Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 16 de 16
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Fetal Pediatr Pathol ; 30(2): 106-10, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21391750

RESUMO

Intussusception is the leading cause of intestinal obstruction in children and is almost invariably idiopathic. Occasionally, there is a lead point for the intussusception. Intussusception caused by heterotopic pancreas (HPT) as the lead point is exceedingly rare. We report a case of intussusception caused by HPT in a child. Clinical and pathologic features and the successful medical and surgical management of the case are discussed.


Assuntos
Coristoma/complicações , Coristoma/patologia , Doenças do Íleo/etiologia , Intussuscepção/etiologia , Pâncreas/patologia , Criança , Coristoma/cirurgia , Humanos , Doenças do Íleo/patologia , Doenças do Íleo/cirurgia , Lactente , Intussuscepção/patologia , Intussuscepção/cirurgia , Masculino
2.
Fetal Diagn Ther ; 25(1): 163-6, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19293587

RESUMO

Although most prenatally diagnosed pulmonary sequestrations (PS) are asymptomatic, large lesions are associated with pleural effusions and pulmonary hypoplasia. We present the first reported case of a prenatally diagnosed giant extralobar pulmonary sequestration that required the ex utero intrapartum treatment (EXIT) procedure with resection and extracorporeal membrane oxygenation (ECMO). We discuss the compelling rationale for performing EXIT-resection-ECMO in the setting of a large thoracic mass and anticipated severe respiratory failure at birth.


Assuntos
Sequestro Broncopulmonar/cirurgia , Oxigenação por Membrana Extracorpórea , Adulto , Sequestro Broncopulmonar/diagnóstico por imagem , Sequestro Broncopulmonar/terapia , Feminino , Feto/irrigação sanguínea , Feto/cirurgia , Humanos , Recém-Nascido , Masculino , Gravidez , Ultrassonografia
3.
Mol Cancer Res ; 6(1): 1-9, 2008 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-18234958

RESUMO

Vascular endothelial growth factor (VEGF) blockade has been validated clinically as a treatment for human cancers, yet virtually all patients eventually develop progressive disease during therapy. In order to dissect this phenomenon, we examined the effect of sustained VEGF blockade in a model of advanced pediatric cancer. Treatment of late-stage hepatoblastoma xenografts resulted in the initial collapse of the vasculature and significant tumor regression. However, during sustained treatment, vessels recovered, concurrent with a striking increase in tumor expression of perlecan, a heparan sulfate proteoglycan. Whereas VEGF mRNA was expressed at the periphery of surviving clusters of tumor cells, both secreted VEGF and perlecan accumulated circumferential to central vessels. Vascular expression of heparanase, VEGF receptor-2 ligand binding, and receptor activation were concurrently maintained despite circulating unbound VEGF Trap. Endothelial survival signaling via Akt persisted. These findings provide a novel mechanism for vascular survival during sustained VEGF blockade and indicate a role for extracellular matrix molecules that sequester and release biologically active VEGF.


Assuntos
Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Animais , Colágeno/metabolismo , Células Endoteliais/enzimologia , Células Endoteliais/metabolismo , Ativação Enzimática , Feminino , Regulação Neoplásica da Expressão Gênica , Glucuronidase/metabolismo , Proteoglicanas de Heparan Sulfato/metabolismo , Hepatoblastoma/irrigação sanguínea , Hepatoblastoma/enzimologia , Hepatoblastoma/genética , Hepatoblastoma/patologia , Humanos , Camundongos , Camundongos Nus , Modelos Biológicos , Estadiamento de Neoplasias , Neoplasias/irrigação sanguínea , Neoplasias/enzimologia , Neoplasias/patologia , Neovascularização Patológica/genética , Fosforilação , Ligação Proteica , Proteínas Proto-Oncogênicas c-akt/metabolismo , Indução de Remissão , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética , Ensaios Antitumorais Modelo de Xenoenxerto
4.
J Pediatr Surg ; 40(1): 69-73; discussion 73-4, 2005 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-15868561

RESUMO

BACKGROUND/PURPOSE: Formal training in pediatric surgery is highly competitive. The limited number of accredited positions has historically favored applicants with basic science experience, numerous publications, national presentations, and exposure to well-known pediatric surgeons. This review analyzes characteristics of successful applicants and cost associated with the Match. METHODS: A survey was e-mailed to 45 applicants after the 2003 Match. Geographic provenance, demographics, qualifications, costs, and valued program characteristics were assessed. Statistics were formulated by chi2 and Student's t test. RESULTS: Thirty-six applicants (80%) responded. Successful characteristics for matched vs unmatched included number of publications, 11.2 vs 5.7 (P < .01); first-author designation, 6.4 vs 3.1 (P = .02); basic science papers, 5.7 vs 1.7 (P < .01); national presentations, 5.8 vs 2.4 (P = .02); and presentations at pediatric surgical meetings, 2.0 vs 0.6 (P = .04). Ninety percent of matched applicants took time off to perform basic science research (P < .01). Average candidate expense was $6974, which represented 14% of pretax salary. Forty-one percent of applicants noted that cost limited the number of interviews taken. Fifty percent preferred a regional interview process to limit expense. Candidates ranked case diversity, volume, and mentor's advice as the most valued program characteristics. Successful applicants matched at their fifth rank on average. Eighty-six percent of unsuccessful applicants will reapply. CONCLUSIONS: Results of this study are important to those interested in the future of pediatric surgery. Successful applicants were shown to have several national presentations and multiple scientific publications, especially in basic sciences. Applicant costs are high, totaling more than $236,000 for survey respondents.


Assuntos
Custos e Análise de Custo , Educação de Pós-Graduação em Medicina/economia , Pediatria/educação , Seleção de Pessoal , Especialidades Cirúrgicas/educação , Adulto , Criança , Comportamento Competitivo , Coleta de Dados , Bolsas de Estudo , Humanos , Candidatura a Emprego , Critérios de Admissão Escolar , Recursos Humanos
5.
Int J Oncol ; 25(3): 549-53, 2004 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-15289855

RESUMO

We characterized the effect of potent vascular endothelial growth factor (VEGF) blockade on early-stage Wilms tumor xenograft growth, vasculature and metastasis. VEGF is a key mediator of both physiologic and tumor angiogenesis. We recently described that potent VEGF blockade induces regression of established Wilms tumor xenografts and vessels, also reducing the size but not the incidence of pre-existing metastases. In these studies, we examined the effects of potent VEGF blockade on earlier stages of experimental Wilms tumors, focusing on tumor growth, vasculature and metastasis. Athymic mice received intrarenal human Wilms tumor cell implants. Biweekly treatment with vehicle or the VEGF-Trap, a high-affinity soluble decoy receptor incorporating regions of VEGFR1 and VEGFR2, was begun 1 week later (100 or 500 micrograms/dose, n=20 in each group). Mice were euthanized at week 6 to examine tumor weight, incidence of lung metastases, vascularity and expression of angiogenic factors. A cohort of mice was examined 2 weeks after cessation of treatment. Compared to controls, VEGF-Trap treated tumors were significantly smaller (100 micrograms/dose: 92.7% smaller, p=0.0017; 500 micro g/dose: 99.0% smaller, p=0.0009). The incidence of lung metastasis also decreased significantly (p<0.0055). VEGF-Trap nearly eradicated tumor vasculature. Rare persisting vessels were characterized by large caliber, quiescence (lacking proliferation/apoptosis) and arterialization (both phenotypic and molecular). Potent VEGF blockade caused near-arrest of experimental Wilms tumor growth, resulted in nearly avascular tumors, and also decreased the incidence and size of metastases. Persistent vessels in tumors treated with VEGF-Trap displayed specific morphologic and molecular features, suggestive of arterialization. Future strategies that target these persisting vessels may enhance the efficacy of VEGF blockade therapy.


Assuntos
Neoplasias Renais/tratamento farmacológico , Neovascularização Patológica/tratamento farmacológico , Receptores de Fatores de Crescimento do Endotélio Vascular/uso terapêutico , Proteínas Recombinantes de Fusão/uso terapêutico , Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Tumor de Wilms/tratamento farmacológico , Animais , Apoptose , Proliferação de Células/efeitos dos fármacos , Células Endoteliais/efeitos dos fármacos , Feminino , Neoplasias Renais/irrigação sanguínea , Camundongos , Camundongos Nus , Transplante de Neoplasias , Proteínas Recombinantes de Fusão/farmacologia , Regulação para Cima , Fatores de Crescimento do Endotélio Vascular/genética , Tumor de Wilms/irrigação sanguínea , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Mol Cancer Res ; 2(1): 36-42, 2004 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-14757844

RESUMO

The potential for avoiding acquired resistance to therapy has been proposed as one compelling theoretical advantage of antiangiogenic therapy based on the normal genetic status of the target vasculature. However, previous work has demonstrated that tumors may resume growth after initial inhibition if antiangiogenic blockade is continued for an extended period. The mechanisms of this recurrent growth are unclear. In these studies, we characterized molecular changes in vasculature during apparent resumption of xenograft growth after initial inhibition by vascular endothelial growth factor blockade, "metronome" topotecan chemotherapy, and combined agents in a xenograft murine model of human Wilms' tumor. Tumors that grew during antiangiogenic blockade developed as viable clusters surrounding strikingly remodeled vessels. These vessels displayed significant increases in diameter and active proliferation of vascular mural cells and expressed platelet-derived growth factor-B, a factor that functions to enhance vascular integrity via stromal cell recruitment. In addition, remodeled vessels were marked by expression of ephrinB2, required for proper assembly of stromal cells into vasculature. Thus, enhanced vascular stability appears to characterize tumor vessel response to chronic antiangiogenesis, features that potentially support increased perfusion and recurrent tumor growth.


Assuntos
Antineoplásicos/uso terapêutico , Recidiva Local de Neoplasia , Neovascularização Patológica/tratamento farmacológico , Topotecan/uso terapêutico , Tumor de Wilms/irrigação sanguínea , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Biomarcadores Tumorais/metabolismo , Efrina-B2/metabolismo , Feminino , Angiofluoresceinografia , Técnica Indireta de Fluorescência para Anticorpo , Humanos , Hibridização In Situ , Camundongos , Camundongos Nus , Microscopia de Fluorescência , Proteínas de Neoplasias/metabolismo , Proteínas Proto-Oncogênicas c-sis/metabolismo , Receptor beta de Fator de Crescimento Derivado de Plaquetas/metabolismo , Transplante Heterólogo , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Tumor de Wilms/metabolismo , Tumor de Wilms/patologia
7.
J Pediatr Surg ; 38(11): 1569-73, 2003 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-14614702

RESUMO

BACKGROUND: The human epidermal growth factor family (HER) members play a significant role in the mesenchymal-to-epithelial transition during renal tubulogenesis. HER misexpression has been linked also to loss of growth control, invasiveness, and promotion of angiogenesis in breast cancers and other human malignant tumors METHODS: The authors screened Wilms' tumor samples and derived cell lines for expression of her2/neu, which was detected in both unfavorable and favorable histology tissues. Xenografts were implanted in mice using her2/neu(+) and her2/neu(-) cell lines and the effect of specific blockade tested using monoclonal anti-her2/neu antibody. RESULTS: Blocking antibody suppressed tumor growth in her2/neu(+) but not her2/neu(-) experimental Wilms' tumor. In addition, antibody exposure resulted in suppression of tumor angiogenesis but no decrease in tumor cell proliferation in her2/neu(+) xenografts. CONCLUSIONS: Her2/neu contributes to the growth of some Wilms' tumors, and an important mechanism of its action is promotion of angiogenesis.


Assuntos
Neoplasias Renais/irrigação sanguínea , Proteínas de Neoplasias/fisiologia , Neovascularização Patológica/fisiopatologia , Receptor ErbB-2/fisiologia , Tumor de Wilms/irrigação sanguínea , Animais , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados , Divisão Celular/efeitos dos fármacos , Linhagem Celular Tumoral/metabolismo , Linhagem Celular Tumoral/transplante , Feminino , Genes erbB-2 , Humanos , Neoplasias Renais/genética , Neoplasias Renais/metabolismo , Neoplasias Renais/terapia , Camundongos , Camundongos Nus , Proteínas de Neoplasias/deficiência , Proteínas de Neoplasias/imunologia , Neovascularização Patológica/tratamento farmacológico , Receptor ErbB-2/deficiência , Receptor ErbB-2/imunologia , Trastuzumab , Tumor de Wilms/genética , Tumor de Wilms/metabolismo , Tumor de Wilms/terapia , Ensaios Antitumorais Modelo de Xenoenxerto
8.
Int J Oncol ; 23(6): 1651-5, 2003 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-14612937

RESUMO

Thalidomide has previously been shown to have anti-angiogenic properties. More recently, clinical efficacy of this agent has been demonstrated in multiple myeloma and prostate cancer. Neuroblastoma is the most frequent solid tumor of the abdomen of childhood, yet children with this disease frequently have metastases at presentation. Such patients have a very poor prognosis with current therapies. Thus, new approaches are needed. We have previously shown that VEGF antagonists can inhibit neoangiogenesis and tumor growth in experimental neuroblastoma. In this study, we investigated the anti-angiogenic and anti-tumor properties of thalidomide in a xenograft model of human neuroblastoma. Tumors were induced in athymic mice using the human neuroblastoma cell line NGP. Intraperitoneal thalidomide (100 mg/kg/dose) or vehicle was administered beginning one week after implantation, and animals euthanized at six weeks. Thalidomide treatment did not significantly alter tumor growth as compared with controls. However, thalidomide suppressed angiogenesis, as demonstrated both by fluorescein angiography and immunohistochemical staining, and induced apoptosis of endothelial cells in neuroblastoma xenografts. Quantification of microvessel density demonstrated a significant reduction of vasculature in treated tumors (p<0.004). Thalidomide induced co-option of host vasculature, an effect noted previously after VEGF blockade. This study demonstrates that thalidomide has anti-angiogenic properties in experimental neuroblastoma.


Assuntos
Inibidores da Angiogênese/farmacologia , Neuroblastoma/tratamento farmacológico , Talidomida/farmacologia , Animais , Linhagem Celular Tumoral , Endotélio Vascular/citologia , Humanos , Imuno-Histoquímica , Marcação In Situ das Extremidades Cortadas , Camundongos , Camundongos Nus , Músculo Liso/patologia , Transplante de Neoplasias , Neovascularização Patológica , Molécula-1 de Adesão Celular Endotelial a Plaquetas/biossíntese
9.
Oncol Rep ; 10(5): 1271-4, 2003.
Artigo em Inglês | MEDLINE | ID: mdl-12883692

RESUMO

Her2/neu regulates angiogenesis in human breast cancer, in part by stabilizing hypoxia-inducible factor 1alpha (HIF-1alpha), causing accumulation of the HIF-1 heterodimer and thus increasing expression of the proangiogenic cytokine VEGF. Her2/neu has recently been shown to be overexpressed in a subset of Wilms tumors. Using her2/neu (+) and her2/neu (-) Wilms tumor cell lines, we tested the effect of blocking anti-her2/neu antibody in vitro and in vivo. Blocking antibody did not alter VEGF expression in vitro, but decreased expression of VEGF in her2/neu (+) Wilms tumor xenografts. Tumor suppression was less marked than in parallel experiments using agents directly blocking VEGF. HIF-1alpha immunostaining was not altered in her2/neu (+) xenografts exposed to blocking antibody. These results suggest that her2/neu contributes to Wilms tumor angiogenesis in vivo by regulating VEGF, but other processes may act to rescue HIF-1alpha and thus to support tumor growth in this system.


Assuntos
Proteínas de Ligação a DNA/biossíntese , Neoplasias Experimentais/metabolismo , Proteínas Nucleares/biossíntese , Receptor ErbB-2/fisiologia , Fatores de Transcrição , Fator A de Crescimento do Endotélio Vascular/biossíntese , Tumor de Wilms/metabolismo , Animais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais Humanizados , Divisão Celular , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Regulação para Baixo , Feminino , Humanos , Fator 1 Induzível por Hipóxia , Subunidade alfa do Fator 1 Induzível por Hipóxia , Imuno-Histoquímica , Hibridização In Situ , Marcação In Situ das Extremidades Cortadas , Camundongos , Camundongos Nus , Microscopia de Fluorescência , Transplante de Neoplasias , Neovascularização Patológica , Receptor ErbB-2/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Trastuzumab
10.
Proc Natl Acad Sci U S A ; 100(13): 7785-90, 2003 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-12805568

RESUMO

Vascular endothelial growth factor (VEGF) is a critical promoter of blood vessel growth during embryonic development and tumorigenesis. To date, studies of VEGF antagonists have primarily focused on halting progression in models of minimal residual cancer. Consistent with this focus, recent clinical trials suggest that blockade of VEGF may impede cancer progression, presumably by preventing neoangiogenesis. However, VEGF is also a key mediator of endothelial-vascular mural cell interactions, a role that may contribute to the integrity of mature vessels in advanced tumors. Here, we report that high-affinity blockade of VEGF, using the recently described VEGF-Trap, abolishes mature, preexisting vasculature in established xenografts. Eradication of vasculature is followed by marked tumor regression, including regression of lung micrometastases. Thus, the contribution of relatively low levels of VEGF to vessel integrity may be critical to maintenance of even very small tumor masses. Potent blockade of VEGF may provide a new therapeutic option for patients with bulky, metastatic cancers.


Assuntos
Antineoplásicos/farmacologia , Fatores de Crescimento Endotelial/antagonistas & inibidores , Fatores de Crescimento Endotelial/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Linfocinas/antagonistas & inibidores , Linfocinas/metabolismo , Neoplasias/tratamento farmacológico , Proteínas Recombinantes de Fusão/farmacologia , Actinas/metabolismo , Animais , Apoptose , Plaquetas/metabolismo , Progressão da Doença , Endotélio Vascular/citologia , Endotélio Vascular/metabolismo , Humanos , Imuno-Histoquímica , Hibridização In Situ , Marcação In Situ das Extremidades Cortadas , Lectinas/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/secundário , Camundongos , Camundongos Nus , Microscopia Confocal , Músculo Liso/metabolismo , Necrose , Metástase Neoplásica , Transplante de Neoplasias , Neovascularização Patológica , Perfusão , Molécula-1 de Adesão Celular Endotelial a Plaquetas/biossíntese , Receptores de Fatores de Crescimento do Endotélio Vascular , Fatores de Tempo , Células Tumorais Cultivadas , Fator A de Crescimento do Endotélio Vascular , Fatores de Crescimento do Endotélio Vascular
11.
J Pediatr Surg ; 38(3): 308-14; discussion 308-14, 2003 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-12632340

RESUMO

BACKGROUND: Hepatoblastoma is the most common primary hepatic malignancy of childhood, frequently presenting as advanced disease. Vascular endothelial growth factor (VEGF) is an endothelial mitogen and survival factor critical to growth and angiogenesis in many human cancers. Inhibition of VEGF effectively suppresses tumorigenesis in multiple experimental models. The authors hypothesized that anti-VEGF antibody would alter vascular architecture and impede tumor growth in experimental hepatoblastoma. METHODS: The Institutional Animal Care and Use Committee of Columbia University approved all protocols. Xenografts were established in athymic mice by intrarenal injection of cultured human hepatoblastoma cells. Anti-VEGF antibody (100 microg/dose) or vehicle was administered intraperitoneally 2 times per week for 5 weeks. At week 6, 10 control/treated mice were killed and remaining animals maintained without treatment until week 8. Tumor weights were compared by Kruskal-Wallis analysis, and vascular alterations ascertained by fluorescein angiography and specific immunostaining. RESULTS: Anti-VEGF antibody significantly inhibited tumor growth at 6 weeks (1.85 g +/- 0.60 control, 0.05 +/- 0.03 antibody, P <.0003). In comparison with controls, treated xenografts showed decreased vascularity and dilated surviving vessels with prominent vascular smooth muscle elements. CONCLUSIONS: Specific anti-VEGF therapy inhibits neoangiogenesis and significantly suppresses tumor growth in experimental hepatoblastoma. Surviving vasculature displays dilation and increased vascular smooth muscle. Anti-VEGF agents may represent new therapeutic alternatives for children with advanced disease.


Assuntos
Inibidores da Angiogênese/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Fatores de Crescimento Endotelial/antagonistas & inibidores , Hepatoblastoma/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Linfocinas/antagonistas & inibidores , Proteínas de Neoplasias/antagonistas & inibidores , Neovascularização Patológica/tratamento farmacológico , Animais , Anticorpos Monoclonais/imunologia , Especificidade de Anticorpos , Fatores de Crescimento Endotelial/imunologia , Feminino , Hepatoblastoma/irrigação sanguínea , Hepatoblastoma/secundário , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/imunologia , Neoplasias Hepáticas/irrigação sanguínea , Linfocinas/imunologia , Camundongos , Camundongos Nus , Proteínas de Neoplasias/imunologia , Transplante de Neoplasias , Neoplasias Peritoneais/secundário , Células Tumorais Cultivadas , Fator A de Crescimento do Endotélio Vascular , Fatores de Crescimento do Endotélio Vascular , Ensaios Antitumorais Modelo de Xenoenxerto
12.
Proc Natl Acad Sci U S A ; 99(17): 11399-404, 2002 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-12177446

RESUMO

Vascular endothelial growth factor (VEGF) plays a key role in human tumor angiogenesis. We compared the effects of inhibitors of VEGF with different specificities in a xenograft model of neuroblastoma. Cultured human neuroblastoma NGP-GFP cells were implanted intrarenally in nude mice. Three anti-VEGF agents were tested: an anti-human VEGF(165) RNA-based fluoropyrimidine aptamer; a monoclonal anti-human VEGF antibody; and VEGF-Trap, a composite decoy receptor based on VEGFR-1 and VEGFR-2 fused to an Fc segment of IgG1. A wide range of efficacy was observed, with high-dose VEGF-Trap causing the greatest inhibition of tumor growth (81% compared with controls). We examined tumor angiogenesis and found that early in tumor formation, cooption of host vasculature occurs. We postulate that this coopted vasculature serves as a source of blood supply during the initial phase of tumor growth. Subsequently, control tumors undergo vigorous growth and remodeling of vascular networks, which results in disappearance of the coopted vessels. However, if VEGF function is blocked, cooption of host vessels may persist. Persistent cooption, therefore, may represent a novel mechanism by which neuroblastoma can partly evade antiangiogenic therapy and may explain why experimental neuroblastoma is less susceptible to VEGF blockade than a parallel model of Wilms tumor. However, more effective VEGF blockade, as achieved by high doses of VEGF-Trap, can lead to regression of coopted vascular structures. These results demonstrate that cooption of host vasculature is an early event in tumor formation, and that persistence of this effect is related to the degree of blockade of VEGF activity.


Assuntos
Inibidores da Angiogênese/uso terapêutico , Antineoplásicos/uso terapêutico , Fatores de Crescimento Endotelial/antagonistas & inibidores , Linfocinas/antagonistas & inibidores , Neuroblastoma/irrigação sanguínea , Neuroblastoma/tratamento farmacológico , Animais , Modelos Animais de Doenças , Fatores de Crescimento Endotelial/genética , Humanos , Linfocinas/genética , Camundongos , Camundongos Nus , Neuroblastoma/patologia , Transplante Heterólogo , Células Tumorais Cultivadas , Fator A de Crescimento do Endotélio Vascular , Fatores de Crescimento do Endotélio Vascular
13.
J Pediatr Surg ; 37(6): 857-61, 2002 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-12037749

RESUMO

BACKGROUND: Advanced hepatoblastoma often is lethal despite current therapies, yet development of novel approaches has been hampered by the lack of biologically relevant models. One new strategy selectively targets endothelium rather than tumor cells using frequently administered, low-dose ("metronome") chemotherapy. Metronome topotecan has antiangiogenic activity in some experimental tumors. The authors developed a xenograft model of human hepatoblastoma to test the effect of metronome topotecan in this system. METHODS: Xenografts resulted from intrarenal injection of cultured human hepatoblastoma cells in athymic mice. Topotecan (0.36 mg/kg/dose) or vehicle was injected intraperitoneally 5 times per week. At week 6, 10 control/treated mice were killed, and remaining animals were maintained without treatment until week 8. Tumor weights were compared by Kruskal-Wallis analysis, and vascular alterations were ascertained by specific immunostaining. RESULTS: Metronome topotecan affected tumor weights in a delayed fashion: weights were diminished significantly only at 8 weeks (treated v control: 6 weeks, 0.59 g v 82 g, P value, not significant; 8 weeks, 1.13 g v 3.82; P <.02). Decreased vascularity and increased endothelial cell apoptosis were observed in treated xenografts. CONCLUSIONS: Metronome topotecan inhibits growth and neovascularization in experimental hepatoblastoma. The durability of this effect is novel and has not been observed in other xenograft tumor models. Cytotoxic targeting of endothelial cells may hold particular promise for therapy of children with advanced hepatoblastoma. .


Assuntos
Inibidores da Angiogênese/farmacologia , Hepatoblastoma/tratamento farmacológico , Neoplasias Hepáticas Experimentais/tratamento farmacológico , Topotecan/farmacologia , Animais , Feminino , Hepatoblastoma/irrigação sanguínea , Hepatoblastoma/patologia , Humanos , Neoplasias Hepáticas Experimentais/patologia , Neoplasias Hepáticas Experimentais/fisiopatologia , Neoplasias Pulmonares/secundário , Camundongos , Camundongos Nus , Neovascularização Patológica/patologia , Transplante Heterólogo , Células Tumorais Cultivadas
14.
J Pediatr Surg ; 37(3): 518-22, 2002 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-11877680

RESUMO

BACKGROUND: The authors have shown previously that experimental neuroblastoma is partially inhibited (48%) by antivascular endothelial growth factor (anti-VEGF) antibody. The topoisomerase-I inhibitor, topotecan, has been shown to have antiangiogenic activity when administered in a low-dose, high-frequency regimen. We hypothesized that combining topotecan with anti-VEGF would suppress neuroblastoma more effectively than either agent alone. METHODS: A total of 10(6) neuroblastoma cells were implanted intrarenally in athymic mice. Animals received vehicle, topotecan, anti-VEGF, or topotecan plus anti-VEGF (n = 9, 20, 20, 20, respectively). All control and half the treated mice were killed at 6 weeks. Remaining (rebound) mice were maintained without treatment for 3 more weeks. Patterns of vasculature and apoptosis were determined immunohistochemically. RESULTS: Tumor weights at 6 weeks were reduced significantly in topotecan-only (0.07g) and combination-treated animals (0.08 g), compared with controls or anti-VEGF--treated mice (1.18 g, 0.53 g; P <.0007, all). At 9 weeks, rebound tumor weights were greatest in anti-VEGF (2.82 g), intermediate in topotecan (1.82 g), and least in combination-treated animals (1.47 g); however, the only significant difference was between anti-VEGF and combination therapy (P = 0.04). All treated tumors were vascularized sparsely in comparison with controls at 6 weeks, but exhibited brisk neoangiogenesis at 9 weeks. CONCLUSIONS: Topotecan either with or without anti-VEGF antibody significantly suppresses neuroblastoma xenograft growth in comparison with controls or anti-VEGF antibody alone. Combining topotecan with anti-VEGF antibody significantly inhibited rebound tumor growth in comparison with anti-VEGF antibody alone. Combination therapy may improve durability of antiangiogenic inhibition of neuroblastoma.


Assuntos
Inibidores da Angiogênese/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Experimentais/irrigação sanguínea , Neoplasias Experimentais/tratamento farmacológico , Neuroblastoma/irrigação sanguínea , Neuroblastoma/tratamento farmacológico , Animais , Anticorpos Monoclonais/administração & dosagem , Modelos Animais de Doenças , Fatores de Crescimento Endotelial/imunologia , Inibidores Enzimáticos/administração & dosagem , Feminino , Linfocinas/imunologia , Camundongos , Camundongos Nus , Transplante de Neoplasias , Inibidores da Topoisomerase I , Topotecan/administração & dosagem , Células Tumorais Cultivadas , Fator A de Crescimento do Endotélio Vascular , Fatores de Crescimento do Endotélio Vascular
15.
J Pediatr Surg ; 37(3): 523-7, 2002 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-11877681

RESUMO

BACKGROUND/PURPOSE: Unfavorable histology (UH) in Wilms tumor has been linked to malfunction of the p53 tumor suppressor gene, which regulates (1) the endogenous angiogenesis suppressor thrombospondin-1 (TSP-1) and (2) vascular endothelial growth factor (VEGF). The authors hypothesized that clinically aggressive favorable histology Wilms tumor (FH), like UH, but distinct from standard-risk FH disease, would display altered p53/TSP-1 function and upregulated angiogenesis. METHODS: Three Wilms tumor specimens manifesting different histology and clinical behavior were obtained: clinically aggressive UH, clinically aggressive FH, and standard-risk FH disease. Xenografts were induced intrarenally in athymic mice. P53, TSP-1, and VEGF status and neovascularity were assessed in tumor tissues. Lungs were evaluated for metastasis. RESULTS: Clinically aggressive FH Wilms tumor displayed progressive alteration in p53/TSP-1 status and upregulation of VEGF. Such alteration was observed in the UH tumor, but was absent from the standard-risk FH tumor. Xenografts from clinically aggressive tumors displayed brisk neoangiogenesis and yielded lung metastases. CONCLUSIONS: This is the first report of altered p53/TSP-1 function in association with clinically aggressive behavior in FH Wilms tumor. These characteristics were not observed in parallel studies of a nonaggressive FH tumor. Loss of wild-type p53 function may contribute to disease progression in FH Wilms tumor, in part by upregulation of VEGF.


Assuntos
Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Proteína Supressora de Tumor p53/metabolismo , Tumor de Wilms/irrigação sanguínea , Tumor de Wilms/metabolismo , Animais , Fatores de Crescimento Endotelial/análise , Fatores de Crescimento Endotelial/fisiologia , Humanos , Imuno-Histoquímica , Rim/cirurgia , Neoplasias Renais/química , Neoplasias Renais/metabolismo , Neoplasias Pulmonares/química , Neoplasias Pulmonares/secundário , Linfocinas/análise , Linfocinas/fisiologia , Camundongos , Camundongos Nus , Transplante de Neoplasias , Neoplasias Experimentais , Inclusão em Parafina , Molécula-1 de Adesão Celular Endotelial a Plaquetas/análise , Trombospondina 1/análise , Trombospondina 1/fisiologia , Transplante Heterólogo , Células Tumorais Cultivadas , Proteína Supressora de Tumor p53/análise , Proteína Supressora de Tumor p53/fisiologia , Regulação para Cima/fisiologia , Fator A de Crescimento do Endotélio Vascular , Fatores de Crescimento do Endotélio Vascular , Tumor de Wilms/patologia
16.
J Pediatr Surg ; 37(3): 528-32, 2002 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-11877682

RESUMO

BACKGROUND/PURPOSE: Rhabdoid tumor of the kidney (RTK) is a lethal malignancy of childhood for which there currently are no effective therapies. Because vascular endothelial growth factor (VEGF) is nearly ubiquitous in human tumors, the authors hypothesized that a xenograft model of RTK would (1) express VEGF and (2) respond to anti-VEGF intervention. METHODS: A total of 2 x 10(6) cultured RTK cells were implanted intrarenally (G-401) in athymic mice. Control/treated animals received either vehicle (phosphate-buffered saline, PBS) or anti-VEGF antibody (anti-VEGF) for 5 weeks (n = 20, 17, respectively). Vasculature was mapped by angiography and immunostaining. Apoptosis was assessed by TdT-mediated dUTP nick end labeling (TUNEL) assay, VEGF expression examined by reverse transcription polymerase chain reaction, and tumor weights compared by Kruskal-Wallis analysis. RESULTS: Mean tumor weights were not altered significantly by anti-VEGF (0.78-g, controls v 0.56-g treated tumors; P value, not significant). Grossly, xenografts grew in a novel manner, encasing rather than invading the kidney, and did not metastasize. PECAM-1 immunostaining and fluorescein angiography showed similar vascularity in control and treated xenografts. Both apoptosis and VEGF expression were unchanged in treated specimens. CONCLUSIONS: Unexpectedly, growth of RTK xenografts was not inhibited by specific anti-VEGF antibody, although these tumors express significant amounts of VEGF. In addition, RTK vasculature, apoptosis, and VEGF expression were not substantially altered by anti-VEGF antibody. These results suggest that tumor-derived VEGF is of highly variable importance in different malignancies.


Assuntos
Anticorpos Monoclonais/farmacologia , Antineoplásicos/farmacologia , Fatores de Crescimento Endotelial/imunologia , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/patologia , Linfocinas/imunologia , Tumor Rabdoide/tratamento farmacológico , Tumor Rabdoide/patologia , Transplante Heterólogo/patologia , Animais , Resistencia a Medicamentos Antineoplásicos , Fatores de Crescimento Endotelial/biossíntese , Feminino , Humanos , Imuno-Histoquímica , Neoplasias Renais/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Linfocinas/biossíntese , Camundongos , Camundongos Nus , Inclusão em Parafina , Molécula-1 de Adesão Celular Endotelial a Plaquetas/imunologia , Tumor Rabdoide/metabolismo , Fator A de Crescimento do Endotélio Vascular , Fatores de Crescimento do Endotélio Vascular
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA