Dear Editor

We read with interest the article by Scott and cols. in the February, 2004 issue of JCP, in which the expression of gastrin-releasing peptide and gastrin-releasing peptide receptors in gastrointestinal carcinoid tumors is discussed.[1]

Currently, we are completing a Phase I trial with the new synthetic bombesin/gastrin-releasing peptide antagonist RC-3095 in patients with advanced refractory solid malignancies. This agent was shown to produce marked tumor responses in a variety of human solid tumors, including those of gastrointestinal origin, in the nude mouse model, with negligible toxicity.[2] In our Phase I trial, five dose escalation steps were studied so far, from 8 to 96 ug/kg daily by subcutaneous injection, with no significant toxic effects. Notably, evidence of antitumor effects were documented in one patient with medullary carcinoma or the thyroid and in two patients with hormone-refractory prostatic cancer. In order to guide us in the identification of a suitable dose to be applied in future Phase II trials of RC-3095, plasma gastrin levels were measured as a surrogate marker of its biological activity in patients included in the study. As a proof of concept, RC-3095 was also given as a single subcutaneous drug administration at the highest dose escalation level to a clearly hypergastrinemic patient with the Zollinger-Ellison syndrome. Interestingly, his basal plasma gastrin levels were almost 20 times above normal levels, and dropped dramatically to about 50% six hours following RC-3095 administration (from 1985,4 down to 1081,3 pg/ml). The observation of antitumor effects in patients included in our Phase I trial of RC-3095, as well as the rapid decrease in plasma gastrin levels in the patient with the Zollinger-Ellison syndrome gives support to the presence of an gastrin-releasing peptide-dependent autocrine/paracrine cell proliferation pathway in endocrine-related gastrointestinal tumors.

References

1. Scott N, Millward E, Cartwright EJ, Preston SR, Coletta PL. Gastrin releasing peptide and gastrin releasing peptide receptor expression in gastrointestinal carcinoid tumors. J. Clin. Pathol. 57(2):189-92, 2004.

2. Koppan M, Halmos G, Arencibia JM, Lamharzi N, Schally AV. Bombesin/gastrin releasing peptide antagonists RC-3095 and RC-3940II inhibit tumor growth and decrease the levels and mRNA expression of epidermal growth factor receptors in H-69 small cell lung carcinoma. Cancer, 83(7): 1335-1343, 1998.