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1.
Cancer Res ; 62(5): 1410-9, 2002 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-11888913

RESUMO

FTY720 is a unique immunosuppressive agent that exerts its activity by inducing apoptosis in lymphocytes. We conducted the present study to investigate the effects of FTY720 on cancer growth and metastasis, as well as its mechanism of action. In vitro treatment with FTY720 induced dramatic cancer cell apoptosis in a mouse breast cancer cell line, JygMC(A). Electron microscopy revealed distinct changes on the cell surface with decreased filopodias and microvilli in cancer cells treated with FTY720 at 2 microM and clear evidence of apoptosis at 10 microM. Interestingly, the effect of FTY720 was significantly less in the normal fibroblasts than in the cancer cells, indicating greater susceptibility of cancer cells to the agent. We then tested the in vivo effect of FTY720 in a mouse breast cancer model created by inoculating JygMC(A) cells (s.c.) in the flank region of BALB/c-nu/nu mice at three different dosages (2, 5, and 10 mg/kg/day; n = 30/group). Tumor growth was markedly suppressed at a dosage of 5 mg/kg or more without notable side effects. In addition, tumor metastasis, which was dramatically evident in control mice, was significantly prevented even at a low dose (2 mg/kg/day), resulting in a significant prolongation of animal survival. These data led us to additionally investigate the mechanism of action, especially the prevention of metastasis at a low dose. FTY720 treatment at 2 microM caused a remarkable cytoskeletal change with deformed and decreased filopodias in cancer cells. In addition, it significantly decreased the ability of cancer cells to adhere and migrate to extracellular matrix components, and markedly reduced the expression of integrins on the cancer cell surface. These results indicate that FTY720 is a potent anticancer agent that induces cancer cell apoptosis and is markedly effective for prevention of metastasis. The changes of cellular structure with reduction of integrin expression may be one of its underlying mechanisms of action.


Assuntos
Imunossupressores/uso terapêutico , Neoplasias Mamárias Experimentais/tratamento farmacológico , Metástase Neoplásica/prevenção & controle , Propilenoglicóis/farmacologia , Actinas/metabolismo , Animais , Apoptose/efeitos dos fármacos , Adesão Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Citoesqueleto/efeitos dos fármacos , Feminino , Cloridrato de Fingolimode , Integrinas/análise , Neoplasias Mamárias Experimentais/patologia , Neoplasias Mamárias Experimentais/ultraestrutura , Camundongos , Camundongos Endogâmicos BALB C , Microscopia Eletrônica , Propilenoglicóis/efeitos adversos , Esfingosina/análogos & derivados , Células Tumorais Cultivadas
2.
Chin Med J (Engl) ; 117(4): 552-7, 2004 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-15109448

RESUMO

BACKGROUND: Von Hippel-Lindau (VHL) disease is a heraditary cancer syndrome caused by germline mutations of the VHL tumor on the suppressor gene. This study was to show the clinical characteristics of a large Chinese kindred with von Hippel-Lindau disease and to evaluate the role of the genetic test of VHL disease in the diagnosis of VHL disease and clinical screening of members of the VHL disease family. METHODS: DNA extracted from peripheral blood was amplified by PCR to three exons of the VHL gene in 27 members of a large kindred with VHL disease. PCR products were directly sequenced. The involvements of multi-organs in the kindred with VHL disease were confirmed by history taking and radiography. RESULTS: Of 47 members in the four generations of the kindred, 18 members were diagnosed as having VHL disease. Clinical manifestations of 18 patients included: central nervous system (CNS) hemangioblastoma (5), renal cell carcinoma and CNS hemangioblastoma (3), renal cell carcinoma and retinal angioma (3), renal cell carcinoma and multiple pancreatic cysts (1), renal cell carcinoma and retinal angioma and multiple pancreatic cysts (2), renal cell carcinoma and CNS hemangioblastomas and multiple pancreatic cysts (1), and multiple pancreatic cysts and multiple renal cysts (1), multiple pancreatic cysts (2). The common lesions of the 18 patients were renal cell carcinoma (55.6%), CNS hemangioblastoma (50.0%), retinal angioma (27.8%), and multiple pancreatic cysts (38.9%). Among the 27 members who volunteered for genetic analysis, 15 members including 9 affected family patients and 2 asymptomatic patients and 4 carriers, who are still alive, presented a codon 78 from Asn to Ser change at nucleotide 446 (A-->G) in exon 1. Four members were carriers with the same VHL gene mutation. Two asymptomatic patients were initially diagnosed by genetic testing and subsequently confirmed radiologically and surgically. Members without gene mutation had no clinical evidence of VHL disease. CONCLUSIONS: The large Chinese kindred with VHL disease was classified as type I. The main characteristics in the kindred were higher incidence of renal cell carcinoma and lower incidence of retinal angioma. Genetic test plays an important role in early detecting asymptomatic patients and the carriers in clinical screening of members of the families with VHL disease. It is also important to prevent the transmission of VHL disease to their offsprings in the kindred.


Assuntos
Doença de von Hippel-Lindau/genética , Adolescente , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Linhagem , Proteínas Supressoras de Tumor/genética , Ubiquitina-Proteína Ligases/genética , Proteína Supressora de Tumor Von Hippel-Lindau , Doença de von Hippel-Lindau/complicações , Doença de von Hippel-Lindau/diagnóstico
3.
Artigo em Zh | MEDLINE | ID: mdl-14767899

RESUMO

OBJECTIVE: To report the clinical characterization of a large Chinese kindred with von Hippel-Lindau (VHL) disease and to evaluate the role of VHL genetic testing in diagnosis of VHL disease and clinical screening for members in VHL disease family. METHODS: A large kindred with VHL disease was studied. DNA extracted from peripheral blood was amplified by PCR to three exons of VHL gene in 27 members. PCR products were directly sequenced. The data on involvement of multi-organs in the VHL disease kindred were obtained by medical history taking and radiography. RESULTS: There were 47 members in the four generations of the Chinese VHL kindred; among them, 18 members were patients with diagnostically proven VHL disease. Their clinical manifestations included: central nervous system(CNS) hemangioblastoma (n=5), renal cell carcinomas and CNS hemangioblastoma (n=3), renal cell carcinomas and retinal angiomas (n=3), renal cell carcinomas and multiple pancreatic cysts (n=1), renal cell carcinomas and retinal angiomas and multiple pancreatic cysts (n=2), renal cell carcinomas and CNS hemangioblastomas and multiple pancreatic cysts (n=1), and multiple pancreatic cysts and multiple renal cysts (n=1), and multiple pancreatic cysts (n=2). The common lesions of 18 patients in the large kindred were: renal cell carcinomas (56%), CNS hemangioblastomas(50%),retinal angiomas(28%), and multiple pancreatic cysts(39%). Of the 27 members who volunteered for genetic analysis, all 11 affected family patients who are still alive, including 9 affected family patients and 2 asymptomatic patients, presented a codon 78 from Asn to Ser change at nucleotide 446(A to G) in exon 1. Four members were carriers with the same VHL gene mutation. Two asymptomatic cases were initially diagnosed by genetic testing and subsequently confirmed by radiological imaging and surgery. Members not having the gene mutation had no clinical evidence of VHL disease. CONCLUSION: The large Chinese kindred with VHL disease was classified as type . The main characteristics of the kindred are higher incidence of renal cell carcinomas and lower incidence of retinal angiomas. The genetic testing played an important role in early detecting asymptomatic patients and the carriers in clinical screening for members in the VHL families. Also, it is important to prevent the transmission of VHL disease to the offspring in the kindred.


Assuntos
Mutação , Proteínas Supressoras de Tumor/genética , Ubiquitina-Proteína Ligases/genética , Doença de von Hippel-Lindau/genética , Sequência de Bases , China , DNA/química , DNA/genética , Análise Mutacional de DNA , Saúde da Família , Feminino , Testes Genéticos , Humanos , Masculino , Linhagem , Proteína Supressora de Tumor Von Hippel-Lindau , Doença de von Hippel-Lindau/classificação , Doença de von Hippel-Lindau/diagnóstico
4.
Clin Transplant ; 16 Suppl 8: 24-30, 2002.
Artigo em Inglês | MEDLINE | ID: mdl-12464128

RESUMO

Chronic allograft dysfunction is multi-factorial, and histology of long-term renal allograft shows variable findings. It is important to characterize the pathological features of graft kidneys with normal function to understand the natural course of transplants, which in turn would contribute to elucidate the causes of chronic allograft nephropathy (CAN). To address this issue, we performed 'non-episode' biopsies on well-functioning renal allografts, and evaluated the correlation between clinical outcome and histopathological findings. Patients who underwent a non-episode biopsy had a serum creatinine concentration less than 2.0 mg/dL, urinary protein of less than 500 mg/day and a stable clinical course. In total, 90 such biopsies were performed. Mean follow-up period after biopsy was 29 +/- 16 months. We evaluated the histopathological findings and clinical outcome on each finding. Moreover, we compared the findings in the patients on tacrolimus with those of patients taking cyclosporin. Twenty-three biopsy specimens were essentially normal. Graft dysfunction during the follow-up period was recognized more frequently in patients showing more than one pathological process than in those with isolated findings. Graft outcome was not associated with drug-induced nephropathy, but with acute rejection (P = 0.0193) and CAN (P = 0.0032). Patients found to have CAN-b had a worse outcome than those with CAN-a. CAN-b was less common in the tacrolimus group than in the cyclosporin group. Non-episode biopsy has a predictive value of the long-term outcome of a renal allograft. CAN is associated with graft dysfunction; neither is drug-induced nephropathy. Patients treated with tacrolimus had lower rates of CAN-b than did cyclosporin-treated subjects.


Assuntos
Biópsia , Transplante de Rim , Rim/patologia , Rim/fisiologia , Adulto , Creatinina/sangue , Ciclosporina , Sobrevivência de Enxerto , Humanos , Imunossupressores/uso terapêutico , Prognóstico , Proteinúria , Tacrolimo/uso terapêutico , Transplante Homólogo , Resultado do Tratamento
5.
Int J Cancer ; 98(2): 167-72, 2002 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-11857403

RESUMO

Despite the high frequency of prostate cancer, therapeutic options for advanced disease are limited to chemotherapy, radiation or hormonal therapy and eventually fail in all patients. Therefore, alternative approaches need to be developed. We previously reported that FTY720, a metabolite from Isaria sinclarii, is a unique antitumor agent for an androgen-independent prostate cancer cell line and requires caspase-3 activation in apoptosis. In our study, we have evaluated the effect of FTY720 on a family of mitogen-activated protein kinases (MAPKs), focal adhesion kinase (FAK), mitochondrial transmembrane potential, caspase-9 and caspase-8 and analyzed the expression of some cell-cycle regulator proteins in DU145 cells in order to understand the various antitumor effects of FTY720. Apoptosis was quantified by phosphatidylserine exposure. Activation of MAPKs, cleavage of caspase-9 and caspase-8, status of cyclin-dependent kinases (CDKs) and Cip1/p21, a cyclin-dependent kinase inhibitor, were evaluated by Western blot analysis, in addition to FAK and phospho-FAK immunoprecipitation and cell-cycle analysis by FACScan. We found that in DU145 cells, 40 microM FTY720 caused activation of p38 MAPK and the upstream kinase MKK3/MKK6 but not SAPK/JNK. Mitochondrial transmembrane potential, FAK and ERK1/2 were reduced while caspase-9 and caspase-8 were cleaved. The p38-specific inhibitor had no effect on apoptosis induced by FTY720, whereas z-VAD.FMK, a broad-spectrum caspase inhibitor, did not inhibit the p38 MAPK activation. An amount of 20 microM FTY720 resulted in G(1) arrest and a decrease of CDK2 as well as CDK4, whereas it induced Cip1/p21. FTY720 may exert anticarcinogenic effects against prostate cancer cells possibly involving modulation of mitogenic signaling, cell-cycle regulators, induction of G(1) arrest and apoptotic death in DU145 cells.


Assuntos
Adenocarcinoma/metabolismo , Antineoplásicos/farmacologia , Apoptose , Propilenoglicóis/farmacologia , Neoplasias da Próstata/metabolismo , Adenocarcinoma/enzimologia , Adenocarcinoma/patologia , Clorometilcetonas de Aminoácidos/farmacologia , Antineoplásicos/antagonistas & inibidores , Inibidores de Caspase , Caspases/metabolismo , Ciclo Celular , Proteínas de Ciclo Celular/metabolismo , Inibidores de Cisteína Proteinase/farmacologia , Inibidores Enzimáticos/farmacologia , Cloridrato de Fingolimode , Quinase 1 de Adesão Focal , Proteína-Tirosina Quinases de Adesão Focal , Humanos , Cinética , MAP Quinase Quinase 3 , Masculino , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Mitógenos/farmacologia , Propilenoglicóis/antagonistas & inibidores , Neoplasias da Próstata/enzimologia , Neoplasias da Próstata/patologia , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/metabolismo , Transdução de Sinais/efeitos dos fármacos , Esfingosina/análogos & derivados , Células Tumorais Cultivadas , Proteínas Quinases p38 Ativadas por Mitógeno
6.
J Am Soc Nephrol ; 12(6): 1280-1292, 2001 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-11373353

RESUMO

Long-term renal isografts in humans and laboratory animals exhibit features similar to those of chronic allograft nephropathy (CAN), indicating that antigen-independent factors, such as acute renal ischemia, are likely to be involved in the development of CAN. Hepatocyte growth factor (HGF) has been demonstrated to play a renotropic role in renal regeneration and protection from acute ischemic injury. This study was thus conducted to investigate the effect of HGF on the development of CAN, using an established rat model. HGF was administered daily (100 microg/d, intravenously) for 4 wk after engraftment. Control animals received saline solution. Allografts from control animals exhibited early evidence of severe structural collapse and necrotic cell death in the proximal tubules and outer medulla, with mononuclear cell infiltration, within 1 wk after engraftment. This was followed by sequential upregulation of adhesion molecules and cytokines, accompanied by dense macrophage infiltration. Fibrogenic events, as indicated by marked increases in transforming growth factor-beta1 expression and the accumulation of smooth muscle alpha-actin, occurred during the same period. Control animals ultimately developed features typical of CAN, with functional deterioration and severe histologic changes; a survival rate of 50.6% by 32 wk was observed. In contrast, remarkably little early injury and no late fibrogenic events were observed for the HGF-treated group. All treated animals survived, with well preserved graft function, during the 32-wk follow-up period. These results indicate that renal protection and recovery from early allograft injury with HGF treatment greatly contribute to a reduction of susceptibility to the subsequent development of CAN in a rat model. The potential application of HGF in the prevention of CAN warrants further attention.


Assuntos
Rejeição de Enxerto/patologia , Rejeição de Enxerto/prevenção & controle , Fator de Crescimento de Hepatócito/farmacologia , Transplante de Rim , Rim/patologia , Animais , Fragmentação do DNA , Eletroforese em Gel de Ágar , Imuno-Histoquímica , Marcação In Situ das Extremidades Cortadas , Rim/efeitos dos fármacos , Masculino , Microscopia Eletrônica , RNA/análise , Ratos , Ratos Endogâmicos F344 , Ratos Endogâmicos Lew , Reação em Cadeia da Polimerase Via Transcriptase Reversa
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