cholecystokinin and Astrocytoma

Gastrin and cholecystokinin (CCK) mediate their effects through at least two types of receptors (CCK receptors A and B). While it has been hypothesized that gastrin, a stimulator of gastric acid secretion, is also a neurotransmitter and a stimulator of cell proliferation in various normal and neoplastic tissues, its effect on astrocytic brain tumors has not been actively investigated.. Our goal was to determine the effects of gastrin and gastin and/or CCK antagonists on the proliferation in vitro of astrocytic tumor cells by use of both established cell lines and primary cell cultures of tumor tissue.. Ten established astrocytic tumor cell lines, SW1088, SW1783, Hs683, H4, U87, U118, U138, U373, T98G, and A172, were studied. The effects of added gastrin (at 0.01, 0.1, and microM) and the gastrin/CCK antagonists L-365,260, CI-988, L-364,718, and JMV 234 (each at 0.01, 0.1, and 1 microM) on the cellular proliferation rates of the 10 cell lines were indirectly measured by use of the colorimetric tetrazolium assay. The influence of gastrin (at 0.01 microM) on the cellular proliferation of primary cultures from nine freshly explanted astrocytic tumors was assessed by means of tritiated thymidine uptake and autoradiography.. At specific concentrations, added gastrin increased the cellular proliferation of three established astrocytic cell lines (A172, Hs683, and SW1088), decreased it in two (U373 and T98G), and was without effect on the remaining five. Gastrin decreased cellular proliferation in one primary astrocytic tumor cell culture, stimulated it in five, and had no apparent effect in the remaining three. L-365,260, a CCK receptor B antagonist used at 0.01 microM, increased cellular proliferation in seven cell lines (A172, H4, Hs683, SW1783, T98G, U118, and U138), decreased it in one (U87), and had no effect in the remaining two. CI-988, another CCK receptor B antagonist used at 0.01 microM, inhibited cellular proliferation in five cell lines (A172, H4, SW1783, U373, and U87), stimulated it in two (T98G and U138), and had no effect in three. The CCK receptor A antagonists L-364,718 and JMV 234, both used at 0.01 microM, affected the cellular proliferation of only three of the 10 cell lines.. These results suggest that gastrin (and perhaps CCK that belongs to the same peptide family) may play a role in the growth of a substantial proportion of human astrocytic tumors.

Topics: Amino Acid Sequence; Astrocytoma; Autoradiography; Benzodiazepinones; Brain Neoplasms; Cell Division; Cholecystokinin; Devazepide; Gastrins; Hormone Antagonists; Humans; Indoles; Meglumine; Molecular Sequence Data; Peptide Fragments; Phenylurea Compounds; Receptors, Cholecystokinin; Sincalide; Thymidine; Tritium; Tumor Cells, Cultured

We have investigated the potential role of gastrin in the regulation of cell growth in human astrocytic tumors. To this end we have used synthetic analogs of gastrin and cholecystokinin (CCK) which behave as gastrin and/or CCK antagonists, e.g. compounds JMV-97, JMV-209 and JMV-179. Their effects on astrocytic tumor cell proliferation was investigated by the use of the colorimetric MTT assay. The in vitro biological models used in the present study included the SW1088, U87 and U373 astrocytic tumor cell lines. The results demonstrated marked influence of gastrin and CCK antagonists in the regulation of astrocytic tumor growth. This suggests that gastrin and/or CCK antagonists might be tested in experimental glioblastoma.

Topics: Astrocytes; Astrocytoma; Brain Neoplasms; Cholecystokinin; Gastrins; Glioblastoma; Humans; Peptide Fragments; Sincalide; Tumor Cells, Cultured

Both the sulphated and non-sulphated forms of cholecystokinin (CCK) octapeptide are susceptible to hydrolysis by the cell-surface peptidases endopeptidase-24.11 (NEP), angiotensin converting enzyme and aminopeptidase N (AP-N). Indirect studies have previously implicated an elastase-like serine endopeptidase in CCK metabolism in brain. We have therefore compared the hydrolysis of CCK, in both sulphated and non-sulphated forms by solubilized membrane preparations from the human astrocytoma clone D384 and the neuroblastoma line SH-SY5Y. Selective peptidase inhibitors were used to elucidate the principal activities involved in CCK metabolism. In the glial cell line the hydrolysis of cholecystokinin octapeptide (CCK-8), sulphated or non-sulphated, was inhibited predominantly by the NEP inhibitor, phosphoramidon (PR). In contrast, in the neuroblastoma line, angiotensin converting enzyme (ACE) was seen to play a major role in metabolism of CCK-8 with a lesser effect attributable to NEP but with some differences between sulphated and non-sulphated forms reflecting the preference of ACE for CCK-8ns. In neither cell line was a significant effect of the serine peptidase inhibitor Dip-F seen on CCK metabolism arguing against the presence of a putative CCK-degrading serine peptidase in these cell lines. Both NEP and ACE remain as candidates for inactivation of CCK at the cell surface.

Topics: Amino Acid Sequence; Aminopeptidases; Astrocytoma; Brain Neoplasms; CD13 Antigens; Cell Membrane; Cholecystokinin; Clone Cells; Endopeptidases; Humans; Hydrolysis; Molecular Sequence Data; Neprilysin; Neuroblastoma; Neuroglia; Neurons; Peptidyl-Dipeptidase A; Tumor Cells, Cultured

Topics: Astrocytoma; Cell Line; Cell Membrane; Cholecystokinin; Glycopeptides; Humans; Hydrolysis; Kinetics; Neprilysin; Neuroblastoma; Sincalide; Tumor Cells, Cultured

Using immunohistochemistry, well-preserved neuronal cell bodies and fibres containing neuropeptide Y, somatostatin, and cholecystokinin immunoreactivity have been identified in all seven supratentorial anaplastic astrocytomas studied. These neurones have been shown not only on the edge but also in the depth of the neoplastic tissue. These neuropeptides were not present in 18 other intracranial tumours (3 astrocytomas, 1 subependymoma, 8 glioblastoma multiformes, 1 meningioma, and 5 metastases). In all 25 intracranial tumours studied, no immunoreactivity was found for vasoactive intestinal polypeptide, substance P, methionine-enkephalin, leucine-enkephalin, synenkephalin, neurophysin I-II, and corticotropin releasing factor.

Topics: Astrocytoma; Cholecystokinin; Humans; Immunohistochemistry; Neuropeptide Y; Somatostatin; Supratentorial Neoplasms