RESUMEN

Oxothiazolidine carboxylic acid is a prodrug of cysteine that acts as an anti-diabetic agent via insulin secretion and the formation of the Ca2+-mobilizing second messenger, cyclic ADP-ribose (cADPR). Here we show that a hybrid compound, arginine thiazolidine carboxylate (ATC), increases cytoplasmic Ca2+ in pancreatic ß-cells, and that the ATC-induced Ca2+ signals result from the sequential formation of two Ca2+-mobilizing second messengers: nicotinic acid adenine dinucleotide phosphate (NAADP) and cADPR. Our data demonstrate that ATC has potent insulin-releasing properties, due to the additive action of its two components; thiazolidine carboxylate (TC) and L-arginine. TC increases glutathione (GSH) levels, resulting in cAMP production, followed by a cascade pathway of NAADP/nitric oxide (NO)/cGMP/cADPR synthesis. L-arginine serves as the substrate for NO synthase (NOS), which results in cADPR synthesis via cGMP formation. Neuronal NOS is specifically activated in pancreatic ß-cells upon ATC treatment. These results suggest that ATC is an ideal candidate as an anti-diabetic, capable of modulating the physiological Ca2+ signalling pathway to stimulate insulin secretion.

Asunto(s)

Arginina/farmacología , Calcio/metabolismo , ADP-Ribosa Cíclica/biosíntesis , Hipoglucemiantes/farmacología , Islotes Pancreáticos/efectos de los fármacos , NADP/análogos & derivados , Profármacos/farmacología , Tiazolidinas/farmacología , Animales , Arginina/química , Señalización del Calcio , AMP Cíclico/biosíntesis , GMP Cíclico/metabolismo , Expresión Génica , Glutatión/metabolismo , Hipoglucemiantes/química , Insulina/metabolismo , Secreción de Insulina , Islotes Pancreáticos/metabolismo , Masculino , Ratones , Ratones Endogámicos ICR , Ratones Noqueados , NADP/biosíntesis , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo I/genética , Óxido Nítrico Sintasa de Tipo I/metabolismo , Profármacos/química , Tiazolidinas/química , Técnicas de Cultivo de Tejidos

RESUMEN

PURPOSE: The aim of this study was to analyze the oncologic outcomes and the risk factors for recurrence after a tumor-specific mesorectal excision (TSME) of resectable rectal cancer in a single institution. METHODS: A total of 782 patients who underwent a TSME for resectable rectal cancer between February 1995 and December 2005 were enrolled retrospectively. Oncologic outcomes included 5-year cancer-specific survival and its affecting factors, as well as risk factors for local and systemic recurrence. RESULTS: The 5-year cancer-specific survival rate was 77.53% with a mean follow-up period of 61 ± 31 months. The overall local and systemic recurrence rates were 9.2% and 21.1%, respectively. The risk factors for local recurrence were pN stage (P = 0.015), positive distal resection margin, and positive circumferential resection margin (P < 0.001). The risk factors for systemic recurrence were pN stage (P < 0.001) and preoperative carcinoembryonic antigen level (P = 0.005). The prognostic factors for cancer-specific survival were pT stage (P < 0.001), pN stage (P < 0.001), positive distal resection margin (P = 0.005), and positive circumferential resection margin (P = 0.016). CONCLUSION: The oncologic outcomes in our institution after a TSME for patients with resectable rectal cancer were similar to those reported in other recent studies, and we established the risk factors that could be crucial for the planning of treatment and follow-up.