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1.
Ann Oncol ; 30(10): 1613-1621, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31504118

RESUMO

BACKGROUND: Chemotherapy-induced damage of hematopoietic stem and progenitor cells (HSPC) causes multi-lineage myelosuppression. Trilaciclib is an intravenous CDK4/6 inhibitor in development to proactively preserve HSPC and immune system function during chemotherapy (myelopreservation). Preclinically, trilaciclib transiently maintains HSPC in G1 arrest and protects them from chemotherapy damage, leading to faster hematopoietic recovery and enhanced antitumor immunity. PATIENTS AND METHODS: This was a phase Ib (open-label, dose-finding) and phase II (randomized, double-blind placebo-controlled) study of the safety, efficacy and PK of trilaciclib in combination with etoposide/carboplatin (E/P) therapy for treatment-naive extensive-stage small-cell lung cancer patients. Patients received trilaciclib or placebo before E/P on days 1-3 of each cycle. Select end points were prespecified to assess the effect of trilaciclib on myelosuppression and antitumor efficacy. RESULTS: A total of 122 patients were enrolled, with 19 patients in part 1 and 75 patients in part 2 receiving study drug. Improvements were seen with trilaciclib in neutrophil, RBC (red blood cell) and lymphocyte measures. Safety on trilaciclib+E/P was improved with fewer ≥G3 adverse events (AEs) in trilaciclib (50%) versus placebo (83.8%), primarily due to less hematological toxicity. No trilaciclib-related ≥G3 AEs occurred. Antitumor efficacy assessment for trilaciclib versus placebo, respectively, showed: ORR (66.7% versus 56.8%, P = 0.3831); median PFS [6.2 versus 5.0 m; hazard ratio (HR) 0.71; P = 0.1695]; and OS (10.9 versus 10.6 m; HR 0.87; P = 0.6107). CONCLUSION: Trilaciclib demonstrated an improvement in the patient's tolerability of chemotherapy as shown by myelopreservation across multiple hematopoietic lineages resulting in fewer supportive care interventions and dose reductions, improved safety profile, and no detriment to antitumor efficacy. These data demonstrate strong proof-of-concept for trilaciclib's myelopreservation benefits. CLINICAL TRAIL NUMBER: NCT02499770.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Neoplasias Pulmonares/tratamento farmacológico , Células Mieloides/efeitos dos fármacos , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Neoplasias Encefálicas/enzimologia , Neoplasias Encefálicas/secundário , Carboplatina/administração & dosagem , Cisplatino/administração & dosagem , Método Duplo-Cego , Etoposídeo/administração & dosagem , Feminino , Seguimentos , Humanos , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/patologia , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Paclitaxel/administração & dosagem , Prognóstico , Pirimidinas/administração & dosagem , Pirróis/administração & dosagem , Carcinoma de Pequenas Células do Pulmão/enzimologia , Carcinoma de Pequenas Células do Pulmão/patologia , Taxa de Sobrevida , Distribuição Tecidual
2.
Curr Oncol ; 22(6): e457-61, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26715883

RESUMO

BACKGROUND: The liver is a common site of primary and metastatic cancer. Liver-directed therapies are commonly used to treat cancer involving the liver. We report on the patterns, predictors, and outcomes of liver-directed therapies in hospitalized cancer patients in the United States. METHODS: Data were obtained from all U.S. states that contributed to the Nationwide Inpatient Sample maintained by the Agency for Healthcare Research and Quality between 2006 and 2010. Univariate and multivariate testing was used to identify factors significantly associated with patient outcome. RESULTS: For the 5-year period of interest, 12,540 patient discharges were identified. Mean age in the sample was 60 years. Primary liver lesions (n = 8840) made up 26.9% of the sample; the remaining cases were metastases. Most procedures were performed in large (79%) urban (98%) hospitals and in patients with insurance (97.9%). The most common intervention was partial hepatectomy (42.7%), followed by open (9.9%), percutaneous (7.2%), and laparoscopic (5.04%) ablation of liver lesions; embolization (9.8%); and liver transplantation (2.64%). The incidence of in-hospital mortality was very low (2.4%), and the complication rate was 12.2%. Complications such as acute liver necrosis, ascites, hepatic coma, hepatorenal syndrome, liver abscess, and high number of comorbid illnesses (>8) accounted for 60% of the in-hospital mortality. CONCLUSIONS: The low rate of morbidity and mortality associated with liver-directed therapies in hospitalized cancer patients supports the continuing utility of such procedures in the management of primary and metastatic liver cancer. The patterns of health disparities observed with respect to the use of liver-directed therapies are concerning.

3.
Br J Cancer ; 108(4): 762-5, 2013 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-23322195

RESUMO

BACKGROUND: This phase 1 trial utilising a Bayesian continual reassessment method evaluated bortezomib and sunitinib to determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLT), and recommended doses of the combination. METHODS: Patients with advanced solid organ malignancies were enrolled and received bortezomib weekly with sunitinib daily for 4 weeks, every 6 weeks. Initial doses were sunitinib 25 mg and bortezomib 1 mg m(-2). Cohort size and dose level estimation was performed utilising the Escalation with Overdose Control (EWOC) adaptive method. Seven dose levels were evaluated; initially, sunitinib was increased to a goal dose of 50 mg with fixed bortezomib, then bortezomib was increased. Efficacy assessment occurred after each cycle using RECIST criteria. RESULTS: Thirty patients were evaluable. During sunitinib escalation, DLTs of grade 4 thrombocytopenia (14%) and neutropenia (6%) at sunitinib 50 mg and bortezomib 1.3 mg m(-2) were seen. Subsequent experience showed tolerability and activity for sunitinib 37.5 mg and bortezomib 1.9 mg m(-2). Common grade 3/4 toxicities were neutropenia, thrombocytopenia, hypertension, and diarrhoea. The recommended doses for further study are bortezomib 1.9 mg m(-2) and sunitinib 37.5 mg. Four partial responses were seen. Stable disease >6 months was noted in an additional six patients. CONCLUSION: Bortezomib and sunitinib are well tolerated and have anticancer activity, particularly in thyroid cancer. A phase 2 study of this combination in thyroid cancer patients is planned.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ácidos Borônicos/administração & dosagem , Indóis/administração & dosagem , Pirazinas/administração & dosagem , Pirróis/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Teorema de Bayes , Bortezomib , Esquema de Medicação , Feminino , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Neoplasias/tratamento farmacológico , Sunitinibe , Neoplasias da Glândula Tireoide/tratamento farmacológico
4.
Oncogene ; 35(4): 459-67, 2016 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-25867065

RESUMO

Inhibition of B-Raf/MEK/ERK signaling is an effective therapeutic strategy against certain types of cancers such as melanoma and thyroid cancer. While demonstrated to be effective anticancer agents, B-Raf or MEK inhibitors have also been associated with early tumor progression and development of secondary neoplasms. The ligation of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) with its receptor, death receptor 5 (DR5), leading to induction of apoptosis, offers a promising anticancer strategy. Importantly, this is also a natural immunosurveillance mechanism against cancer development. We previously demonstrated that activated B-Raf/MEK/ERK signaling positively regulates DR5 expression. Hence, our current work sought to address whether B-Raf/MEK/ERK inhibition and the consequent suppression of DR5 expression impede cancer cell response to DR5 activation-induced apoptosis and activated immune cell-induced killing. We found that both B-Raf (for example, PLX4032) and MEK inhibitors (for example, AZD6244 and PD0325901) effectively inhibited ERK1/2 phosphorylation and reduced DR5 levels in both human thyroid cancer and melanoma cells. Similar to the observed effect of genetic knockdown of the B-Raf gene, pre-treatment of cancer cell lines with either B-Raf or MEK inhibitors attenuated or abolished cellular apoptotic response induced by TRAIL or the DR5 agonistic antibody AMG655 or cell killing by activated T cells. Our findings clearly show that inhibition of B-Raf/MEK/ERK signaling suppresses DR5 expression and impairs DR5 activation-induced apoptosis and T cell-mediated killing of cancer cells. These findings suggest a potential negative impact of B-Raf or MEK inhibition on TRAIL- or DR5-mediated anticancer therapy and on TRAIL/DR5-mediated immune-clearance of cancer cells.


Assuntos
Inibidores Enzimáticos/farmacologia , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , MAP Quinase Quinase Quinases/metabolismo , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Apoptose/efeitos dos fármacos , Benzimidazóis/farmacologia , Linhagem Celular Tumoral/efeitos dos fármacos , MAP Quinases Reguladas por Sinal Extracelular/antagonistas & inibidores , Humanos , Indóis/farmacologia , MAP Quinase Quinase Quinases/antagonistas & inibidores , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas B-raf/metabolismo , RNA Interferente Pequeno , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/genética , Transdução de Sinais/efeitos dos fármacos , Sulfonamidas/farmacologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/metabolismo , Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Vemurafenib
5.
East Afr Med J ; 75(12): 718-23, 1998 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-10065214

RESUMO

A total of 254 cases of colorectal neoplasms were studied. A male predominance was noted with both benign and malignant neoplasms (M:F of 4.6:1 and 1.1:1 respectively). The peak incidence was in the fifth decade. The rectum was the commonest site for both benign and malignant neoplasms (75% and 63% respectively) followed by the sigmoid colon (11% and 16% respectively). Right-sided cancers presented commonly as fungating masses (74%) while left sided cancers were predominantly of the ulcerating/infiltrating pattern (81%). The commonest benign neoplasm was tubular adenoma (39%) while the commonest malignant neoplasm was adenocarcinoma (90%) followed by squamous cell carcinoma (4%). Advanced stage on presentation was noted with these cancers, especially the mucinous adenocarcinoma variant. This may be explained by the usual late presentation of patients to orthodox doctors in our environment.


Assuntos
Neoplasias Colorretais , Adolescente , Adulto , Distribuição por Idade , Idoso , Idoso de 80 Anos ou mais , Criança , Neoplasias Colorretais/etiologia , Neoplasias Colorretais/patologia , Neoplasias Colorretais/cirurgia , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Nigéria , Distribuição por Sexo
6.
Cell Death Differ ; 21(7): 1160-9, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24769731

RESUMO

Mcl-1 is a unique antiapoptotic Bcl2 family member with a short half-life due to its rapid turnover through ubiquitination. We discovered that Ku70, a DNA double-strand break repair protein, functions as a deubiquitinase to stabilize Mcl-1. Ku70 knockout in mouse embryonic fibroblast (MEF) cells or depletion from human lung cancer H1299 cells leads to the accumulation of polyubiquitinated Mcl-1 and a reduction in its half-life and protein expression. Conversely, expression of exogenous Ku70 in Ku70(-/-) MEF cells restores Mcl-1 expression. Subcellular fractionation indicates that Ku70 extensively colocalizes with Mcl-1 in mitochondria, endoplasmic reticulum and nucleus in H1299 cells. Ku70 directly interacts with Mcl-1 via its C terminus (that is, aa 536-609), which is required and sufficient for deubiquitination and stabilization of Mcl-1, leading to suppression of apoptosis. Purified Ku70 protein directly deubiquitinates Mcl-1 by removing K48-linked polyubiquitin chains. Ku70 knockdown not only promotes Mcl-1 turnover but also enhances antitumor efficacy of the BH3-mimetic ABT-737 in human lung cancer xenografts. These findings identify Ku70 as a novel Mcl-1 deubiquitinase that could be a potential target for cancer therapy by manipulating Mcl-1 deubiquitination.


Assuntos
Antígenos Nucleares/fisiologia , Apoptose , Proteínas de Ligação a DNA/fisiologia , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Ubiquitinação , Animais , Antineoplásicos/farmacologia , Compostos de Bifenilo/farmacologia , Sobrevivência Celular , Células HCT116 , Células HEK293 , Meia-Vida , Humanos , Autoantígeno Ku , Camundongos , Camundongos Nus , Nitrofenóis/farmacologia , Piperazinas/farmacologia , Domínios e Motivos de Interação entre Proteínas , Estabilidade Proteica , Transporte Proteico , Estaurosporina/farmacologia , Sulfonamidas/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
7.
Oncogene ; 30(35): 3802-12, 2011 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-21478903

RESUMO

Cancer progression involves multiple complex and interdependent steps, including progressive proliferation, angiogenesis and metastases. The complexity of these processes requires a comprehensive elucidation of the integrated signaling networks for better understanding. EAPII interacts with multiple cancer-related proteins, but its biological significance in cancer development remains unknown. In this report we identified the elevated level of EAPII protein in non-small-cell lung carcinoma (NSCLC) patients and NSCLC cell lines in culture. The oncogenic role of EAPII in lung cancer development was demonstrated using NSCLC cells with genetic manipulations that influence EAPII expression: EAPII overexpression increases proliferation of NSCLC cells with an accelerated transition of cell cycle and facilitates xenograft tumor growth in vivo; EAPII knockdown results in apoptosis of NSCLC cells and reduces xenograft tumor formation. To further explore the mechanism of EAPII's oncogenic role in lung cancer development and to elucidate the potential signaling pathway(s) that EAPII may impact, we employed antibody array to investigate the alternation of the major signaling pathways in NSCLC cells with altered EAPII level. We found that EAPII overexpression significantly activated Raf1 and ERK1/2, but not c-Jun N-terminal kinase and p38 pathways. Consistently, the protein and mRNA levels of MYC and cyclin D1, which are targets of the mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK-ERK) pathway, are significantly increased by EAPII overexpression. Taken together, we demonstrated that EAPII is an oncogenic factor and the activation of MAPK-ERK signaling pathway by EAPII may contribute to lung cancer development.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/metabolismo , Neoplasias Pulmonares/metabolismo , Quinases de Proteína Quinase Ativadas por Mitógeno/biossíntese , Proteínas Nucleares/fisiologia , Oncogenes/fisiologia , Fatores de Transcrição/fisiologia , Apoptose/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Proliferação de Células , Proteínas de Ligação a DNA , Ativação Enzimática , Técnicas de Silenciamento de Genes , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Proteínas Nucleares/genética , Oncogenes/genética , Diester Fosfórico Hidrolases , Fatores de Transcrição/genética
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