Growth inhibition of experimental pancreatic cancers and sustained reduction in epidermal growth factor receptors during therapy with hormonal peptide analogs

Reduction in receptors for epidermal growth factor (EGF) in cancers appears to be one of the principal mechanisms through which peptide hormone analog s can inhibit tumor growth. In this study, hamsters with nitrosamine-induce d pancreatic cancers were treated for 8 weeks with bombesin/gastrin-releasi ng peptide (GRP) antagonist RC-3095, somatostatin analog RC-160 or the lute inizing hormone-releasing hormone antagonist Cetrorelix, using sustained de livery systems releasing 20, 35 and 20 mu g analog/day respectively. To est ablish the pattern of changes in the number and affinity of EGF receptors o n tumors, groups of animals were sacrificed at regular intervals during the rapy Chronic treatment with RC-3095 or Cetrorelix re suited in an early (da y 10) and sustained reduction (71% or 69% respectively) in EGF receptors on pancreatic tumors. In contrast, RC-160 decreased receptor concentration by 60% only after 20 days. Among the histological characteristics of prolifer ation, the decrease in argyrophilic nucleolar organizer regions, but not ap optotic and mitotic indices, showed a correlation with the fall in EGF rece ptors. The concentration of the receptors returned to the control level 4 d ays after cessation of chronic treatment with RC-3095. The effect of single injections of RC-3095, RC-160 and Cetrorelix on EGF receptors was also inv estigated. RC-160 decreased the number of EGF receptors on pancreatic cance rs by 31% 3 h after administration, but the receptors had returned to norma l level at 6 h. RC-3095 and Cetrorelix caused a 67% and 59% decline, respec tively, in EGF receptors only 6 h after injection and thc concentration of receptors remained low for 24 h. Thus, the pattern of downregulation of EGF receptors in pancreatic cancers appears to depend on the peptide used for therapy. Since the antitumor effect may be the result of the fall in EGF re ceptors in cancers, information on the time course of changes in these rece ptors during treatment with these analogs may lead to an improvement in the rapeutic regimens.