A novel early-stage orthotopic model for ovarian cancer in the Fischer 344 rat.

The purpose of our study was to ascertain the progression of metastases in a novel ovarian cancer model designed to mimic early-stage disease by utilizing an orthotopic injection technique. Female Fischer 344 rats were injected with either 10(4) or 10(5) NuTu-19 cells by intraperitoneal or orthotopic injection. Peritoneal washings and histologic specimens were examined to correlate the incidence and extent of tumor growth. In a second phase, orthotopic injections of 10(2) and 10(3) cells were compared to that of 10(4) cells. Progression of ovarian cancer was observed by gross and microscopic examinations in both intraperitoneal and orthotopic models. Pelvic extension and abdominal adhesions uniquely characterized the orthotopically injected animals. Numbers of identifiable metastases declined with lower cell inocula, confirming that early-stage disease was extended to at least 14 days with 10(2) NuTu-19 cells. The orthotopic ovarian cancer model emulates early disease with the initiation of a primary tumor that is localized within the inherent microenvironment. The orthotopic model offers a clinically relevant alternative for future cancer research that allows for the investigation of therapeutic strategies against early stages of the disease process.

Tetracycline delivery from fibrin controls peritoneal infection without measurable systemic antibiotic.

The addition of antibiotics to an adhesive haemostat results in an ideal system for the treatment of a localized infectious disease. Fibrin sealant (FS) is a biocompatible, resorbable, adherent haemostat that can deliver antibiotics. Previous use of fibrin to deliver antibiotics resulted in rapid release and limited bioactivity. We have reported previously that poorly soluble antibiotics significantly retard release from FS, resulting in extended delivery in vitro, and overcome antibiotic-resistant infection. We now report that localized antibiotic delivery from FS controls peritoneal infection without measurable systemic antibiotic. Rats and mice were implanted with preformed FS discs containing tetracycline free-base to evaluate control of peritoneal sepsis and to measure serum tetracycline levels. Infection was initiated with Staphylococcus aureus. Morbidity and mortality were evaluated for 14 days. Serum was isolated from jugular vein blood with subsequent evaluation for antimicrobial activity. Mice prophylactically treated with FS-tetracycline (FS-TET) 500 mg/kg 2 days before infection cleared the S. aureus infection, resulting in 100% survival. Mice treated with FS-TET 500 mg/kg 7 days before infection survived. Mice treated with FS-TET 1750 mg/kg 35 days before infection also survived. Rats treated with FS-TET 500 mg/kg had undetectable serum tetracycline levels, whereas in vitro release of tetracycline from FS-TET pellets in rat serum was readily detected. We conclude that fibrin is an excellent vehicle for extended delivery of low solubility tetracycline. Tetracycline delivered from FS is an appropriate chemotherapy for S. aureus peritonitis. FS-TET controls localized infection without a measurable concentration of systemic tetracycline.

The role of AT1 angiotensin receptor activation in the pathogenesis of preeclampsia.

OBJECTIVES: Preeclampsia is characterized by an increase in vascular tone associated with reduced uteroplacental flow. The nature of hypertension arising in pregnancy suggests that the abnormal increase in blood pressure is dependent on some humoral factor that mediates vasospasm. There is evidence that preeclampsia results from a breakdown in the balance between vasodilators such as prostacyclin and prostaglandin E2 and nitric oxide and the vasoconstrictors angiotensin II, thromboxane A2, serotonin, and endothelin. Furthermore, vascular reactivity to angiotensin II is greatly enhanced in preeclampsia as opposed to normal pregnancies. The increased vascular tone and the enhanced thromboxane production noted in preeclampsia may be mediated by the increased sensitivity to angiotensin II because angiotensin II coupled to an AT1 receptor is a potent vasoconstrictor and stimulates the accumulation of free arachidonic acid, the precursor of thromboxane and the prostaglandins. STUDY DESIGN: We used a rat model that has been shown to express the relevant clinical features of human preeclampsia to investigate the involvement of the AT1 angiotensin receptor in this pathologic condition. Pregnant rats were divided into three groups that were either infused with saline or endotoxin on the 14th day of pregnancy. One of the endotoxin-infused groups was further treated with the AT1-selective antagonist losartan from day 11 until day 19 of pregnancy. RESULTS: Perinatal outcome, blood pressure, and urine protein were monitored for each group. We observed that endotoxin infusion resulted in a decrease in pup weight and number of pups and caused an increase in mean arterial pressure as well as increased proteinuria when compared with saline solution-infused animals. In contrast, endotoxin-infused rats receiving losartan exhibited no change in number or weight of pups when compared with control, and losartan tended to diminish the rise in mean arterial pressure. In addition, the increase in urinary protein excretion was completely blocked by losartan. CONCLUSIONS: Endotoxin infusion in pregnant rats appears to be a suitable model for the study of preeclampsia. Moreover, the angiotensin II-dependent activation of an AT1 receptor appears to mediate a portion of the pathophysiologic features associated with preeclampsia.