mutated or activated RTKs in 14 MM cell lines and 70 primary tumors. Expression of phosphorylated RTKs was analyzed by Western blotting and a membrane-based antibody array in normal growth conditions and after treatment by specific inhibitors. MET and epidermal growth factor receptor (EGFR) mutations were screened by sequencing. MET, hepatocyte growth factor, insulin-like growth factor 1 receptor, and EGFR expression were studied by Western blotting, immunohistochemistry, enzyme-linked immunosorbent assay, and by Affymetrix expression microarrays. RESULTS: Profiling of the phosphorylation status of 42 RTKs showed prominent coactivation of MET and EGFR in 8 of 14 (57%) MM cell lines. MET, EGFR, and insulin-like growth factor 1 receptor were the main RTKs activated after mTOR inhibition and contributed to AKT feedback activation. Knockdown of MET by RNA interference inhibited not only the phosphorylation of MET but also that of EGFR. Conversely, stimulation with hepatocyte growth factor increased both phospho-MET and phospho-EGFR. The combination of PHA-665752 and the EGFR inhibitor, erlotinib, suppressed cell growth more than either agent alone in three of six cell lines tested. Finally, combinations of rapamycin and different RTK inhibitors were more active than either drug alone in 12 of 13 cell lines. CONCLUSION: Combination targeting of kinase signaling pathways is more effective than single agents in most MM.


Assuntos
Receptores ErbB/metabolismo , Mesotelioma/enzimologia , Neoplasias Pleurais/enzimologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-met/metabolismo , Receptor IGF Tipo 1/metabolismo , Receptores de Fatores de Crescimento/metabolismo , Apoptose/efeitos dos fármacos , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Western Blotting , Proliferação de Células/efeitos dos fármacos , Quimioterapia Combinada , Ensaio de Imunoadsorção Enzimática , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Perfilação da Expressão Gênica , Humanos , Imunossupressores/farmacologia , Indóis/farmacologia , Mesotelioma/tratamento farmacológico , Mesotelioma/patologia , Mutação/genética , Análise de Sequência com Séries de Oligonucleotídeos , Fosforilação/efeitos dos fármacos , Neoplasias Pleurais/tratamento farmacológico , Neoplasias Pleurais/patologia , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-met/genética , RNA Mensageiro/genética , RNA Interferente Pequeno/genética , Receptor IGF Tipo 1/genética , Receptores de Fatores de Crescimento/antagonistas & inibidores , Receptores de Fatores de Crescimento/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Sirolimo/farmacologia , Sulfonas/farmacologia , Serina-Treonina Quinases TOR , Células Tumorais Cultivadas
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