Phosphodiesterase 10A: a novel target for selective inhibition of colon tumor cell growth and ß-catenin-dependent TCF transcriptional activity.

The cyclic nucleotide phosphodiesterase 10A (PDE10) has been mostly studied as a therapeutic target for certain psychiatric and neurological conditions, although a potential role in tumorigenesis has not been reported. Here we show that PDE10 is elevated in human colon tumor cell lines compared with normal colonocytes, as well as in colon tumors from human clinical specimens and intestinal tumors from Apc(Min/+) mice compared with normal intestinal mucosa, respectively. An isozyme and tumor-selective role of PDE10 were evident by the ability of small-molecule inhibitors and small interfering RNA knockdown to suppress colon tumor cell growth with reduced sensitivity of normal colonocytes. Stable knockdown of PDE10 by short hairpin RNA also inhibits colony formation and increases doubling time of colon tumor cells. PDE10 inhibition selectively activates cGMP/cGMP-dependent protein kinase signaling to suppress ß-catenin levels and T-cell factor (TCF) transcriptional activity in colon tumor cells. Conversely, ectopic expression of PDE10 in normal and precancerous colonocytes increases proliferation and activates TCF transcriptional activity. These observations suggest a novel role of PDE10 in colon tumorigenesis and that inhibitors may be useful for the treatment or prevention of colorectal cancer.

Efficacy of tenoxicam on intra-abdominal adhesion prevention in a rat model.

The aim of this study was to investigate the effect of tenoxicam as a non-steroidal anti-inflammatory drug (NSAID) on intra-abdominal adhesion prevention in a rat model. Altogether 50 Wistar-Albino rats weighing 220-280 g were assigned to five groups, each of which was made up of 10 rats. All the rats were anaesthetized and prepared for sterile surgery. After a mid-line laparotomy was performed, a 1 cm area of the caecum was rubbed with gauze until subserosal haemorrhage developed, and then a 5 mm-diameter part of the peritoneum on the right side of the abdominal wall was removed. Prior to complete closure, 3 ml of the test material was placed into the abdominal cavity. On the eighth day the rats were killed and the adhesion score was determined. The groups and their mean adhesion scores were as follows: control group (normal saline), 2.5; group of dilution buffer, 1.8; tenoxicam (0.125 mg/kg), 1.3; tenoxicam (0.25 mg/kg), 1.3; and tenoxicam (0.5 mg/kg), 0.9. The differences between the adhesion scores among all the groups (P < 0.05, Kruskal-Wallis test), and those between the tenoxicam groups and control group (P < 0.05, Mann-Whitney U-test), were significant. Thus a single instillation of tenoxicam into the peritoneal cavity at the time of surgery reduced adhesion formation effectively in this model, irrespective of dosage.

Anti-emetic efficacy of tropisetron and metoclopramide.

Post-operative vomiting, especially in ambulatory surgical patients, remains a troublesome problem. This placebo-controlled, randomized, prospective double-blind trial was designed to evaluate the efficacy of two prophylactic anti-emetic regimens on post-operative vomiting in 1-day thyroid surgery. Altogether 60 elective surgical patients were followed for 4 h post-operatively. All patients were American Society of Anesthesiologists physical status of I or II and aged between 22 and 60 years: group 1 was saline control; in groups 2 and 3, metoclopramide (0.2 mg/kg) or tropisetron (5 mg) was administered, respectively, as an intravenous single dose during induction. Patients were pre-medicated. A standardized anaesthetic technique consisting of thiopentone-succinylcholine for induction and fentanyl-nitrous oxide-halothane-pancuronium for maintenance of anaesthesia was used. A 'rescue' anti-emetic was provided in case of continued vomiting or at the patient's request. Anti-emetic inefficacy was defined as request for rescue anti-emetic and/or vomiting episode during the first 4 h post-operation. The number of patients vomiting was 12/20 (60%), 10/20 (50%) and 1/20 (5%) within the first 2 h post-operation in groups 1, 2 and 3, respectively (P > 0.05 for groups 1 and 2; P < 0.01 for groups 2 and 3; P < 0.001 for groups 1 and 3). In group 2, three patients required rescue medication during the first 2 h post-operation, but no significant difference was observed between groups 2 and 3 (P > 0.05). None of the cases in any of the groups needed any rescue medication during post-operative 2-4 h. It is concluded that tropisetron is a highly effective anti-emetic drug in the prophylaxis of post-operative vomiting.