15 research outputs found
Retinoic acid receptor-Ī± signalling antagonizes both intracellular and extracellular amyloid-Ī² production and prevents neuronal cell death caused by amyloid-Ī²
Alzheimerās disease (AD) is characterized by amyloid-Ī² (AĪ²) deposition in the brain, neuronal cell loss and cognitive decline. We show here that retinoic acid receptor (RAR)Ī± signalling in vitro can prevent both intracellular and extracellular AĪ² accumulation. RARĪ± signalling increases the expression of a disintegrin and metalloprotease 10, an Ī±-secretase that processes the amyloid precursor protein into the non-amyloidic pathway, thus reducing AĪ² production. We also show that RARĪ± agonists are neuroprotective, as they prevent AĪ²-induced neuronal cell death in cortical cultures. If RARĪ± agonists are given to the Tg2576 mouse, the normal AĪ² production in their brains is suppressed. In contrast, neither RARĪ² nor Ī³-agonists affect AĪ² production or AĪ²-mediated neuronal cell death. Therefore, RARĪ± agonists have therapeutic potential for the treatment of AD
Gastrazole (JB95008), a novel CCK2/gastrin receptor antagonist, in the treatment of advanced pancreatic cancer: results from two randomised controlled trials
Gastrin has been shown to be a growth stimulant in pancreatic cancer cells. Gastrazole is a potent and selective gastrin receptor antagonist. Two randomised blinded trials were conducted to assess the effect of gastrazole in advanced pancreatic cancer. Patients with biopsy-proven, inoperable pancreatic carcinoma were recruited. Trial A compared protracted venous infusion (PVI) gastrazole with PVI placebo, whereas trial B compared PVI gastrazole with PVI fluorouracil (5-FU). Eighteen patients were randomised in trial A. Gastrazole produced significantly better survival compared to placebo (median 7.9 months vs 4.5 months; 1-year survival: 33 vs 11%, respectively; log rank P=0.02). No difference in toxicity was seen between gastrazole and placebo, except central venous catheter and pump complications. Ninety-eight patients were randomised in trial B. No significant survival difference was detected between gastrazole and 5-FU (median: 3.6 vs 4.2 months; 1-year survival: 13.2 vs 26.2%, respectively; log rank P=0.42). Toxicity of gastrazole was mild with significantly less diarrhoea (P=0.03), stomatitis (P<0.001) and handā foot syndrome (P<0.001) compared to 5-FU. Quality of life (QoL) assessment showed similar QoL between gastrazole and 5-FU at baseline and no significant differences occurred with treatment either between arms or within arms. Compared to placebo, patients with advanced pancreatic cancer treated with gastrazole appeared to live longer, albeit in a very small trial and will require confirmation with large-scale randomised data. However, it did not produce survival advantage over PVI 5-FU. Lack of toxicity for gastrazole may allow its combination with cytotoxic drugs