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Comparative effect of the gastrin receptor (GR) antagonists, CR2093 and L-365,260 on the growth of gastrointestinal (GI) tumour xenografts
262 COMPARATIVE EFFECT OF THE GASTRIN RECEPTOR (GR) ANTAGONISTS, CR2093 AND L-365,260 ON THE GROWTH OF GASTROINTESTINAL (GI) TUMOUR XENOGRAFTS.
1S.A. WATSON, aD.M. CROSBEE, 2J.F.R. ROBERTSON, 2j.D. HARDCASTLE. 1Department of Cancer Research and 2Department of Surgery, University of Nottingham, Nottingham, NG7 2RD. Two GR antagonists were evaluated in this study; CR2093, a glutamic acid derivative (Rotta) and L-365,260, a benzodiazepine (Merck, Sharp and Dohme). The ability of the GR antagonists to displace 1251I]gastrin-17 (5xl0l°M) from GR on AR4ZI cells (rat adenocarcinoma) was compared. Both GR antagonists displaced 125[I]-G17. The molar concentrations inducing 50% displacement were 6.0 x 10-9 for G17, 4.5x10-8 for L-365,260 and 8.0x10-5 for CR2093, ie, CR2093 was 1780 x less effective than L-365,260 in displacing G17. The effect of L-365,260 and CR2093 on basal and gastrin-stimulated (10/zg/mouse/day by osmotic mini pump) growth of AR42J xenografts was evaluated (n=10 mice/group). L365,260 was administered orally (in suspension due to its poor solubility properties in aqueous solution) at 5mg/kg bid and CR2093 by intravenous injection (40/~g/kg, once daily). CR2093 significantly reduced gastrin-stimulated growth (p=0.0109) as did L-365,260 (p=0.034) neither had any effect on basal growth. The inhibitory effect of the 2 compounds was also compared on the basal and gastrin-stimulated growth of the GR positive human gastric adenocarcinoma, MKN45. CR2093 significantly reduced gastrin-stimulated growth of MKN45 (p=0.0454), whereas L-365,260 had no significant effect. Both failed to inhibit basal growth. In conclusion, GR antagonists with favourable pharmacokinetics may reduce the growth of gastrinsensitive GI tumours.
DEXAMETHASONE-INDUCED INCREASE IN HYPOTHALAMIC NEUROPEPTIDE Y (NPY) IS REVERSED BY INSULIN J.P.H. Wilding, S.G. Gilbey, N. Aslam, M.A. Ghatei and S.R. Bloom. Hammersmith Hospital, Du Cane Road, London W12 0NN.
Obesity and diabetes cause insulin resistance and altered hypothalamic NPY. We treated wistar rats for 28 days with dexamethasone (0,4mg/kg/day), dexamethasone plus insulin (60U/kg/day), or saline. We measured NPY by RIA in microdissected hypothalamic nuclei ( n = 10/group), and NPY expression in individual hypothalami by Northern blot analysis ( n = 4 ) . Dexamethasone produced significant elevations in NPY in the paraventricular (11.0+ 1.3 vs 7.1 -I-0.4 fmol//~g protein, p < 0.05) and arcuate (6.2+0.3 vs 3.8___0.2fmol//~g protein, p < 0.02) nuclei, paralleled by increased in hypothalamic NPY mRNA (6185+351 vs 3750-t-464 counts, p < 0 . 0 2 ) . These changes were not seen in the dexamethasone/insulin group, (paraventricular nucleus 8.7-t-0.8 fmol//zg protein; arcuate nucleus 4.2 + 0.4fmol/#g protein; mRNA 4034 + 272). Plasma glucose was similar in the 3 g r o u p s ( 5 . 4 + 0 . 2 m m o 1 / 1 c o n t r o l s ; 6 . 0 + 0 . 6 m m o l / l d e x a m e t h a s o n e ; 4.5_0.4mmol/1 dexamethasone/insulin). Dexamethasone-induced changes in hypothalamic NPY reflect alterations in peripheral metabolism and/or nutritional state rather than a direct effect of steroids on the hypothalamus.
1S.A. WATSON, aD.M. CROSBEE, 2J.F.R. ROBERTSON, 2j.D. HARDCASTLE. 1Department of Cancer Research and 2Department of Surgery, University of Nottingham, Nottingham, NG7 2RD. Two GR antagonists were evaluated in this study; CR2093, a glutamic acid derivative (Rotta) and L-365,260, a benzodiazepine (Merck, Sharp and Dohme). The ability of the GR antagonists to displace 1251I]gastrin-17 (5xl0l°M) from GR on AR4ZI cells (rat adenocarcinoma) was compared. Both GR antagonists displaced 125[I]-G17. The molar concentrations inducing 50% displacement were 6.0 x 10-9 for G17, 4.5x10-8 for L-365,260 and 8.0x10-5 for CR2093, ie, CR2093 was 1780 x less effective than L-365,260 in displacing G17. The effect of L-365,260 and CR2093 on basal and gastrin-stimulated (10/zg/mouse/day by osmotic mini pump) growth of AR42J xenografts was evaluated (n=10 mice/group). L365,260 was administered orally (in suspension due to its poor solubility properties in aqueous solution) at 5mg/kg bid and CR2093 by intravenous injection (40/~g/kg, once daily). CR2093 significantly reduced gastrin-stimulated growth (p=0.0109) as did L-365,260 (p=0.034) neither had any effect on basal growth. The inhibitory effect of the 2 compounds was also compared on the basal and gastrin-stimulated growth of the GR positive human gastric adenocarcinoma, MKN45. CR2093 significantly reduced gastrin-stimulated growth of MKN45 (p=0.0454), whereas L-365,260 had no significant effect. Both failed to inhibit basal growth. In conclusion, GR antagonists with favourable pharmacokinetics may reduce the growth of gastrinsensitive GI tumours.
DEXAMETHASONE-INDUCED INCREASE IN HYPOTHALAMIC NEUROPEPTIDE Y (NPY) IS REVERSED BY INSULIN J.P.H. Wilding, S.G. Gilbey, N. Aslam, M.A. Ghatei and S.R. Bloom. Hammersmith Hospital, Du Cane Road, London W12 0NN.
Obesity and diabetes cause insulin resistance and altered hypothalamic NPY. We treated wistar rats for 28 days with dexamethasone (0,4mg/kg/day), dexamethasone plus insulin (60U/kg/day), or saline. We measured NPY by RIA in microdissected hypothalamic nuclei ( n = 10/group), and NPY expression in individual hypothalami by Northern blot analysis ( n = 4 ) . Dexamethasone produced significant elevations in NPY in the paraventricular (11.0+ 1.3 vs 7.1 -I-0.4 fmol//~g protein, p < 0.05) and arcuate (6.2+0.3 vs 3.8___0.2fmol//~g protein, p < 0.02) nuclei, paralleled by increased in hypothalamic NPY mRNA (6185+351 vs 3750-t-464 counts, p < 0 . 0 2 ) . These changes were not seen in the dexamethasone/insulin group, (paraventricular nucleus 8.7-t-0.8 fmol//zg protein; arcuate nucleus 4.2 + 0.4fmol/#g protein; mRNA 4034 + 272). Plasma glucose was similar in the 3 g r o u p s ( 5 . 4 + 0 . 2 m m o 1 / 1 c o n t r o l s ; 6 . 0 + 0 . 6 m m o l / l d e x a m e t h a s o n e ; 4.5_0.4mmol/1 dexamethasone/insulin). Dexamethasone-induced changes in hypothalamic NPY reflect alterations in peripheral metabolism and/or nutritional state rather than a direct effect of steroids on the hypothalamus.