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1.
J Dent Res ; 99(5): 552-560, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32119600

RESUMO

Extracellular vesicles (EVs), several tens to hundreds of nanometers in size, are vesicles secreted by cells for intercellular communication. EVs released from mesenchymal stem cells (MSC-EVs) have the potential to treat multiple diseases. This study aimed to determine the effects of MSC-EVs on bisphosphonate-related osteonecrosis of the jaw (BRONJ), whose pathogenesis and treatment are not yet established. To this end, zoledronic acid (ZOL) was administered to bone marrow cells and fibroblasts in vitro. In vivo, a BRONJ model was produced by administering ZOL to rats and extracting teeth. Each MSC-EV-treated and nontreated group was compared histologically and molecularly. In vitro, the nontreated group showed an increased number of ß-galactosidase-positive cells and expression of senescence-associated genes p21, pRB and senescence-related inflammatory cytokines. Conversely, MSC-EV administration decreased the number of senescent cells and expression levels of p21, pRB and inflammatory cytokines. In vivo, in the nontreated group, the socket was partially uncovered by the oral epithelium, leaving an exposed bone. Conversely, in the MSC-EV-treated group, the socket was healed. Besides, in the nontreated group, ß-galactosidase-positive cells existed in the socket and colocalized with the CD90 and periostin-positive cells. However, there were few ß-galactosidase-positive cells in the MSC-EV-treated group. Furthermore, gene expression of stem cell markers Bmi1 and Hmga2 and the vascular endothelial marker VEGF was significantly increased in the MSC-EV-treated group, compared with that in the nontreated group. These results indicate that MSC-EVs prevent ZOL-induced senescence in stem cells, osteoblasts, and fibroblasts and reduce inflammatory cytokines. Furthermore, administration of MSC-EVs prevented senescence of cells involved in wound healing and the spread of chronic inflammation around senescent cells, thereby promoting angiogenesis and bone regeneration and preventing BRONJ.


Assuntos
Vesículas Extracelulares , Animais , Osteonecrose da Arcada Osseodentária Associada a Difosfonatos , Modelos Animais de Doenças , Células-Tronco Mesenquimais , Ratos , Ácido Zoledrônico
2.
Cancer Gene Ther ; 24(2): 45-47, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28106046

RESUMO

We previously described the development of a highly-invasive, triple-negative breast cancer (TNBC) variant using serial orthotopic implantation of MDA-MB-231 human breast cancer in nude mice. The isolated variant is highly invasive in the mammary gland and metastasized to lymph nodes in 10 of 12 mice compared with 2 of 12 of the parental cell line. OBP-401 is a telomerase-dependent cancer-specific, green fluorescent protein (GFP)-expressing adenovirus. OBP-401 was used to infect parental MDA-MB-231P cells and high-metastatic MDA-MB-231H and MDA-MB-231HLN isolated from a lymph node metastasis and MDA-MB-231HLM isolated from a lung metastasis. Time-course imaging showed that OBP-401 labeled MDA-MB-231HP, MDA-MB-231HLN, and MDA-MB-231HLM cells more brightly than MDA-MB-231 parental cells. OBP-401 killed MDA-MB-231H, MDA-MB-231HLN, and MDA-MB-231HLM cells more efficiently than MDA-MB-231P parental cells. These results indicate that OBP-401 could infect, label and then kill high-metastatic MDA-MB-231 more efficiently than low-metastatic MDA-MB-231.


Assuntos
Adenoviridae/genética , Vetores Genéticos/genética , Proteínas de Fluorescência Verde/genética , Vírus Oncolíticos/genética , Telomerase/metabolismo , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia , Animais , Linhagem Celular Tumoral , Sobrevivência Celular , Expressão Gênica , Genes Reporter , Humanos , Camundongos , Metástase Neoplásica , Neoplasias de Mama Triplo Negativas/terapia
4.
Cancer Gene Ther ; 22(7): 344-50, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-26088297

RESUMO

Precise fluorescence-guided surgery (FGS) for pancreatic cancer has the potential to greatly improve the outcome in this recalcitrant disease. To achieve this goal, we have used genetic reporters to color code cancer and stroma cells in a patient-derived orthotopic xenograft (PDOX) model. The telomerase-dependent green fluorescent protein (GFP)-containing adenovirus OBP-401 was used to label the cancer cells of a pancreatic cancer PDOX. The PDOX was previously grown in a red fluorescent protein (RFP) transgenic mouse that stably labeled the PDOX stroma cells bright red. The color-coded PDOX model enabled FGS to completely resect the pancreatic tumors including stroma. Dual-colored FGS significantly prevented local recurrence, which bright-light surgery or single-color FGS could not. FGS, with color-coded cancer and stroma cells has important potential for improving the outcome of recalcitrant-cancer surgery.


Assuntos
Recidiva Local de Neoplasia/prevenção & controle , Neoplasias Pancreáticas/cirurgia , Cirurgia Assistida por Computador , Animais , Genes Reporter , Proteínas de Fluorescência Verde/biossíntese , Proteínas de Fluorescência Verde/genética , Proteínas Luminescentes/biossíntese , Proteínas Luminescentes/genética , Camundongos Nus , Camundongos Transgênicos , Transplante de Neoplasias , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Proteína Vermelha Fluorescente
5.
J Clin Pharmacol ; 54(6): 657-64, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24374821

RESUMO

The objectives of this study were to evaluate the safety, tolerability and pharmacokinetics (PK) of BMS-986001 as a single oral dose in healthy male subjects. Sixty-four healthy male subjects were randomized to receive a single dose of BMS-986001 or placebo in this single-blind, placebo-controlled, sequential ascending-dose study. There were eight treatment groups (10, 30, 100, 300, 600, and 900 mg fed; and 100 and 300 mg fasted) of eight subjects each (BMS-986001 n = 6/placebo n = 2). BMS-986001 was well tolerated, with no serious adverse events (AEs), deaths, or discontinuations due to AEs reported. AEs were experienced by 14.6% of subjects receiving BMS-986001; however, these did not appear to be dose related and were not considered to be related to study drug. BMS-986001 was rapidly absorbed and exhibited a linear dose-exposure relationship across the dose range studied. PK appeared similar whether administered with or without food. Administration of BMS-986001 as a single dose was generally safe and well tolerated. A linear dose-exposure relationship was seen across all doses studied, with no apparent food effect. Further clinical development is warranted.


Assuntos
Fármacos Anti-HIV/farmacocinética , Interações Alimento-Droga , Inibidores da Transcriptase Reversa/farmacocinética , Timidina/análogos & derivados , Adulto , Fármacos Anti-HIV/efeitos adversos , Fármacos Anti-HIV/sangue , Fármacos Anti-HIV/urina , Relação Dose-Resposta a Droga , Jejum/metabolismo , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Inibidores da Transcriptase Reversa/efeitos adversos , Inibidores da Transcriptase Reversa/sangue , Inibidores da Transcriptase Reversa/urina , Método Simples-Cego , Timidina/efeitos adversos , Timidina/sangue , Timidina/farmacocinética , Timidina/urina , Adulto Jovem
6.
Nature ; 502(7471): 346-9, 2013 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-24132291

RESUMO

Super-luminous supernovae that radiate more than 10(44) ergs per second at their peak luminosity have recently been discovered in faint galaxies at redshifts of 0.1-4. Some evolve slowly, resembling models of 'pair-instability' supernovae. Such models involve stars with original masses 140-260 times that of the Sun that now have carbon-oxygen cores of 65-130 solar masses. In these stars, the photons that prevent gravitational collapse are converted to electron-positron pairs, causing rapid contraction and thermonuclear explosions. Many solar masses of (56)Ni are synthesized; this isotope decays to (56)Fe via (56)Co, powering bright light curves. Such massive progenitors are expected to have formed from metal-poor gas in the early Universe. Recently, supernova 2007bi in a galaxy at redshift 0.127 (about 12 billion years after the Big Bang) with a metallicity one-third that of the Sun was observed to look like a fading pair-instability supernova. Here we report observations of two slow-to-fade super-luminous supernovae that show relatively fast rise times and blue colours, which are incompatible with pair-instability models. Their late-time light-curve and spectral similarities to supernova 2007bi call the nature of that event into question. Our early spectra closely resemble typical fast-declining super-luminous supernovae, which are not powered by radioactivity. Modelling our observations with 10-16 solar masses of magnetar-energized ejecta demonstrates the possibility of a common explosion mechanism. The lack of unambiguous nearby pair-instability events suggests that their local rate of occurrence is less than 6 × 10(-6) times that of the core-collapse rate.

7.
Gene Ther ; 20(1): 112-8, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22241176

RESUMO

Adenovirus serotype 5 (Ad5) is frequently used as an effective vector for induction of therapeutic transgenes in cancer gene therapy or of tumor cell lysis in oncolytic virotherapy. Ad5 can infect target cells through binding with the coxsackie and adenovirus receptor (CAR). Thus, the infectious ability of Ad5-based vectors depends on the CAR expression level in target cells. There are conventional methods to evaluate the CAR expression level in human target cells, including flow cytometry, western blotting and immunohistochemistry. Here, we show a simple system for detection and assessment of functional CAR expression in human tumor cells, using the green fluorescent protein (GFP)-expressing telomerase-specific replication-competent adenovirus OBP-401. OBP-401 infection induced detectable GFP expression in CAR-expressing tumor cells, but not in CAR-negative tumor cells, nor in CAR-positive normal fibroblasts, 24 h after infection. OBP-401-mediated GFP expression was significantly associated with CAR expression in tumor cells. OBP-401 infection detected tumor cells with low CAR expression more efficiently than conventional methods. OBP-401 also distinguished CAR-positive tumor tissues from CAR-negative tumor and normal tissues in biopsy samples. These results suggest that GFP-expressing telomerase-specific replication-competent adenovirus is a very potent diagnostic tool for assessment of functional CAR expression in tumor cells for Ad5-based antitumor therapy.


Assuntos
Adenoviridae/genética , Telomerase/genética , Replicação Viral/genética , Linhagem Celular Tumoral , Proteína de Membrana Semelhante a Receptor de Coxsackie e Adenovirus/genética , Técnicas de Transferência de Genes , Vetores Genéticos/genética , Proteínas de Fluorescência Verde/genética , Humanos , Vírus Oncolíticos/genética , Telomerase/metabolismo , Transcrição Gênica , Transformação Genética
8.
Cancer Gene Ther ; 19(11): 767-72, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22956040

RESUMO

Replication-selective oncolytic viruses are being developed for human cancer therapy. We previously developed an attenuated adenovirus (OBP-301, Telomelysin), in which the human telomerase reverse transcriptase promoter element drives expression of E1A and E1B genes linked with an internal ribosome entry site. OBP-301 can replicate in, and causes selective lysis of, human cancer cells. Valproic acid (VPA), which is an effective antiepileptic drug, is known to inhibit the histone deacetylase activities. We determined whether the antitumor effect of OBP-301 could be enhanced by VPA in human lung cancer cells. In an in vitro cell viability assay, OBP-301 infection killed four human lung cancer cell lines, H1299, H1299-R5 (a subline of H1299 with a low level of the coxsackievirus and adenovirus receptor (CAR) expression), H460, and A549, more efficiently in the presence of VPA than in its absence. VPA treatment increased CAR expression in all the four lung cancer cells. Consistent with their CAR upregulation, the infection efficiency of adenoviruses in the presence of VPA was significantly higher than that in its absence. The molecular mechanism of this combined effect could be explained by an increase in adenovirus infectivity via VPA-mediated upregulation of CAR. These results suggest that treatment with OBP-301 in combination with VPA is a promising strategy for human lung cancer.


Assuntos
Adenoviridae/metabolismo , Antineoplásicos/farmacologia , Proteína de Membrana Semelhante a Receptor de Coxsackie e Adenovirus/metabolismo , Vírus Oncolíticos/metabolismo , Telomerase/metabolismo , Ácido Valproico/farmacologia , Adenoviridae/genética , Adenoviridae/fisiologia , Proteínas E1A de Adenovirus/genética , Proteínas E1A de Adenovirus/metabolismo , Proteínas E1B de Adenovirus/genética , Proteínas E1B de Adenovirus/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular , Proteína de Membrana Semelhante a Receptor de Coxsackie e Adenovirus/genética , Enterovirus/genética , Enterovirus/metabolismo , Enterovirus/fisiologia , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Terapia Viral Oncolítica/métodos , Vírus Oncolíticos/genética , Vírus Oncolíticos/fisiologia , Telomerase/genética , Replicação Viral
9.
Br J Cancer ; 107(3): 448-54, 2012 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-22735905

RESUMO

BACKGROUND: Recently developed detection system for circulating tumour cells (CTCs) using a telomerase-specific replicative adenovirus generated nonspecific green fluorescent protein (GFP) signals because of the co-presence of white blood cells (WBCs) nonspecifically infected by viruses. Here, we established a unique detection system for CTCs that completely excludes nonspecific signals. METHODS: Blood obtained from the patients was subjected to haemolytic processes to eliminate red blood cells. The cell pellets were then infected with OBP-401, fixed, incubated with fluorescence-labelled anti-CD45 antibody to mark white blood WBCs, and examined on slides under a microscope. RESULTS: Preparatory experiments with cancer cells artificially added to healthy donor samples confirmed that CD45 labelling could distinguish GFP-positive cancer cells from WBCs. In 53 patients with gynaecological cancers, CTCs were detected in 21 patients (39.6%) when CD45-positive cells were excluded as WBCs among GFP-positive cells. No CTCs were detected in samples from healthy volunteers. There was no significant correlation between CTC counts and known clinicopathological factors. The CTCs rapidly vanished after surgery or chemotherapy in most patients whose treatments were effective. In contrast, the persistence of CTCs even after treatments was tightly associated with poor response to the treatments (P<0.005). CONCLUSION: The presence of CTCs in our system may potentially be a novel therapeutic marker in gynaecological cancers.


Assuntos
Adenoviridae/química , Biomarcadores Tumorais/sangue , Neoplasias dos Genitais Femininos/sangue , Células Neoplásicas Circulantes/patologia , Adulto , Idoso , Feminino , Neoplasias dos Genitais Femininos/diagnóstico , Neoplasias dos Genitais Femininos/metabolismo , Neoplasias dos Genitais Femininos/patologia , Proteínas de Fluorescência Verde/química , Humanos , Antígenos Comuns de Leucócito/metabolismo , Pessoa de Meia-Idade , Células Neoplásicas Circulantes/metabolismo , Sensibilidade e Especificidade , Telomerase/metabolismo
10.
Nature ; 476(7361): 421-4, 2011 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-21866154

RESUMO

Supermassive black holes have powerful gravitational fields with strong gradients that can destroy stars that get too close, producing a bright flare in ultraviolet and X-ray spectral regions from stellar debris that forms an accretion disk around the black hole. The aftermath of this process may have been seen several times over the past two decades in the form of sparsely sampled, slowly fading emission from distant galaxies, but the onset of the stellar disruption event has not hitherto been observed. Here we report observations of a bright X-ray flare from the extragalactic transient Swift J164449.3+573451. This source increased in brightness in the X-ray band by a factor of at least 10,000 since 1990 and by a factor of at least 100 since early 2010. We conclude that we have captured the onset of relativistic jet activity from a supermassive black hole. A companion paper comes to similar conclusions on the basis of radio observations. This event is probably due to the tidal disruption of a star falling into a supermassive black hole, but the detailed behaviour differs from current theoretical models of such events.

11.
Cancer Gene Ther ; 17(7): 484-91, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20168351

RESUMO

OBP-301 (a telomerase-specific, replication-competent adenovirus with hTERT promoter) was constructed in a previous study and it showed a strong anticancer effect by inducing cell lysis in human lung and prostate cancer cells. This study investigated the effectiveness of a combination therapy of OBP-301 and interleukin-2 (IL-2) in a mouse model of renal cell carcinoma (RCC). The cell-killing effect of OBP-301 was confirmed in vitro in the RENCA cancer cells. In in vivo experiment, luciferase-expressing RENCA cells were implanted in the left kidney and lung of BALB/c mice to prepare the RCC metastatic model. The animals were randomly divided into four treatment groups: PBS, IL-2 alone, OBP-301 alone and the combination. The analyses of orthotopic tumor weight, lung metastasis and luciferin-stained tumor images 14 days after each treatment showed significant tumor growth inhibition in the combination group in comparison with that in the OBP-301- or IL-2-treated groups. In addition, the percentage of regulatory T-cells (Tregs) in the combination group was significantly suppressed in comparison with that in the PBS and single-agent treatment groups. The outcomes of this study suggest that tumor-specific oncolytic immunovirotherapy may become an attractive strategy for the treatment of human RCC.


Assuntos
Carcinoma de Células Renais/terapia , Terapia Genética/métodos , Interleucina-2/administração & dosagem , Neoplasias Renais/terapia , Terapia Viral Oncolítica/métodos , Telomerase/metabolismo , Adenoviridae/enzimologia , Adenoviridae/genética , Adenoviridae/fisiologia , Animais , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/patologia , Carcinoma de Células Renais/virologia , Linhagem Celular Tumoral , Terapia Combinada , Modelos Animais de Doenças , Feminino , Citometria de Fluxo , Humanos , Imuno-Histoquímica , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/patologia , Neoplasias Renais/virologia , Camundongos , Camundongos Endogâmicos BALB C , Replicação Viral
12.
Oncogene ; 29(8): 1145-54, 2010 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-19935710

RESUMO

Malignant pleural mesothelioma (MPM) is a highly aggressive tumor that is related to asbestos exposure. MPM is characterized by rapid and diffuse local growth in the thoracic cavity, and it has a poor prognosis because it is often refractory to conventional therapy. Although MPM is an extraordinarily challenging disease to treat, locoregional virotherapy may be useful against this aggressive disease because of the accessibility by intrapleural virus delivery. In this study, we show that telomerase-specific, replication-selective adenovirus OBP-301 can efficiently infect and kill human mesothelioma cells by viral replication. Intrathoracic administration of virus significantly reduced the number and size of human mesothelioma tumors intrathoracically implanted into nu/nu mice. A high-definition, fluorescence optical imaging system with an ultra-thin, flexible fibered microprobe clearly detected intracellular replication of green fluorescent protein-expressing oncolytic virus in intrathoracically established mesothelioma tumors. As the extracellular matrix (ECM) may contribute to the physiological resistance of a solid tumor by preventing the penetration of therapeutic agents (including oncolytic viruses), we also examined whether the co-expression of heparanase, an endoglucuronidase capable of specifically degrading heparan sulfate, that influences the physiological barrier to macromolecule penetration, can modify the permeability of the ECM, resulting in profound therapeutic efficacy. Co-injection of OBP-301 and a replication-defective adenovirus (Ad-S/hep)-expressing heparanase resulted in more profound antitumor effects without apparent toxicity in an orthotopic pleural dissemination model. Our results suggest that intrathoracic dual virotherapy with telomerase-specific oncolytic adenovirus in combination with heparanase-expressing adenovirus may be efficacious in the prevention and treatment of pleural dissemination of human malignant mesothelioma.


Assuntos
Adenoviridae/genética , Terapia Genética , Glucuronidase/genética , Mesotelioma/terapia , Terapia Viral Oncolítica , Neoplasias Pleurais/terapia , Transfecção/métodos , Adenoviridae/enzimologia , Adenoviridae/crescimento & desenvolvimento , Animais , Linhagem Celular Tumoral , Terapia Combinada , Regulação Neoplásica da Expressão Gênica , Técnicas de Transferência de Genes , Glucuronidase/metabolismo , Humanos , Neoplasias Pulmonares/induzido quimicamente , Neoplasias Pulmonares/terapia , Mesotelioma/induzido quimicamente , Camundongos , Camundongos Nus , Transplante de Neoplasias , Neoplasias Pleurais/patologia , Biossíntese de Proteínas , Replicação Viral , Ensaios Antitumorais Modelo de Xenoenxerto
13.
Cancer Gene Ther ; 17(1): 11-9, 2010 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-19662088

RESUMO

Despite tremendous development in chemotherapy for ovarian cancer over the past few decades, the prognosis of advanced cases with massive peritoneal dissemination is still unsatisfactory, and novel treatment modalities that can combine with chemotherapy are urgently needed. We recently developed virotherapy for solid tumors using telomerase-specific replication-selective adenoviruses (Telomelysin: OBP-301), in which the human telomerase reverse transcriptase (hTERT) gene promoter has been inserted to direct tumor-specific E1 gene expression. In this study, we investigated the anti-tumor effects of OBP-301, combined with cisplatin (CDDP), on ovarian cancer cells. In vitro treatment of SKOV3 cells with OBP-301 at a multiplicity of infection (MOI) of 0.01-100 induced significant cell death in a dose-dependent manner, with moderate cytotoxicity at an MOI of 1-10 and maximal cytotoxicity at an MOI of 100. In contrast, OBP-301 treatment of normal human cells showed no significant cell death at an MOI of 1-10 and exhibited modest cytotoxicity at an MOI of 100. The effects of low-dose CDDP at 0.5-1 microM, which induced only 20% cell death, were significantly augmented by combination with OBP-301 at an MOI of 1-10, finally achieving 40% cell death. Such enhancement of CDDP sensitivity was also observed in CDDP-resistant ovarian cancer cells. The combinatorial effects were further tested using a xenograft mouse model of SKOV3 with peritoneal dissemination. After intraperitoneal administration of OBP-301, we confirmed that injected OBP-301 fused with the green fluorescent protein (GFP) gene (OBP-401) was preferentially localized to peritoneal disseminations, as determined by fluorescence imaging. Treatment of mice with CDDP at low dose (0.5 mg kg(-1)) had modest effects, showing a 10% decrease in disseminations, whereas combination with intraperitoneal administration of OBP-301 at an MOI of 10 led to enhanced effects, achieving an approximately 80% decrease in disseminations. Kaplan-Meier analysis showed improved overall survival of mice treated with CDDP plus OBP-301 compared with CDDP alone. These findings support the therapeutic potential of intraperitoneal administration of OBP-301 to sensitize ovarian cancer cells to CDDP.


Assuntos
Adenoviridae/fisiologia , Cisplatino/farmacologia , Terapia Viral Oncolítica/métodos , Neoplasias Ovarianas/terapia , Neoplasias Peritoneais/terapia , Telomerase/genética , Adenoviridae/genética , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Terapia Combinada , Feminino , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Humanos , Injeções Intraperitoneais , Camundongos , Camundongos Endogâmicos BALB C , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/virologia , Neoplasias Peritoneais/tratamento farmacológico , Neoplasias Peritoneais/secundário , Neoplasias Peritoneais/virologia , Análise de Sobrevida , Ensaios Antitumorais Modelo de Xenoenxerto
14.
Gene Ther ; 15(17): 1233-9, 2008 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-18580968

RESUMO

Oncolytic adenoviruses are a promising tool in cancer therapy. In this study, we characterized the role of autophagy in oncolytic adenovirus-induced therapeutic effects. OBP-405, an oncolytic adenovirus regulated by the human telomerase reverse transcriptase promoter (hTERT-Ad, OBP-301) with a tropism modification (RGD) exhibited a strong antitumor effect on glioblastoma cells. When autophagy was inhibited pharmacologically, the cytotoxicity of OBP-405 was attenuated. In addition, autophagy-deficient Atg5(-/-) mouse embryonic fibroblasts (MEFs) were less sensitive than wild-type MEFs to OBP-405. These findings indicate that OBP-405-induced autophagy is a cell killing effect. Moreover, autophagy-inducing therapies (temozolomide and rapamycin) synergistically sensitized tumor cells to OBP-405 by stimulating the autophagic pathway without altering OBP-405 replication. Mice harboring intracranial tumors treated with OBP-405 and temozolomide survived significantly longer than those treated with temozolomide alone, and mice treated with OBP-405 and the rapamycin analog RAD001 survived significantly longer than those treated with RAD001 alone. The observation that autophagy inducers increase OBP-405 antitumor activity suggests a novel strategy for treating patients with glioblastoma.


Assuntos
Autofagia/efeitos dos fármacos , Neoplasias Encefálicas/terapia , Terapia Genética/métodos , Glioblastoma/terapia , Terapia Viral Oncolítica/métodos , Adenoviridae/genética , Animais , Linhagem Celular Tumoral , Dacarbazina/análogos & derivados , Dacarbazina/uso terapêutico , Camundongos , Vírus Oncolíticos/genética , Sirolimo/uso terapêutico , Temozolomida
15.
Cancer Gene Ther ; 15(5): 315-22, 2008 May.
Artigo em Inglês | MEDLINE | ID: mdl-18274558

RESUMO

We previously constructed OBP-301 (Telomelysin, a telomerase-specific replication-competent adenovirus with human telomerase reverse transcriptase (hTERT) promoter), which showed a strong anticancer effect by inducing cell lysis of human non-small cell lung cancer and colorectal cancer cells. To investigate the utility of OBP-301 for prostate cancer treatment, we herein evaluate the cell killing and antitumor effects. First, in vitro hTERT-specific adenovirus transduction in human prostate cancer cells (LNCaP, PC3, DU145) was confirmed using OBP-401 (Telomelysin-green fluorescent protein (GFP)). There was no detectable GFP transduction in the human prostate normal cells (PrEC, PrSC). Consistently, the cell-killing effect of OBP-301 was observed only in the cancer cells. Second, using an in vivo subcutaneous LNCaP tumor model in nude mice, we demonstrated that three intratumoral OBP-301 injections (10(7) PFU per tumor x 3 days) were sufficient to eradicate the detectable LNCaP prostate tumor. We also demonstrated that the ispilateral treatment with OBP-301 significantly suppressed contralateral LNCaP tumor growth in both sides of the tumor model. Histological and immunohistochemical analyses revealed diffuse oncolytic degeneration and adenoviral E1A protein expression in both sides of the tumors. Therefore, in situ OBP-301 administration could be a promising therapeutic strategy against prostate cancer and its metastatic lesions.


Assuntos
Adenoviridae/genética , Antineoplásicos/uso terapêutico , Antivirais/uso terapêutico , Neoplasias da Próstata/tratamento farmacológico , Taxoides/uso terapêutico , Telomerase/uso terapêutico , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos Fitogênicos/uso terapêutico , Modelos Animais de Doenças , Docetaxel , Terapia Genética/métodos , Proteínas de Fluorescência Verde/uso terapêutico , Humanos , Masculino , Camundongos
16.
Kyobu Geka ; 61(2): 135-7, 2008 Feb.
Artigo em Japonês | MEDLINE | ID: mdl-18268951

RESUMO

A 78-year-old woman who had undergone double valve replacement 13 years before was referred to our department because of postoperative wound dehiscence and exudate. Although the result of exudate culture was negative, the wound was disinfected continuously for 4 weeks and showed a transient remission. However, the exudate was observed again 3 weeks later. By chest computed tomography (CT), a highly bright shadow was revealed in the mediastinum, which was suspected to be a foreign body and, therefore, the cause of the exudate. Considering the possibility of infection, the patient underwent an operation. Following incision of the epigastric region and the resection of the xiphoid process, ePTFE membrane with poor granulation tissue was found. The membrane was removed, the lesion was washed with warm saline, and then the wound was closed. The postoperative course was uneventful without recurrence. This complication was considered to be caused by biological reaction to a foreign body.


Assuntos
Parede Abdominal , Fístula/etiologia , Corpos Estranhos/complicações , Doenças do Mediastino/etiologia , Mediastino , Politetrafluoretileno/efeitos adversos , Idoso , Feminino , Fístula/cirurgia , Corpos Estranhos/cirurgia , Reação a Corpo Estranho/etiologia , Reação a Corpo Estranho/cirurgia , Implante de Prótese de Valva Cardíaca/efeitos adversos , Humanos , Doenças do Mediastino/cirurgia , Mediastino/cirurgia , Membranas Artificiais , Resultado do Tratamento
17.
Oncogene ; 27(17): 2375-81, 2008 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-17982491

RESUMO

Dendritic cells (DCs) are the most potent antigen-presenting cells and acquire cellular antigens and danger signals from dying cells to initiate antitumor immune responses via direct cell-to-cell interaction and cytokine production. The optimal forms of tumor cell death for priming DCs for the release of danger signals are not fully understood. OBP-301 (Telomelysin) is a telomerase-specific replication-competent adenovirus that induces selective E1 expression and exclusively kills human cancer cells. Here, we show that OBP-301 replication produced the endogenous danger signaling molecule, uric acid, in infected human tumor cells, which in turn stimulated DCs to produce interferon-gamma (IFN-gamma) and interleukin 12 (IL-12). Subsequently, IFN-gamma release upregulated the endogenous expression of the proteasome activator PA28 in tumor cells and resulted in the induction of cytotoxic T-lymphocytes. Our data suggest that virus-mediated oncolysis might be the effective stimulus for immature DCs to induce specific activity against human cancer cells.


Assuntos
Neoplasias/imunologia , Terapia Viral Oncolítica , Complexo de Endopeptidases do Proteassoma/metabolismo , Transdução de Sinais , Linfócitos T Citotóxicos/enzimologia , Linfócitos T Citotóxicos/imunologia , Regulação para Cima , Adenoviridae/imunologia , Adenoviridae/fisiologia , Linhagem Celular Tumoral , Células Dendríticas/imunologia , Ativação Enzimática , Humanos , Neoplasias/patologia , Neoplasias/virologia , Ácido Úrico/metabolismo
18.
Br J Cancer ; 96(8): 1191-6, 2007 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-17387341

RESUMO

This study aimed to identify predictive factors associated with prognostic benefits of gefitinib. A total of 221 Japanese patients who received gefitinib (250 mg day(-1)) were examined retrospectively and potential predictive factors analysed. Overall response rate (ORR) was 24.4% and median survival time (MST) was 8.0 months. In a log-rank test, survival was significantly better in females, patients with adenocarcinoma, never-smokers, favourable performance status (PS) and patients with epidermal growth factor receptor (EGFR) mutation. The lower the smoking exposure (Brinkman Index (BI)=cigarettes per day x years smoked), the better the MST (BI 0: 14.5 months, BI <500: 9.5 months, BI 500 to <1000: 6.9 months, BI > or =1000: 4.0 months). Positive-EGFR mutation status and PS 0-1 were independent predictors of favourable prognosis by multivariate analysis. Prognosis was significantly different according to EGFR mutation status (with the same smoking status), but not according to smoking status (with the same EGFR mutation status). EGFR mutation status is the most important independent predictor of survival benefit with gefitinib treatment. Although differences in prognosis were observed according to relative smoking status and smoking exposure, the results suggested that smoking is not a direct predictor of prognosis, yet is a surrogate marker of EGFR mutation status.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Receptores ErbB/antagonistas & inibidores , Neoplasias Pulmonares/tratamento farmacológico , Quinazolinas/uso terapêutico , Adulto , Idoso , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Receptores ErbB/genética , Feminino , Gefitinibe , Humanos , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Mutação , Quinazolinas/efeitos adversos , Estudos Retrospectivos , Fumar/efeitos adversos
19.
Skeletal Radiol ; 36 Suppl 1: S86-90, 2007 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-16649043

RESUMO

We present the first known adult case of solitary myofibroma of bone, which affected a lumbar vertebra in a 33-year-old male. Radiography identified a purely lytic lesion with a sclerotic rim in the right pedicle of L1. CT showed an expansile lytic lesion with a sclerotic rim. MRI of the lesion revealed an isointense signal on T1-weighted images, an inhomogeneously hyperintense signal on T2-weighted images, and marked enhancement with gadolinium. Pathological study showed a mixed picture of nodular proliferation of spindle-shaped myoid cells and hemangiopericytomatous proliferation of short spindle/small round cells. The tumor cells were immunoreactive for smooth muscle actin and immunonegative for desmin. This case of solitary myofibroma of bone is exceptionally rare because of its occurrence in an adult older than 20 years of age and its location at an extra-craniofacial site.


Assuntos
Vértebras Lombares/patologia , Imageamento por Ressonância Magnética , Miofibromatose/diagnóstico , Neoplasias da Coluna Vertebral/diagnóstico , Adulto , Diagnóstico Diferencial , Humanos , Masculino , Miofibromatose/patologia , Neoplasias da Coluna Vertebral/patologia
20.
Respir Med ; 96(6): 469-74, 2002 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-12117049

RESUMO

Alternative medicine use has increased at a remarkable pace all over the world in recent years. Although herbal medicine for the treatment of asthma is becoming the focus of public attention, randomized studies had not been performed, even in Eastern countries including Japan. This study was designed to investigate whether one of the Japanese government approved herbal complexes Saiboku-to (TJ-96) is effective for the treatment of atopic asthma, and to investigate whether this protective activity is associated with a reduction in eosinophilic inflammation. A double-blind, randomized, crossover design was used. Subjects received 2.5 g of TJ-96 or placebo orally 3 times daily for 4 weeks and then, after a washout period of at least 4 weeks, crossed over to receive the alternative treatment. We assessed the effects of pretreatment with TJ-96 on bronchoconstriction precipitated by inhalation of methacholine. Furthermore, eosinophil counts and measurement of eosinophilic cationic protein (ECP) were performed. After 4 weeks of treatment with TJ-96, values of PC20 -methacholine significantly improved in the treatment with TJ-96. Also, patients' symptoms, blood eosinophils, serum ECP, sputum eosinophils, and sputum ECP were significantly decreased. Our results suggest that TJ-96 has an antiinflammatory effect on bronchial eosinophilic infiltration. This study raises further interesting therapeutic possibilities and argues for further trials of new approaches to the treatment of asthma.


Assuntos
Asma/tratamento farmacológico , Medicamentos de Ervas Chinesas/uso terapêutico , Imunossupressores/uso terapêutico , Medicina Kampo , Fitoterapia , Adulto , Estudos Cross-Over , Método Duplo-Cego , Feminino , Volume Expiratório Forçado/efeitos dos fármacos , Humanos , Masculino , Capacidade Vital/efeitos dos fármacos
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