Gastrazole (JB95008), a novel CCK2/gastrin receptor antagonist, in the treatment of advanced pancreatic cancer: results from two randomised controlled trials

Abstract

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 ¼ 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 ¼ 0.42). Toxicity of gastrazole was mild with significantly less diarrhoea (P ¼ 0.03), stomatitis (Po0.001) and hand -foot syndrome (Po0.001) 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.

Gastrin Enhances the Angiogenic Potential of Endothelial Cells via Modulation of Heparin-Binding Epidermal-Like Growth Factor

“…Reversal of G17 and GlyG17 effects was assessed using the specific CCK-2R antagonists YM022 and JB95008 (Gastrazole; ref. 22), at concentrations of 10 À6 mol/L.…”

Inactivating cholecystokinin-2 receptor inhibits progastrin-dependent colonic crypt fission, proliferation, and colorectal cancer in mice

“…Other groups have demonstrated in preclinical studies the possible efficacy of CCK2R antagonists in carcinogenesis (67,68). A number of CCK2/gastrin receptor antagonists have been developed, but only a few have been tested in clinical trials in human patients, and mostly in patients with advanced cancer (69). Thus, future studies should explore further the utility of targeting CCK2R in cancer prevention.…”

Z-360, a Novel Cholecystokinin-2/Gastrin Receptor Antagonist, Inhibits Gemcitabine-Induced Expression of the Vascular Endothelial Growth Factor Gene in Human Pancreatic Cancer Cells

“…In fact, the efficacy of some CCK-2/gastrin receptor antagonists for advanced pancreatic carcinoma was evaluated in several clinical trials. Gastrazole (JB95008), a CCK-2/gastrin receptor antagonist, significantly prolonged survival compared with placebo, 14,15) and this observation provides evidence that the inhibition of gastrin-dependent pathophysiological changes can be effective therapy for pancreatic carcinoma.…”

“…In fact, the efficacy of some CCK-2/gastrin receptor antagonists for advanced pancreatic carcinoma was evaluated in several clinical trials. Gastrazole (JB95008), a CCK-2/gastrin receptor antagonist, significantly prolonged survival compared with placebo, 14,15) and this observation provides evidence that the inhibition of gastrin-dependent pathophysiological changes can be effective therapy for pancreatic carcinoma.Vascular endothelial growth factor (VEGF) is a potent angiogenic peptide and is overexpressed in tumor tissues of patients with some cancers such as pancreatic cancer or nonsmall lung cancer. [16][17][18] Many studies show that the expression of VEGF is correlated with the survival of patients with pancreatic cancer 19,20) and that VEGF is an important prognostic factor for the survival of patients with pancreatic cancer.…”