RESUMO
OBJECTIVE: The Toll-like receptors (TLRs) have been implicated in inflammation, innate immunity and cancer. The goal of this paper is to review the available published research about Toll-like receptors and their roles in gynecologic malignancies. METHODS: A Medline search was conducted and published articles from the late 1990s to the present (2014) were reviewed using search phrases, Toll-like receptors and cervical, endometrial and ovarian cancers. RESULTS: TLR4 and TLR5 are commonly absent in normal cervix, however TLR5 expression is strong in high grade cervical dysplasia as well as invasive cancer. The expression of TLR3 and TLR4 is low in endometrial cancer. TLR2, TLR3, TLR4 and TLR5 are highly expressed in normal and neoplastic ovarian epithelium. TLR3 has been shown to have a dual function: it can contribute to tumor elimination by upregulation of interferons α and ß (INF) and natural killer cell (NK) activation or it can indirectly contribute to tumor progression. CONCLUSIONS: Inflammation is an essential element in tumorigenesis. Toll-like receptors can trigger an inflammatory response and cell survival in the tumor micro-environment. TLRs are critical immunomodulators that may play an important role in the development of gynecologic cancers. Currently TLR agonists are being investigated for a potential role as an adjuvant in the treatment of gynecologic malignancies.
Assuntos
Adenocarcinoma/imunologia , Carcinoma de Células Escamosas/imunologia , Carcinoma/imunologia , Neoplasias do Endométrio/imunologia , Neoplasias Ovarianas/imunologia , Infecções por Papillomavirus/imunologia , Receptores Toll-Like/imunologia , Neoplasias do Colo do Útero/imunologia , Adenocarcinoma/tratamento farmacológico , Carcinoma/tratamento farmacológico , Carcinoma de Células Escamosas/tratamento farmacológico , Neoplasias do Endométrio/tratamento farmacológico , Feminino , Humanos , Neoplasias Ovarianas/tratamento farmacológico , Receptores Toll-Like/agonistas , Neoplasias do Colo do Útero/tratamento farmacológicoRESUMO
Crystallographic studies of a range of 3-substituted anilinopyrimidine inhibitors of EphB4 have highlighted two alternative C-2 aniline conformations and this discovery has been exploited in the design of a highly potent series of 3,5-disubstituted anilinopyrimidines. The observed range of cellular activities has been rationalised on the basis of physicochemical and structural characteristics.
Assuntos
Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Receptor EphB4/antagonistas & inibidores , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/química , Pirimidinas/químicaRESUMO
A series of bis-anilinopyrimidines have been identified as potent inhibitors of the tyrosine kinase EphB4. Structural information from two alternative series identified from screening efforts was combined to identify the initial leads.
Assuntos
Compostos de Anilina/farmacologia , Desenho de Fármacos , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Receptor EphB4/antagonistas & inibidores , Compostos de Anilina/síntese química , Ligação de Hidrogênio , Isomerismo , Modelos Químicos , Inibidores de Proteínas Quinases/síntese química , Pirimidinas/síntese química , Relação Estrutura-AtividadeAssuntos
Dispneia/etiologia , Rejeição de Enxerto/tratamento farmacológico , Imunossupressores/efeitos adversos , Transplante de Pulmão , Metemoglobinemia/complicações , Idoso , Biópsia , Broncoscopia , Diagnóstico Diferencial , Dispneia/sangue , Dispneia/diagnóstico , Feminino , Seguimentos , Humanos , Imunossupressores/uso terapêutico , Metemoglobina/efeitos dos fármacos , Metemoglobina/metabolismo , Metemoglobinemia/sangue , Metemoglobinemia/induzido quimicamente , Doença Pulmonar Obstrutiva Crônica/cirurgia , EspirometriaRESUMO
â¢The case presented is that of a primary debulking surgery for presumed ovarian cancer.â¢Final pathology revealed diffusely metastatic endocervical adenocarcinoma.â¢After primary chemotherapy, the patient has remained disease-free 30 months after surgery.
RESUMO
BACKGROUND: Colorectal cancer (CRC) is a heterogeneous and biologically poorly understood disease. To tailor CRC treatment, it is essential to first model this heterogeneity by defining subtypes of patients with homogeneous biological and clinical characteristics and second match these subtypes to cell lines for which extensive pharmacological data is available, thus linking targeted therapies to patients most likely to respond to treatment. METHODS: We applied a new unsupervised, iterative approach to stratify CRC tumor samples into subtypes based on genome-wide mRNA expression data. By applying this stratification to several CRC cell line panels and integrating pharmacological response data, we generated hypotheses regarding the targeted treatment of different subtypes. RESULTS: In agreement with earlier studies, the two dominant CRC subtypes are highly correlated with a gene expression signature of epithelial-mesenchymal-transition (EMT). Notably, further dividing these two subtypes using iNMF (iterative Non-negative Matrix Factorization) revealed five subtypes that exhibit activation of specific signaling pathways, and show significant differences in clinical and molecular characteristics. Importantly, we were able to validate the stratification on independent, published datasets comprising over 1600 samples. Application of this stratification to four CRC cell line panels comprising 74 different cell lines, showed that the tumor subtypes are well represented in available CRC cell line panels. Pharmacological response data for targeted inhibitors of SRC, WNT, GSK3b, aurora kinase, PI3 kinase, and mTOR, showed significant differences in sensitivity across cell lines assigned to different subtypes. Importantly, some of these differences in sensitivity were in concordance with high expression of the targets or activation of the corresponding pathways in primary tumor samples of the same subtype. CONCLUSIONS: The stratification presented here is robust, captures important features of CRC, and offers valuable insight into functional differences between CRC subtypes. By matching the identified subtypes to cell line panels that have been pharmacologically characterized, it opens up new possibilities for the development and application of targeted therapies for defined CRC patient sub-populations.
Assuntos
Neoplasias Colorretais/classificação , Neoplasias Colorretais/tratamento farmacológico , Terapia de Alvo Molecular , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Análise por Conglomerados , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Bases de Dados Genéticas , Epitélio/efeitos dos fármacos , Epitélio/patologia , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Mesoderma/efeitos dos fármacos , Mesoderma/patologia , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , TranscriptomaRESUMO
PURPOSE: To test the hypothesis that simultaneous, equipotent inhibition of epidermal growth factor receptor (EGFR; erbB1), erbB2 (human epidermal growth factor receptor 2), and erbB3 receptor signaling, using the novel small-molecule inhibitor AZD8931, will deliver broad antitumor activity in vitro and in vivo. EXPERIMENTAL DESIGN: A range of assays was used to model erbB family receptor signaling in homodimers and heterodimers, including in vitro evaluation of erbB kinase activity, erbB receptor phosphorylation, proliferation in cells, and in vivo testing in a human tumor xenograft panel, with ex vivo evaluation of erbB phosphorylation and downstream biomarkers. Gefitinib and lapatinib were used to compare the pharmacological profile of AZD8931 with other erbB family inhibitors. RESULTS: In vitro, AZD8931 showed equipotent, reversible inhibition of EGFR (IC(50), 4 nmol/L), erbB2 (IC(50), 3 nmol/L), and erbB3 (IC(50), 4 nmol/L) phosphorylation in cells. In proliferation assays, AZD8931 was significantly more potent than gefitinib or lapatinib in specific squamous cell carcinoma of the head and neck and non-small cell lung carcinoma cell lines. In vivo, AZD8931 inhibited xenograft growth in a range of models while significantly affecting EGFR, erbB2, and erbB3 phosphorylation and downstream signaling pathways, apoptosis, and proliferation. CONCLUSIONS: AZD8931 has a unique pharmacologic profile providing equipotent inhibition of EGFR, erbB2, and erbB3 signaling and showing greater antitumor activity than agents with a narrower spectrum of erbB receptor inhibition in specific preclinical models. AZD8931 provides the opportunity to investigate whether simultaneous inhibition of erbB receptor signaling could be of utility in the clinic, particularly in the majority of solid tumors that do not overexpress erbB2.