thromboxane-a2 and Esophageal-Neoplasms

Barrett's esophagus (BE), a complication of gastroesophageal reflux disease (GERD), predisposes patients to esophageal adenocarcinoma (EAC). Reliable biomarkers for early detection and discovery of potential drug targets are urgently needed for improved BE and EAC patient outcomes.. Patient biopsy samples were evaluated for COX1/2, and thromboxane A2 synthase (TBXAS) expression. Circulating prostaglandins biosynthesis was determined using enzyme immunoassay kits. Anchorage-independent cell growth assay, crystal violet staining assay, and xenograft experiments were conducted to assess BE and EAC cell growth. A surgical mouse model of reflux (i.e., esophagoduodenostomy) was established and samples were analyzed using an enzyme immunoassay kit, immunohistochemistry, immunoblotting, or RT-PCR. Esophageal biopsy samples (pre- and post-intervention) were obtained from a randomized clinical trial in which participants were administered esomeprazole (40 mg) twice daily in combination with an acetylsalicylic acid (ASA) placebo or 81 or 325 mg ASA for 28 days. Esophageal biopsy specimens before and after the intervention period were analyzed.. COX2 and TBXAS are highly expressed in BE and EAC patients accompanied by a pronounced elevation of circulating TXA2 levels. ASA suppressed BE and EAC growth by targeting the TXA2 pathway. Additionally, biopsies from 49 patients (with similar baseline characteristics) showed that ASA substantially decreased serum TXA2 levels, resulting in reduced inflammation.. This study establishes the importance of the COX1/2-driven TXA2 pathway in BE and EAC pathophysiology and lays the groundwork for introducing a TXA2-targeting strategy for EAC prevention and early detection.. Hormel Foundation, Exact Sciences, Pentax Medical, Intromedic and National Cancer.

Topics: Adenocarcinoma; Animals; Aspirin; Barrett Esophagus; Carcinogenesis; Cell Line, Tumor; Cell Proliferation; Cyclooxygenase 1; Cyclooxygenase 2; Disease Models, Animal; Esophageal Neoplasms; Extracellular Signal-Regulated MAP Kinases; Female; Humans; Inflammation; Male; Mice, Inbred C57BL; Middle Aged; Molecular Targeted Therapy; Signal Transduction; STAT3 Transcription Factor; Thromboxane A2

In experimental studies using mongrel dogs, 60 minutes after total thoracic esophagectomy the dog lung transiently released into the systemic circulation up to about 6000 micrograms/ml of thromboxane A2(TXA2) measured by radioimmunoassay as its metabolite thromboxane B2(TXB2). To determine whether lung TX release had effects on pulmonary function, we measured the changes in extravascular lung water (EVLW), lung resistance (RL) before, 10, 30, and 60 minutes after total thoracic esophagectomy in 14 anesthetized dogs. In seven untreated dogs, EVLW and RL increased and CL decreased approximately twofold at 60 minutes after the surgery, which corresponded well with a large transpulmonary plasma concentration gradient of TXB2. In remaining 7 dogs pretreated with intravenous OKY-046 which was TXA2 synthetase inhibitor, increase in EVLW and RL and decrease in CL were minimal and plasma concentration of TXB2 remained low value of a preoperative level. In clinical studies, 20 patients with esophageal carcinoma were evaluated. All of these patients underwent total thoracic esophagectomy with extended lymph node dissection of a similar extent. In 5 control patients, significant increase in EVLW and pulmonary vascular resistance were noted at 60 minutes after surgery. On the other hand, while the patients who had intravenous OKY-046 administration during operation at a dose of 1 microgram/kg/min or 5 micrograms/kg/min showed significant decrease in EVLW and pulmonary vascular resistance at 60 minutes after surgery. Based on these results, it is concluded that TXA2 appears to be one of the most important factors to cause the postoperative pulmonary complication after total thoracic esophagectomy for esophageal cancer.

Topics: Animals; Dogs; Epoprostenol; Esophageal Neoplasms; Esophagus; Humans; Lung; Lymph Node Excision; Male; Postoperative Period; Respiration; Thromboxane A2; Vascular Resistance