Membrane Receptors for Peptides in Experimental and Human Pancreatic Cancers

Abstract

Membrane receptors for [D-Trp6]-luteinizing hormone-releasing hormone ([D-T~P~I-LH-RH), somatostatin , and epidermal growth factor (EGF) were investigated in experimental N-nitrosobis-(2-oxopropyl)-amine (BOP)-induced pancreatic cancers of hamsters and in specimens of normal human pancreas and human pancreatic cancer obtained from autopsies. Membrane receptors for [ D -T~~~I -L H -R H were absent in the pancreas of normal hamsters, but appeared after the carcinoma was induced with BOP. Binding capacity of SS-14 receptors was lower in membranes of BOP-induced pancreatic cancers than in the normal pancreas. In the BOP-induced pancreatic cancers, the receptors were also characterized following in vivo treatment of hamsters with microcapsules of the agonist [ D -T~~~I -L H -R H , somatostatin analog RC-160, and the combination of both peptides, which resulted in significant tumor inhibition. Therapy with [ D -T~~~I -L H -R H and RC-160, alone or in combination, decreased the binding capacity of receptors for [ D -T~~I -L H -R H , but increased B,,, for SS-14. There were no significant changes in characteristics of the EGF receptor following these therapies. Membranes from human pancreatic cancers showed binding sites for [ D -T~~I -L H -R H , but no binding was detected in normal human pancreas. The presence of receptors for LH-RH in pancreatic tumors of hamster and humans raises the intriguing possibility that LH-RH could be involved in complex interactions that contribute to the appearance of pancreatic cancer. The binding capacity of receptors for SS-14 in human pancreatic cancer membranes was lower, while B,, for EGF was higher, as compared to normal pancreas. Observed changes in receptors and tumor suppression suggest that the agonist [ D -T~~~I -L H -R H and somatostatin analogs might exert some direct inhibitory effects on experimental pancreatic cancer of hamsters. It is possible that LH-RH agonists and somatostatin analogs could also be used for treatment of human pancreatic cancer. The presence of membrane receptors for [ D -T~~~I -L H -R H , SS-14, and EGF in specimens of human pancreatic cancer also implies that this malignancy might be responsive to hormonal manipulations. Key Words: Binding sites for luteinizing hormone-releasing hormone (LH-RH)-Somatostatin-Epidermal growth factor-Hormonal manipulations-Pancreatic carcinoma.Adenocarcinoma of the exocrine pancreas is almost invariably fatal. In the United States, the in-~ cidence of this adenocarcinoma is increasing and more than 26,000 new cases are diagnosed every year (1-3). This malignancy is now the fifth leading cause of cancer-related deaths among adult Americans (1-3). Early diagnosis of pancreatic carcinoma is difficult and current modalities of treatment are unsatisfactory (1-6). Several studies indicate that 521

Regulation of luteinizing hormone-releasing hormone receptor binding by heterologous and autologous receptor-stimulated tyrosine phosphorylation.

“…The higher binding is consistent with the fact that in our work pure pancreatic cancer cell membranes were used from a cell culture line known to be responsive to EGF (10). In addition, the affinity constant was somewhat lower (i.e., binding was of higher affinity) but of a similar order as previously reported (33,34). This supports the view that the LH-RHRs investigated by us are similar to LH-RHRs reported by others.…”

“…The results of pretreatment with EGF are shown in Fig. 2A (33,34). The higher binding is consistent with the fact that in our work pure pancreatic cancer cell membranes were used from a cell culture line known to be responsive to EGF (10).…”

“…The protein concentration was adjusted to 50 ,ug per 50 ,ul and then divided into aliquots and stored at -70°C. Protein concentration was determined by using the Bio-Rad protein assay kit as described (33).…”

Hormonal treatment of pancreatic carcinoma: a phase II study of LHRH agonist goserelin plus hydrocortisone

“…Ten patients had markedly significant elevation of (Fekete et al, 1989). Carcinogen induced pancreatic tumours in hamsters showed a significantly greater response to the combination of somatostatin and LHRH agonist when compared to either drug administered on its own (Szende et al, 1990a).…”

“…Experimental work in animals has shown that testosterone stimulates and oestrogens inhibit the growth of pre-neoplastic pancreatic foci in male and female rats (Andren-Sandberg, 1989;Scarpelli & Konishi, 1990 (Szende et al, 1991). No such binding sites were detected in normal pancreatic cells (Fekete et al, 1989 (Serrano et al, 1988 (Furr & Woodburn, 1988) and has been shown to be an effective therapy in premenopausal women with metastatic breast carcinoma and patients with prostatic carcinoma. Toxicity to goserelin is minimal and is predictable on the basis of hormonal deprivation.…”