Inhibitory effect of bombesin receptor antagonist RC-3095 on the growth of human pancreatic cancer cells in vivo and in vitro.

Abstract

In this study, we investigated the effect of bombesin/GRP antagonist RC-3095 on the growth of CFPAC-1 human pancreatic cancer cells transplanted to nude mice or cultured in vitro. Nude mice bearing xenografts of the CFPAC-1 cell line received s.c. injections of RC-3095 (10 micrograms twice a day) or the vehicle (control) for 25 days. Chronic administration of RC-3095 inhibited the growth of CFPAC-1 tumors in nude mice as shown by a significant decrease in tumor volume throughout the period of treatment. Tumor volume doubling time was prolonged by RC-3095 treatment from 7.2 days to 10 days, and the tumor growth rate was decreased by 49%. In mice treated with RC-3095, the tumor growth delay time was 5.8 days. Treatment with RC-3095 decreased the final tumor weight by 37% and reduced DNA and protein contents in tumor tissues by 44 and 39.9%, respectively, compared to the controls. In cultures of the CFPAC-1 cell line, the addition of bombesin(1-14) (1 pM-0.1 microM) to the medium induced a dose-dependent increase in cell number. RC-3095 at 1 nM concentration effectively inhibited the bombesin-stimulated growth of CFPAC-1 cells in cultures. In the presence of 1 microM RC-3095 in the culture medium, the bombesin-induced growth of CFPAC-1 cells was totally suppressed. Bombesin was also shown to stimulate the DNA synthesis in CFPAC-1 cells in vitro as based on [3H]thymidine incorporation assay. When the cells were cultured in the presence of 1-100 nM bombesin, the uptake of [3H]thymidine by the cells was increased by 89-131%. RC-3095 inhibited both the basal and bombesin-stimulated DNA synthesis of CFPAC-1 cells. Addition of RC-3095 (10-100 nM) alone to the cultures caused a 39-40% decrease in the [3H]thymidine incorporation by the cells. Concomitant addition of RC-3095 (1 microM) and bombesin (1-100 nM) to the cultures induced a significant reduction in the uptake of [3H]thymidine by the cells compared to the values obtained with bombesin alone. Receptor binding assays showed the presence of two classes of specific binding sites for bombesin on CFPAC-1 cells, one with high affinity (Kd = 4.25 +/- 0.77 nM) and low capacity (Bmax = 0.268 +/- 0.052 pmol/10(6) cells) and the other with low affinity (Kd = 321.70 +/- 68.46 nM) and high capacity (Bmax = 3.991 +/- 0.374 pmol/10(6) cells).(ABSTRACT TRUNCATED AT 400 WORDS)

• Authors: Y Qin, T Ertl, R Z Cai, G Halmos, A V Schally
• Journal: Cancer research (Cancer Res) Vol. 54 Issue 4 Pg. 1035-41 (Feb 15 1994) ISSN: 0008-5472 [Print] United States
• PMID: 8313359 (Publication Type: Journal Article, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antineoplastic Agents
• DNA, Neoplasm
• Neoplasm Proteins
• Peptide Fragments
• Receptors, Bombesin
• bombesin (6-14), Tpi(6)-Leu(13)-psi(CH2NH)-Leu(14)-
• Bombesin

Topics

• Animals
• Antineoplastic Agents (therapeutic use)
• Bombesin (analogs & derivatives, antagonists & inhibitors, metabolism, pharmacology, therapeutic use)
• DNA, Neoplasm (analysis, biosynthesis)
• Humans
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Neoplasm Proteins (analysis)
• Neoplasm Transplantation
• Pancreatic Neoplasms (drug therapy, pathology)
• Peptide Fragments (pharmacology, therapeutic use)
• Receptors, Bombesin (antagonists & inhibitors)