Growth inhibition of experimental pancreatic cancers and sustained reduction in epidermal growth factor receptors during therapy with hormonal peptide analogs
K. Szepeshazi et al., Growth inhibition of experimental pancreatic cancers and sustained reduction in epidermal growth factor receptors during therapy with hormonal peptide analogs, J CANC RES, 125(8-9), 1999, pp. 444-452
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.