RESUMEN
BACKGROUND: Lymph node (LN) metastasis in patients with duodenal adenocarcinoma is associated with poor prognosis; however, the optimal extent of LN assessment and the interaction between LN assessment and adjuvant systemic therapy is poorly understood. METHODS: Resected non-metastatic duodenal adenocarcinoma patients (n = 1743) were identified in the National Cancer Database (1998-2011). Logistic regression analysis identified covariates associated with LN metastasis. The influence of increasing LN cut-off points on overall survival (OS) was analysed using the log-rank test and Cox proportional hazards modelling. Adjuvant chemotherapy (AC) and surgery alone cohorts were matched (1:1) by propensity scores based on the likelihood of nodal metastasis or survival hazard on Cox modelling. OS in the matched cohort was compared by Kaplan-Meier estimates. RESULTS: LN metastases were present in 865 (49.6%) patients. Increasing LN assessment was associated with an increased likelihood of nodal involvement (P = 0.008). In node-negative patients, increasing LN assessment was associated with a decreased risk of death, with the largest actuarial survival differences observed for ≥15 LN (hazard ratio [HR] 0.63, 95% confidence interval [CI] 0.48-0.82, P = 0.001). In the propensity score-matched cohort of node-negative patients, AC was associated with non-significant improvements in 5-year actuarial (66.1% versus 58.7%, HR 0.79, 95% CI 0.53-1.18, P = 0.249), and did not vary by adequacy of LN counts (<15 LNs: HR 0.79, 95% CI 0.51-1.24, P = 0.305; ≥15 LNs: HR 0.90, 95% CI 0.35-2.30, P = 0.900). CONCLUSIONS: The extent of LN identification has prognostic significance in resected node-negative duodenal adenocarcinoma, but cannot be implicated in the selection of node-negative patients for AC.
Asunto(s)
Adenocarcinoma/cirugía , Neoplasias Duodenales/cirugía , Escisión del Ganglio Linfático/métodos , Ganglios Linfáticos/patología , Adenocarcinoma/patología , Anciano , Estudios de Casos y Controles , Quimioterapia Adyuvante , Estudios de Cohortes , Bases de Datos Factuales , Neoplasias Duodenales/patología , Femenino , Humanos , Estimación de Kaplan-Meier , Modelos Logísticos , Metástasis Linfática , Masculino , Persona de Mediana Edad , Análisis Multivariante , Estadificación de Neoplasias , Pronóstico , Puntaje de Propensión , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Tasa de Supervivencia , Resultado del TratamientoRESUMEN
2C4 (Pertuzumab, Omnitarg) is a monoclonal antibody targeting p185(her2/neu), which is overexpressed in 30% of invasive breast cancer. 2C4 is currently in phase II clinical trials for several types of cancers. This antibody has been reported to disrupt the association between p185(her2/neu) and ErbB3. In our studies of epidermal growth factor receptor (EGFR)-p185(her2/neu) heterodimerization, we noted that 2C4 formed associations with the EGFR-p185(her2/neu) receptor complex. Our data argue against 2C4 as a universal heterodimerization blocker for p185(her2/neu), but indicate that cocktails of monoclonal antibodies binding distinct interaction surfaces of p185(her2/neu) will emerge as the most potent targeted therapy.
Asunto(s)
Anticuerpos Monoclonales/metabolismo , Receptores ErbB/inmunología , Receptor ErbB-2/inmunología , Receptor ErbB-3/inmunología , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales Humanizados , Sitios de Unión de Anticuerpos , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/inmunología , Sinergismo Farmacológico , Femenino , Humanos , Receptor ErbB-2/efectos de los fármacosRESUMEN
Because of increased toxicity, full doses of gemcitabine and radiation therapy cannot routinely be given concurrently. The purpose of the present study was to determine the toxicity and response to treatment with full-dose gemcitabine given between cycles of split-course radiation therapy (nonconcurrent treatment) for inoperable periampullary adenocarcinoma. Treatment consisted of 3 6 week courses for a total of 18 weeks: 1000 mg/m gemcitabine intravenous bolus once a week x 2 weeks; 1 week break; 2 weeks of radiation therapy (1.8 Gy per fraction); 1 week break x 3. The total dose of radiation consisted of 45 Gy to the tumor + regional nodes followed by a 5.4-Gy boost. Patients were restaged at week 15 and at the completion of all treatment. Patients underwent resection if there was sufficient response. A total of 42 patients (40 pancreatic, 1 gallbladder, 1 biliary tract) were enrolled between March 1999 and July 2002. All but 2 medically inoperable patients had evidence of major vessel involvement. Median age was 63 years (range, 40-80 years). All patients were evaluable for response. There were 10 objective partial responses (24%). Six responders underwent resection with a mean survival of 18 months. Mean survival for all 42 patients was 10.3 months (range, 2.0-32.5 months; median, 9.5 months). Four patients experienced grade 3 or 4 gastrointestinal toxicity. Alternating cycles of split-course radiotherapy and gemcitabine chemotherapy permits the delivery of full doses of both modalities with acceptable tolerance. Despite the prolongation in radiation treatment time because of split-course treatment, patients with sufficient response were able to undergo resection.
Asunto(s)
Antimetabolitos Antineoplásicos/uso terapéutico , Neoplasias de los Conductos Biliares/terapia , Carcinoma/terapia , Desoxicitidina/análogos & derivados , Fraccionamiento de la Dosis de Radiación , Neoplasias de la Vesícula Biliar/terapia , Terapia Neoadyuvante , Neoplasias Pancreáticas/terapia , Fármacos Sensibilizantes a Radiaciones/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Antimetabolitos Antineoplásicos/efectos adversos , Neoplasias de los Conductos Biliares/tratamiento farmacológico , Neoplasias de los Conductos Biliares/radioterapia , Neoplasias de los Conductos Biliares/cirugía , Carcinoma/tratamiento farmacológico , Carcinoma/radioterapia , Carcinoma/cirugía , Terapia Combinada , Desoxicitidina/efectos adversos , Desoxicitidina/uso terapéutico , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Esquema de Medicación , Femenino , Neoplasias de la Vesícula Biliar/tratamiento farmacológico , Neoplasias de la Vesícula Biliar/radioterapia , Neoplasias de la Vesícula Biliar/cirugía , Humanos , Intestino Delgado/efectos de la radiación , Tablas de Vida , Irradiación Linfática , Masculino , Persona de Mediana Edad , Cuidados Paliativos , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/radioterapia , Neoplasias Pancreáticas/cirugía , Pancreaticoduodenectomía , Estudios Prospectivos , Traumatismos por Radiación/etiología , Análisis de Supervivencia , Resultado del Tratamiento , GemcitabinaRESUMEN
BACKGROUND: Loss of the adenomatous polyposis coli (APC) tumor suppressor gene plays a significant role in colorectal carcinogenesis. One function of the APC gene product is to regulate beta-catenin, a protein that plays a role in cell adhesion and also regulates the activity of certain transcription factors. To more precisely delineate the role of beta-catenin signaling in colon cancer growth, we treated mice bearing APC-mutant SW480 colon cancer xenografts with antisense oligonucleotides (ODNs) directed against beta-catenin mRNA and examined effects on beta-catenin expression and tumor growth. METHODS: Balb/C nude mice underwent subcutaneous injection of 1 x 10(6) SW480 cells to establish tumor xenografts. In one experiment, tumors were allowed to grow for 7 days, after which time animals were randomized to undergo daily intraperitoneal injections of either antisense beta-catenin ODN at doses of 5, 10, or 20 mg/kg, scrambled sequence beta-catenin ODN control, or saline control for 7 days. Tumors were excised and homogenized, and tumor lysates subjected to gel electrophoresis and Western blotting for beta-catenin protein quantification. In a second experiment, tumor-bearing animals began receiving daily intraperitoneal injections of either antisense beta-catenin ODN at doses of 5, 10, or 20 mg/kg, scrambled sequence beta-catenin ODN control, or saline control. Tumor growth was quantitated by measuring tumor volumes twice weekly. A third experiment evaluated the antitumor effects of daily bolus dosing versus continuous infusion of beta-catenin antisense ODNs (20 mg/kg). RESULTS: Treatment of APC-mutant colorectal carcinoma xenografts with beta-catenin antisense resulted in a dose-dependent down-regulation in beta-catenin protein expression as shown by Western blotting. Treatment of tumor-bearing mice with antisense directed at beta-catenin also demonstrated a dose-dependent inhibition of tumor growth. There appears to be little difference in the antitumor effects of antisense ODNs administered by continuous infusion or bolus dosing schedules. CONCLUSIONS: beta-Catenin expression plays a critical role in the tumorigenic growth of APC-mutant colon cancer xenografts. Strategies targeting beta-catenin, including the use of antisense ODNs, may be of use in the treatment of human colon cancer.
Asunto(s)
Carcinoma/metabolismo , Carcinoma/patología , Neoplasias del Colon/metabolismo , Neoplasias del Colon/patología , Proteínas del Citoesqueleto/antagonistas & inhibidores , Proteínas del Citoesqueleto/genética , Oligonucleótidos Antisentido/farmacología , Transactivadores , Animales , Carcinoma/genética , Neoplasias del Colon/genética , Relación Dosis-Respuesta a Droga , Regulación hacia Abajo , Femenino , Genes APC , Humanos , Ratones , Ratones Endogámicos BALB C , Mutación , Trasplante de Neoplasias , Trasplante Heterólogo , Células Tumorales Cultivadas/trasplante , beta CateninaRESUMEN
Mutations involving the adenomatous polyposis coli (APC) tumor suppressorgene/beta-catenin signaling pathway have been identified in the majority of colon carcinomas. However, the role of aberrant beta-catenin signaling in the neoplastic growth of APC-mutant colon cancer cells has not been directly studied. To address this question, antisense oligonucleotides have been used to specifically down-regulate beta-catenin expression in APC-mutant human colon carcinoma cells. Antisense-mediated suppression of beta-catenin inhibits the in vitro proliferation, anchorage-independent growth, and cellular invasiveness of APC-mutant human colon carcinoma cells. The systemic administration of beta-catenin antisense oligonucleotides down-regulates beta-catenin expression in vivo in human colon cancer xenografts in nude mice. Such treatment inhibits the tumorigenic growth of colon cancer xenografts and can completely eradicate tumors in some treated animals. These studies formally demonstrate the critical role of beta-catenin signaling in the neoplastic growth of APC-mutant colon cancer cells and suggest that strategies targeting beta-catenin may be of use in the therapy of colon cancer.
Asunto(s)
Neoplasias del Colon/patología , Proteínas del Citoesqueleto/antagonistas & inhibidores , Genes APC/genética , Transactivadores , Animales , Adhesión Celular/fisiología , División Celular/fisiología , Neoplasias del Colon/genética , Proteínas del Citoesqueleto/biosíntesis , Proteínas del Citoesqueleto/genética , Proteínas del Citoesqueleto/fisiología , Regulación hacia Abajo/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Mutación , Trasplante de Neoplasias , Oligonucleótidos Antisentido/genética , Oligonucleótidos Antisentido/farmacología , ARN Mensajero/biosíntesis , ARN Mensajero/genética , Transducción de Señal/fisiología , Tionucleótidos/genética , Tionucleótidos/farmacología , Trasplante Heterólogo , Células Tumorales Cultivadas , beta CateninaRESUMEN
Poor results after repair of biliary injuries are most common when injuries are above the bifurcation of the left and right hepatic ducts or involve aberrant ducts. We have developed a novel approach to the right-sided component of such injuries. Preoperatively all isolated sections of the biliary tree are intubated percutaneously. At surgery the left duct is found by the Hepp-Couinaud approach. Dissection is continued to the right, staying within the coronal plane of the left hepatic duct, and continuing across the gallbladder plate into segment 5 between the hepatic parenchyma and the Wallerian sheath of the right portal pedicle. Hepatic parenchyma, anterior to the sheath, is resected. After a length of portal pedicle is exposed, right-sided bile ducts are opened on their anterior surface, using the percutaneous transhepatic stents as a guide, and hepaticojejunostomy is performed. Twenty-three patients were treated from May 1993 to February 1999. Injury types and (number of patients) were as follows: B (n = 2), C (n = 5), E4 (n = 10), and E5 (n = 6). There were no perioperative deaths. Follow-up ranged from 8 months to 7 years (median 3 years). There have been no cases of restricture, reoperation, or jaundice, and no interventional procedures. Serum bilirubin is normal in all patients. Alkaline phosphatase is normal or less than two times the normal value in 21 of 22 living patients. This novel approach brings the benefits of the Hepp-Couinaud approach to the right hepatic ducts. Very satisfactory results were obtained in the most severe types of biliary injury.
Asunto(s)
Conductos Biliares/lesiones , Conductos Biliares/cirugía , Colecistectomía/efectos adversos , Disección/métodos , Yeyunostomía/métodos , Adolescente , Adulto , Anciano , Fosfatasa Alcalina/sangre , Bilirrubina/sangre , Drenaje/instrumentación , Drenaje/métodos , Femenino , Estudios de Seguimiento , Humanos , Intubación/instrumentación , Intubación/métodos , Yeyunostomía/instrumentación , Masculino , Persona de Mediana Edad , Atención Perioperativa/métodos , Sepsis/etiología , Sepsis/prevención & control , Stents , Técnicas de Sutura , Factores de Tiempo , Resultado del TratamientoRESUMEN
OBJECTIVE: To present the survival results for patients with colorectal carcinoma metastases who have undergone liver resection after being staged by [(18)F] fluoro-2-deoxy-D-glucose-positron emission tomography (FDG-PET). SUMMARY BACKGROUND DATA: Hepatic resection is standard therapy for colorectal metastases confined to the liver, but recurrence is common because of the presence of undetected cancer at the time of surgery. FDG-PET is a sensitive diagnostic tool that identifies tumors based on the increased uptake of glucose by tumor cells. To date, no survival results have been reported for patients who have actually had liver resection after being staged by FDG-PET. METHODS: Forty-three patients with metastatic colorectal cancer were referred for hepatic resection after conventional tumor staging with computed tomography. FDG-PET was performed on all patients. Laparotomy was performed on patients not staged out by PET. Resection was performed at the time of laparotomy unless extrahepatic disease or unresectable hepatic tumors were found. Patients were examined at intervals in the preoperative period. RESULTS: FDG-PET identified additional cancer not seen on computed tomography in 10 patients. Surgery was contraindicated in six of these patients because of the findings on FDG-PET. Laparotomy was performed in 37 patients. In all but two, liver resection was performed. Median follow-up in the 35 patients undergoing resection was 24 months. The Kaplan-Meier estimate of overall survival at 3 years was 77% and the lower 95% confidence limit of this estimate of survival was 60%. This figure is higher than 3-year estimate of survival found in previously published series. The 3-year disease-free survival rate was 40%. CONCLUSIONS: Preoperative FDG-PET lessens the recurrence rate in patients undergoing hepatic resection for colorectal metastases to the liver by detection of disease not found on conventional imaging.
Asunto(s)
Neoplasias Colorrectales/diagnóstico por imagen , Neoplasias Colorrectales/patología , Fluorodesoxiglucosa F18 , Neoplasias Hepáticas/diagnóstico por imagen , Neoplasias Hepáticas/secundario , Tomografía Computarizada de Emisión , Anciano , Carcinoma/diagnóstico por imagen , Carcinoma/mortalidad , Carcinoma/secundario , Neoplasias Colorrectales/mortalidad , Bases de Datos Factuales , Supervivencia sin Enfermedad , Femenino , Humanos , Neoplasias Hepáticas/mortalidad , Neoplasias Hepáticas/cirugía , Masculino , Persona de Mediana Edad , Missouri/epidemiología , Estadificación de Neoplasias/métodos , Estudios Prospectivos , Radiofármacos , Sensibilidad y Especificidad , Tasa de Supervivencia , Tomografía Computarizada de Emisión/métodosRESUMEN
BACKGROUND: The "classical" biliary injury usually involves misidentification of the common bile duct as the cystic duct. The purpose of this study was to determine if the method of cholecystectomy, specifically the "infundibular technique," might be a contributing factor in this injury. STUDY DESIGN: Twenty-one operative notes of patients who were referred with injury to the common bile duct were examined. Notes were classified as to informativeness. Patient and operative variables potentially related to injury were searched for. RESULTS: Inflammation was the main patient variable associated with injury. The main operative variable was that in most of the injuries the cystic duct was isolated and divided as the first step in the procedure. Often the operative note contained a statement indicating that the surgeon believed that the "cystic" duct (actually the common bile duct) was emanating from the infundibulum of the gallbladder and that this was the anatomic rationale for identification of the cystic duct. In no case was the triangle of Calot completely dissected before injury. CONCLUSIONS: The cystic duct may be hidden in some patients having laparoscopic cholecystectomy, especially in the presence of inflammation. This may lead to the deceptive appearance of a false infundibulum that misleads the surgeon into identifying the common duct as the cystic duct. Biliary injury is more likely when cystic duct identification is made by relying solely on the appearance of the junction of the cystic duct with the infundibulum of the gallbladder, and this technique should be abandoned.
Asunto(s)
Colecistectomía Laparoscópica/efectos adversos , Colecistectomía Laparoscópica/métodos , Conducto Cístico/patología , Conducto Cístico/cirugía , Disección/efectos adversos , Disección/métodos , Errores Médicos/efectos adversos , Errores Médicos/métodos , Adolescente , Adulto , Anciano , Colangiografía , Colecistitis/diagnóstico , Colecistitis/cirugía , Colelitiasis/diagnóstico , Colelitiasis/cirugía , Competencia Clínica , Femenino , Humanos , Masculino , Errores Médicos/prevención & control , Persona de Mediana Edad , Monitoreo Intraoperatorio , Estudios Retrospectivos , Factores de Riesgo , Heridas y Lesiones/clasificación , Heridas y Lesiones/diagnóstico , Heridas y Lesiones/etiología , Heridas y Lesiones/cirugíaRESUMEN
Lymphoepithelial tumors of the pancreas are rare cystic tumors characterized by the presence of a keratinizing squamous epithelium and a dense lymphoid infiltrate on histologic examination. This case report describes the first lymphoepithelial tumor to be resected from the pancreatic head by pancreaticoduodenectomy. This case is also the first in which the cyst was found to be secondarily infected. The radiologic and clinicopathologic features of these unusual tumors are discussed.
Asunto(s)
Quiste Pancreático/cirugía , Pancreaticoduodenectomía , Humanos , Masculino , Persona de Mediana Edad , Quiste Pancreático/microbiología , Quiste Pancreático/patologíaAsunto(s)
Expresión Génica , Neoplasias/genética , Oligonucleótidos Antisentido , Animales , Antineoplásicos/uso terapéutico , Enfermedad de Crohn/tratamiento farmacológico , Enfermedad de Crohn/genética , Humanos , Biología Molecular , Oligodesoxirribonucleótidos Antisentido/uso terapéutico , Oligonucleótidos Antisentido/genética , Oligonucleótidos Antisentido/uso terapéutico , Biosíntesis de Proteínas , Proteínas Proto-Oncogénicas c-raf/genética , ARN Mensajero , Tionucleótidos/uso terapéutico , Transformación Genética , Enfermedades Vasculares/tratamiento farmacológico , Enfermedades Vasculares/genéticaRESUMEN
The HER2/neu oncogene is overexpressed in a significant fraction of human tumors; such overexpression is thought to play a role in the aberrant proliferation of cancer cells. The effects of HER2/neu-specific phosphorothioate antisense oligodeoxyribonucleotides on HER2/neu expression, tumor cell proliferation, and activation of apoptotic cell death pathways have been examined. Antisense treatment down-regulates HER2/neu expression in a dose-dependent and sequence-specific manner. HER2/neu antisense treatment specifically inhibits the growth of tumor lines that overexpress HER2/neu, but it has little effect on the growth of tumor cells that express low levels of HER2/neu. Down-regulation of HER2/neu expression is not only cytostatic, but it also results in the activation of apoptotic cell death pathways in cells that overexpress HER2/neu. These results suggest that, in addition to stimulating tumor cell proliferation, HER2/neu overexpression in cancer cells acts as an antiapoptotic cell survival factor.
Asunto(s)
Apoptosis , Neoplasias/patología , Receptor ErbB-2/fisiología , Caspasa 3 , Caspasas/metabolismo , División Celular , Regulación hacia Abajo , Humanos , Oligonucleótidos Antisentido/farmacología , Células Tumorales CultivadasRESUMEN
Overexpression of the HER2/neu oncogene is observed in approximately 30% of human breast carcinoma specimens. HER2/neu overexpression is a negative prognostic factor in breast cancer patients. Cancer cells that overexpress HER2/neu may also be less sensitive to chemotherapy. In order to further define mechanisms by which HER2/neu overexpression drives neoplastic cell growth and chemoresistance, antisense oligonucleotides (ODNs) have been utilized to selectively down-regulate HER2/neu expression in human breast cancer cells. Such antisense ODNs suppress HER2/neu mRNA and protein levels in a dose-dependent, sequence-specific manner. Down-regulation of HER2/neu expression in HER2/neu overexpressing breast cancer cells inhibits cell cycle progression in G0/G1 and results in apoptotic cell death. In tissue culture studies, combined treatment of HER2/ neu overexpressing breast cancer cells with HER2/neu antisense ODNs and conventional chemotherapeutic agents results in synergistic inhibition of cancer cell growth and activation of apoptotic cell death mechanisms. These studies have been extended to demonstrate synergistic antitumor effects following systemic treatment with antisense ODNs plus doxorubicin in nude mice bearing human breast carcinoma xenografts. Collectively these findings demonstrate that HER2/neu overexpression stimulates anti-apoptotic cell survival mechanisms and suggest that HER2/neu antisense ODNs may be of use in cancer therapeutics.
Asunto(s)
Antineoplásicos/farmacología , Neoplasias de la Mama/terapia , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Oligonucleótidos Antisentido/farmacología , Receptor ErbB-2/genética , Animales , Neoplasias de la Mama/genética , División Celular , Humanos , Células Tumorales CultivadasRESUMEN
INTRODUCTION: Pancreatic lesions may be difficult to diagnose because of small size or inaccessibility. Such lesions are being seen with increasing frequency because of advances in pancreatic imaging techniques. In the past 18 months we have evaluated 14 patients whose pancreatic lesions could not be diagnosed by traditional means, including percutaneous biopsy. METHODS: With the patient under general anesthesia, the anterior surface of the pancreas was exposed by a three-trocar laparoscopic technique. The lesion was located by laparoscopic ultrasonography. A core biopsy needle was inserted into the lesion under simultaneous visual and ultrasonographic guidance using picture-in-picture techniques. RESULTS: The main diagnostic dilemma encountered was the differentiation of pancreatic cancer from pancreatitis. Other conditions were lymphoma and renal cell carcinoma. Excellent tissue samples were obtained, allowing diagnosis and planning of treatment in all cases. Operative time ranged from 1 to 4 hours, and length of stay ranged from 1 to 3 days. Blood transfusions were not required, and there were no complications. Alcohol nerve block was performed laparoscopically in one patient in this group after the diagnosis was made by frozen section. CONCLUSIONS: Direct ultrasonographically guided laparoscopic biopsy provides rapid, safe diagnosis of pancreatic lesions.
Asunto(s)
Laparoscopía , Neoplasias Pancreáticas/patología , Pancreatitis/patología , Adulto , Anciano , Anciano de 80 o más Años , Biopsia/métodos , Diagnóstico Diferencial , Femenino , Humanos , Masculino , Persona de Mediana Edad , Conductos Pancreáticos/diagnóstico por imagen , Conductos Pancreáticos/patología , Neoplasias Pancreáticas/diagnóstico por imagen , Pancreatitis/diagnóstico por imagen , Tomografía Computarizada de Emisión , Tomografía Computarizada por Rayos X , UltrasonografíaRESUMEN
We have studied two anti-p185 antibodies: the monoclonal antibody 7. 16.4 and rhuMAb 4D5, which were raised against the the ectodomain of rat (p185(neu)), and the human (p185(her2/neu)) homolog, respectively. Studies on the structure of these two antibodies indicate that they share structural similarity in the variable region, especially the CDR3 region, which determines the antibody-antigen interaction. Further studies by flow cytometry revealed that 7.16.4 can compete with rhuMAb4D5 for binding to the cell surface p185(her2/neu), suggesting that these two antibodies share an epitope on the p185 receptor. Furthermore, 7.16.4 can also inhibit proliferation and transformation caused by p185(her2/neu). Moreover the rhuMAb 4D5 binds to the rat p185(neu). With the observation that 7.16.4 positively stains human breast cancer tissues that overexpress p185(her2/neu), 7.16.4 may be useful for the pathological diagnosis and therapy of human tumors.
Asunto(s)
Anticuerpos Monoclonales/fisiología , Epítopos/inmunología , Receptor ErbB-2/inmunología , Células 3T3 , Animales , Anticuerpos Monoclonales/química , Anticuerpos Monoclonales Humanizados , Sitios de Unión de Anticuerpos , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Transformación Celular Neoplásica , Reacciones Cruzadas/inmunología , Femenino , Citometría de Flujo , Humanos , Técnicas para Inmunoenzimas , Región Variable de Inmunoglobulina/química , Región Variable de Inmunoglobulina/inmunología , Masculino , Ratones , Modelos Moleculares , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patología , Ratas , Receptor ErbB-2/metabolismo , Sales de Tetrazolio/metabolismo , Tiazoles/metabolismo , TrastuzumabRESUMEN
BACKGROUND: The HER2/neu oncogene is overexpressed in a substantial fraction of human tumors. HER2/neu overexpressing tumors may be intrinsically resistant to chemotherapy. The present study examined the ability of antisense-mediated downregulation of HER2/neu expression to enhance the antitumor effects of conventional chemotherapeutic agents against human tumor cells that overexpress HER2/neu. METHODS: The effects of HER2/neu antisense oligodeoxynucleotides (ODNs) on the growth inhibitory and proapoptotic activity of several distinct chemotherapeutic agents were examined in vitro. In vivo effects of HER2/neu antisense ODNs in combination with doxorubicin hydrochloride were assessed by examining the growth of human tumor xenografts implanted into nude mice. RESULTS: The proliferation of tumor cell lines that overexpress HER2/neu was inhibited by antisense ODNs in combination with conventional chemotherapeutic agents in an additive or synergistic fashion. Such combination therapy also demonstrated synergistic activation of apoptosis. HER2/neu antisense ODNs in combination with doxorubicin hydrochloride demonstrated synergistic antitumor effects in vivo as well. CONCLUSIONS: Downregulation of HER2/neu expression can enhance the sensitivity of human cancer cells, which overexpress HER2/neu to the cytotoxic effects of chemotherapy. Antisense ODNs targeting the HER2/neu gene may play a role in cancer therapy.
Asunto(s)
Antineoplásicos/farmacología , Oligonucleótidos Antisentido/farmacología , Receptor ErbB-2/antagonistas & inhibidores , Animales , Apoptosis/efectos de los fármacos , Regulación hacia Abajo , Doxorrubicina/farmacología , Sinergismo Farmacológico , Femenino , Humanos , Ratones , Ratones Desnudos , Tamoxifeno/farmacología , Células Tumorales CultivadasRESUMEN
The HER2/neu oncogene encodes a cell surface protein which plays a role in growth factor-stimulated mitogenic signaling. HER2/neu is overexpressed in 30-40% of human breast carcinomas. This study tested the hypothesis that inhibiting HER2/neu expression using a phosphorothioate antisense (AS) oligonucleotide would inhibit the growth of breast cancer cells that overexpress this gene. A human breast carcinoma cell line, BT474, which overexpresses the HER2/neu oncogene was exposed to AS, sense (S), or scrambled antisense (SC) phosphorothioate oligonucleotides in tissue culture. Treatment with AS oligonucleotides specifically downregulated HER2/neu mRNA expression and resulted in lower levels of the HER2/neu protein product, p185; control oligonucleotides had no such effect. AS oligonucleotide treatment significantly inhibited the in vitro growth of BT474 cells, whereas S and SC controls had little effect on BT474 growth. HER2/neu AS oligonucleotide treatment had no effect on the growth of a distinct breast cancer line, MCF7, which expresses low levels of the HER2/neu oncogene. Breast carcinoma cells which overexpress the HER2/neu gene appear to be dependent on continued expression of this oncogene for cell growth. AS oligonucleotide pharmaceuticals which interfere with the expression of the HER2/neu oncogene may be of use in the therapy of some patients with breast carcinoma.
Asunto(s)
Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Expresión Génica , Oligonucleótidos Antisentido/genética , Oligonucleótidos Antisentido/farmacología , Receptor ErbB-2/genética , División Celular/efectos de los fármacos , Femenino , Expresión Génica/fisiología , Humanos , ARN Mensajero/metabolismo , Receptor ErbB-2/metabolismo , Células Tumorales CultivadasRESUMEN
The Whipple procedure has undergone a remarkable gradual evolution in the last 20 years, of which many gastroenterologists are unaware. Improvements in staging, particularly staging laparoscopy with ultrasonography, have reduced the incidence of negative laparotomies. The forbidding mortality of pancreaticoduodenectomy, approximately 20% just a generation ago, has decreased precipitously in high-volume referral centers. Near zero mortality rates are now common. Morbidity and length of stay have also been reduced. Cardiac and pulmonary complications have been markedly reduced, whereas others such as pancreatic fistula still remain a problem. Modifications of the procedure have been introduced to improve long-term outcome of pancreatic cancer and to lessen digestive sequelae. Total pancreatectomy and large regional excisions did not improve results. However, 5-year survival rates of 20% are now reported by several centers for adenocarcinoma of the pancreas, and long-term survival rates for other periampullary tumors are approximately 40%. Pylorus-sparing procedures can be performed and may lessen postoperative sequelae. The clinical consequences of improved results are that large numbers of procedures are being performed at specialty centers, providing the opportunity to perform clinical trials, and that the procedure is used more widely, for instance, in benign diseases such as chronic pancreatitis.
Asunto(s)
Gastroenterología/tendencias , Pancreaticoduodenectomía/tendencias , Humanos , Laparoscopía , Morbilidad , Estadificación de Neoplasias , Páncreas/cirugía , Neoplasias Pancreáticas/patología , Pancreaticoduodenectomía/mortalidad , Resultado del TratamientoRESUMEN
Certain strains of transgenic mice that express the rat neu oncogene (neuT) in mammary epithelial cells develop breast tumours at an average of 44 weeks of age. In this study, intraperitoneal injection of a monoclonal anti-receptor antibody specific for the rat neuT oncogene product dramatically affected tumour development in these transgenic mice in a dose-dependent manner. A significant proportion (50%) of mice, when injected with anti-receptor antibodies, did not develop tumours even after 90 weeks of age. The phosphotyrosine levels of the membrane fraction of breast tissues in the anti-receptor antibody-treated mice were almost completely abolished when a higher dose of antibodies was used. This study demonstrates, for the first time, that immunologic manipulation of an oncogene product can effectively prevent the development of tumours in a rodent transgenic model.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Antineoplásicos/uso terapéutico , Inmunización Pasiva , Neoplasias Mamarias Experimentales/prevención & control , Proteínas de Neoplasias/antagonistas & inhibidores , Proteínas Tirosina Quinasas Receptoras/antagonistas & inhibidores , Receptor ErbB-2/antagonistas & inhibidores , Animales , Anticuerpos Monoclonales/inmunología , Anticuerpos Antineoplásicos/inmunología , Relación Dosis-Respuesta Inmunológica , Regulación Neoplásica de la Expresión Génica , Genes Sintéticos , Humanos , Neoplasias Mamarias Experimentales/genética , Virus del Tumor Mamario del Ratón/genética , Ratones , Ratones Transgénicos , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/fisiología , Fosforilación , Procesamiento Proteico-Postraduccional , Ratas , Proteínas Tirosina Quinasas Receptoras/genética , Proteínas Tirosina Quinasas Receptoras/inmunología , Receptor ErbB-2/genética , Receptor ErbB-2/fisiología , Proteínas Recombinantes de Fusión/antagonistas & inhibidores , Proteínas Recombinantes de Fusión/genética , Proteínas Recombinantes de Fusión/inmunología , TransgenesRESUMEN
A cDNA encoding the human homologue of the murine protein tyrosine kinase, blk, has been cloned from a human B-lymphocyte cDNA library by cross-species hybridization using the murine blk cDNA as a probe. The sequence of the 2608 bp human blk cDNA clone contains an open reading frame encoding a predicted 505 amino acid protein with SH3, SH2 and catalytic domains that contain consensus sequences of the src protein tyrosine kinase family. Comparison of human and murine blk sequences indicated that they share 86% amino acid identity, the most conserved region being the catalytic domain (93% identity). Like the murine blk gene human blk is expressed only in B lymphocytes. The human blk gene was mapped to chromosome 8 at p22-23.