Mátyás Fekete

Membrane receptors for peptides in experimental and human pancreatic cancers

Membrane receptors for [D-Trp6]-luteinizing hormone-releasing hormone ([D-Trp6-LH-RH), somatostatin (SS-14), 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-Trp6]-LH-RH 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-Trp6]-LH-RH, somatostatin analog RC-160, and the combination of both peptides, which resulted in significant tumor inhibition. Therapy with [D-Trp6-LH-RH and RC-160, alone or in combination, decreased the binding capacity of receptors for [D-Trp6-LH-RH, but increased Bmax 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-Trp6]-LH-RH, 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 Bmax for EGF2 was higher, as compared to normal pancreas. Observed changes in receptors and tumor suppression suggest that the agonist [D-Trp6-LH-RH 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-Trp6]-LH-RH, SS-14, and EGF in specimens of human pancreatic cancer also implies that this malignancy might be responsive to hormonal manipulations.

Presence of membrane binding sites for [D-TRP6]-luteinizing hormone-releasing hormone in experimental pancreatic cancer

Characteristics of binding sites (dissociation constant: Kd and maximal binding capacity: Bmax) for [D-Trp6]-luteinizing hormone-releasing hormone [( D-Trp6]-LH-RH]), somatostatin (SS-14) and epidermal growth factor (EGF) were evaluated in membrane fractions of N-Nitrosobis (2-oxopropyl) amine (BOP)-induced pancreatic adenocarcinoma of hamsters. Intact, normal hamster pancreata did not show any binding sites for [D-Trp6]-LH-RH, but specific [D-Trp6]-LH-RH binding sites with low affinity and high capacity were found after pancreatic cancer was induced with BOP. Membrane binding sites for SS-14 and EGF, with high affinity and low capacity were present, both in normal and cancerous pancreata. Normal hamster pancreatic tissue had significantly higher levels of SS-14 binding sites and lower concentration of EGF binding sites as compared to pancreatic carcinoma. In vivo treatment of hamsters bearing pancreatic cancers with microcapsules of agonist [D-Trp6]-LH-RH and the somatostatin analog RC-160 alone, or in combination, caused histopathological regression of tumors and concomitantly decreased the Kd and Bmax of [D-Trp6]-LH-RH, and increased the Bmax of the SS-14 binding sites. These findings represent the first demonstration of binding sites for [D-Trp6]-LH-RH in pancreatic cancers. Our results also suggest that tumor inhibitory effects of [D-Trp6]-LH-RH and RC-160 in pancreatic cancer could be mediated not only indirectly through suppression of sex-steroids, gastrointestinal hormones and growth factors, but also directly by an action on specific binding sites located on the tumor membranes.

Effects of intracerebroventricular administration of ovine corticotropin-releasing factor (CRF 1-41) on passive avoidance behaviour: lack of influence on monoamine contents of limbic brain areas.

The effects of intracerebroventricular administration of synthetic ovine corticotropin-releasing factor (CRF 1-41) have been investigated on the retention of passive avoidance behaviour, and on the dopamine, norepinephrine and serotonin contents of the hypothalamus, mesencephalon, amygdala, septum and striatum, as well as on the plasma corticosterone levels of hypophysectomized and sham-operated rats. Treatment with CRF 1-41 20 min before the first retention test, 24 hours after the learning trial, significantly facilitated the passive avoidance behaviour of hypophysectomized animals in a dose-dependent manner. No effect was found in sham-operated rats. No significant effects of a wide dose range of intracerebroventricularly injected CRF on the monoamine contents of limbic brain structures were detected. However, the same doses of CRF 1-41 increased the plasma corticosterone level in sham-operated rats. The data suggest that the release of CRF from neurons in the limbic system does not alter the monoamine contents in this system, although this peptide facilitates the retention of the passive avoidance behaviour of hypophysectomized rats.

Cholecystokinin, Learning and Memory

The presence of cholecystokinins (CCK-s) in the central nervous system has been well established (Rehfeld 1977, Dockray et al., 1978, Muller et al., 1978) In recent years, a large number of data have accumulated demonstrating many different actions of CCK-s on brain functions. Nevertheless the physiological significance of brain CCK-s is still poorly understood.