RESUMEN
We have isolated 462 bp of sequence termed ovarian-specific promoter 1 (OSP-1) that is part of a retrovirus-like element specifically expressed in the rat ovary. We have evaluated the ability of OSP-1 to activate gene expression in normal and neoplastic cell lines derived from the ovaries of rats and women. We have found that there was marked specificity in the ability of OSP-1 to drive reporter gene expression in an ovarian epithelial cell lineage manner. The expression of herpes simplex virus thymidine kinase (HSV-TK) under OSP-1 control was sufficiently ovarian cancer cell line specific to render ganciclovir approximately 50-fold more toxic in the A2780 human ovarian cancer cell line compared with clones of the HCT-116 and HT-29 colon cancer cell lines. Furthermore, ganciclovir had marked antitumor efficacy in vivo in severe combined immunodeficient mice bearing A2780OSP-1-HSV-TK as a s.c. xenograft. We suggest that these data support the use of OSP-1 as a tool to provide specificity to the gene therapy of ovarian cancer and to drive ovarian-specific oncogene expression for the creation of transgenic mouse models of ovarian cancer.
Asunto(s)
Regulación Neoplásica de la Expresión Génica , Neoplasias Ováricas/genética , Regiones Promotoras Genéticas/genética , Retroelementos/genética , Animales , Secuencia de Bases , Biotransformación , Linaje de la Célula/genética , Células Epiteliales/patología , Femenino , Ganciclovir/administración & dosificación , Ganciclovir/farmacocinética , Genes Reporteros , Terapia Genética/métodos , Humanos , Ratones , Ratones Endogámicos ICR , Datos de Secuencia Molecular , Neoplasias Ováricas/metabolismo , Neoplasias Ováricas/patología , Profármacos/farmacocinética , Ratas , Simplexvirus/enzimología , Simplexvirus/genética , Timidina Quinasa/genética , Timidina Quinasa/metabolismo , Activación Transcripcional , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: The timing and length of administration of angiogenesis inhibitor TNP-470 was altered to evaluate the effect on disease progression in a rat model of colorectal hepatic metastases. METHODS: Pair-fed BD-IX rats, injected intrasplenically with rat colon adenocarcinoma K12/TRb cells at day 0, were randomized to receive subcutaneous injections of either placebo or 15 mg/kg TNP-470 on alternate days: for 2 weeks beginning 24 hours after tumor inoculation ("Early"), for 4 weeks beginning 24 hours after tumor inoculation ("Prolonged"), or for 2 weeks beginning at day 15 after macroscopic tumor nodules were confirmed ("Delayed"). Response to treatment was evaluated by counting tumor nodules on the surface of the liver at laparotomy on day 14 and 28 after tumor inoculation. The animals were followed for survival and cause of death. RESULTS: Maximal suppression of hepatic metastases at day 28 required 4-week rather than 2-week TNP-470 administration. Prolonged TNP-470 administration resulted in significantly fewer hepatic metastases at day 28 compared to control (P < .05). Early and prolonged TNP-470 improved survival (Wilcoxon test, P < .05) compared with delayed TNP-470 and placebo. Delayed TNP-470 administration did not increase survival or significantly diminish the number of metastases at day 28 compared with placebo. CONCLUSIONS: These data suggest that prolonged adjuvant antiangiogenic therapy may suppress colorectal hepatic micrometastases.
Asunto(s)
Antibióticos Antineoplásicos/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Hepáticas Experimentales/tratamiento farmacológico , Neoplasias Hepáticas Experimentales/secundario , Neovascularización Patológica/prevención & control , Sesquiterpenos/uso terapéutico , Animales , Neoplasias Colorrectales/patología , Ciclohexanos , Masculino , O-(Cloroacetilcarbamoil) Fumagilol , Ratas , Sesquiterpenos/toxicidad , Factores de Tiempo , Células Tumorales CultivadasRESUMEN
A method was developed for biopsy sampling of masses obstructing the biliary system in patients with a biliary drainage catheter. The biopsy needle is inserted through the drainage catheter, with fluoroscopic guidance, to the site of the lesion. The technique has been used without complication in more than 30 patients with cancer of the pancreas and bile ducts.
Asunto(s)
Biopsia con Aguja/métodos , Catéteres de Permanencia , Colestasis/patología , Neoplasias de los Conductos Biliares/patología , Drenaje/instrumentación , Humanos , Neoplasias Pancreáticas/patologíaRESUMEN
Malignant strictures of the afferent jejunal limbs are difficult to treat. Surgical revision and chronic external drainage, two commonly used palliative procedures, have significant associated morbidity. A combined transhepatic and peroral approach was used to stent malignant jejunal strictures in two patients, allowing antegrade internal drainage of biliary and pancreatic secretions. Excellent palliation was achieved, and there were no associated complications.