Gastrazole

Pancreatic cancer continues to be one of the most difficult malignancies to treat. It is ranked tenth in cancer incidence but is the fourth leading cause of cancer mortality [1]. At present, surgery for resectable tumor and gemcitabine-based chemotherapy for advanced disease are the main forms of treatment; yet disturbingly, its 5-year survival rate of 5% has not improved over the last 30 years. Clearly, there is an urgent need for new therapeutic strategies. Years of intensive research have made pancreatic cancer one of the most described diseases in terms of its molecular biology and pathogenesis, and with that, many therapeutic targets have been identified [2]. One example is the activation of the EGF-receptor (EGFR) signaling pathway. Erlotinib, an EGFR tyrosine kinase inhibitor, was the first targeted therapy to be approved by the US FDA in 2005 for pancreatic cancer treatment. Although it has shown a statistically significant benefit in combination with gemcitabine in a Phase III trial of advanced pancreatic cancer, improvement in survival was small (median survival of 6.24 vs 5.91 months with gemcitabine alone) and appears to favor a subgroup of patients, such as males and those who developed a more severe skin rash [3]. However, cetuximab, a monoclonal antibody that also inhibits EGFR, was ineffective against advanced pancreatic cancer [4]. In fact, a number of other targeted agents have been tested in Phase III trials, including those against VEGF (bevacizumab), gastrin (G17DT), gastrin receptor (gastrazole), Ras farnesyltransferase (tipifarnib) and matrix metalloproteinases (marimastat and tanomastat), but have all failed to make any measurable impact on patient survival [2]. More recently, a Phase III trial of immunotherapy using the GV1001 telomerase peptide vaccine (telomerase is expressed in the majority of pancreatic cancers and contributes to cell immortalization) was stopped prematurely as results showed no survival benefit in combination with gemcitabine in advanced pancreatic cancer patients [5].

The experience of synthesising a novel gastrin receptor antagonist gastrazole and taking it into 3 small clinical studies in pancreatic cancer in man is described. The need for such a compound is illustrated by the observation that inhibition of gastric acid secretion by H2 receptor antagonists results in hypergastrinaemia. A large number of cell types have gastrin receptors including pancreatic cancer cells which have been shown to be stimulated by gastrin. Small numbers of pancreatic cancer patients given gastrazole by continuous intravenous infusion showed prolonged survival compared with best supportive care or placebo, and equivalent survival to those given 5 fluouracil. The results suggest a greater benefit for patients with early stage disease. An alternative gastrin receptor antagonist YF 476 is also described which has the advantage of efficacy given by the oral route. This new compound requires to be studied in pancreatic cancer and other diseases associated with hypergastrinaemia.