Somatostatin analogues and bombesin/gastrin-releasing peptide antagonist RC-3095 inhibit the growth of human glioblastomas in vitro and in vivo.
We investigated the effects of somatostatin analogues and a synthetic bombesin/gastrin-releasing peptide (GRP) antagonist on the growth of the human malignant glioma cell lines U-87MG and U-373MG transplanted to nude mice or cultured in vitro. Nude mice bearing s.c. implanted U-87MG or U-373MG tumors were treated for 4 and 6 weeks, respectively, with various somatostatin analogues or bombesin/GRP antagonist RC-3095. Somatostatin analogues RC-160, RC-160-II, and RC-101-I, given s.c. in doses of 100 micrograms/animal/day, inhibited the growth of U-87MG xenografts as shown by more than 60% reduction in tumor volumes and 45% reduction in tumor weights compared with the control group. Bombesin/GRP antagonist RC-3095, given s.c. at a dose of 20 micrograms/animal twice daily, had the greatest inhibitory effect and decreased tumor volumes and weights by approximately 79% and 72%, respectively. The growth of U-373MG xenografts was also significantly inhibited by treatment with analogue RC-160 or antagonist RC-3095. The mean survival time of nude mice, inoculated orthotopically with U-87MG cells into the brain, was significantly prolonged by 4.9 days by treatment with antagonist RC-3095. Serum gastrin levels in animals bearing U-87MG tumors, treated with antagonist RC-3095 or somatostatin analogues, were decreased compared with controls. All three somatostatin analogues also reduced serum growth hormone levels. Receptor analyses demonstrated high-affinity binding sites for bombesin, somatostatin, and epidermal growth factor on membranes of U-87MG and U-373MG tumors. The concentration of binding sites for epidermal growth factor on both tumors was significantly decreased after in vivo treatment with antagonist RC-3095 or the somatostatin analogues. In studies in vitro, RC-3095, added to the culture medium, significantly inhibited the proliferation of U-87MG and U-373MG cells in the presence of GRP(14-27), as measured by cell number, but only a moderate suppression of growth of both cell lines was observed with somatostatin analogue RC-160. These results demonstrate that bombesin/GRP antagonist RC-3095 and somatostatin analogues such as RC-160 can inhibit the growth of human glioblastoma cell lines U-87MG and U-373MG in vitro as well as in vivo. Our work suggests the merit of further investigations of these analogues for the possible development of new approaches for treatments of patients with malignant gliomas.
Endocrine, Polypeptide and Cancer Institute, Veterans Affairs Medical Center, New Orleans, Louisiana 70146.
J
J
Pinski
A V
AV
Schally
G
G
Halmos
K
K
Szepeshazi
K
K
Groot
D000595:Amino Acid Sequence; D000818:Animals; D001839:Bombesin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D066246:ErbB Receptors / Q000032:analysis; D005755:Gastrins / Q000097:blood; D005909:Glioblastoma / Q000097:blood / Q000401:mortality / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry / Q000494:pharmacology*; D018004:Receptors, Bombesin / Q000032:analysis; D013004:Somatostatin / Q000031:analogs & derivatives* / Q000097:blood / Q000737:chemistry / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D005755:Gastrins; D010446:Peptide Fragments; D018004:Receptors, Bombesin; C071363:bombesin (6-14), Tpi(6)-Leu(13)-psi(CH2NH)-Leu(14)-; C051458:vapreotide; D013004:Somatostatin; D066246:ErbB Receptors; D001839:Bombesin