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

Yunfeng Qin, Tibor Ertl, Ren Zhi Cai, Gabor Halmos, Andrew V Schally

Research output: Contribution to journalArticle

95 Citations (Scopus)

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 μg 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 μM) 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 μM 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 μM) 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 (K(d) = 4.25 ± 0.77 nM) and low capacity (B(max) = 0.268 ± 0.052 pmol/106 cells) and the other with low affinity (K(d) = 321.70 ± 68.46 nM) and high capacity (B(max) = 3.991 ± 0.374 pmol/106 cells). Antagonist RC-3095 inhibited the binding of 125I-Tyr4-bombesin to CFPAC-1 cell membranes in a dose-dependent manner. These observations suggest that bombesin acts as a growth factor and stimulates proliferation of CFPAC-1 human pancreatic cancer through specific receptors for bombesin/GRP present on the cells. RC-3095 appears to inhibit the growth of CFPAC-1 cells by blocking the interaction of bombesin with its receptors. Bombesin/GRP receptor antagonist RC-3095 could be considered for the development of new approaches for treatment of human pancreatic cancers.

Original languageEnglish
Pages (from-to)1035-1041
Number of pages7
JournalCancer Research
Volume54
Issue number4
StatePublished - Feb 15 1994
Externally publishedYes

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Bombesin Receptors
Bombesin
Pancreatic Neoplasms
Growth
Thymidine
Tumor Burden
Nude Mice
Tpi(6)-Leu(13)-psi(CH2NH)-Leu(14)-bombesin (6-14)
In Vitro Techniques
DNA
Neoplasms
Cell Line

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Inhibitory effect of bombesin receptor antagonist RC-3095 on the growth of human pancreatic cancer cells in vivo and in vitro. / Qin, Yunfeng; Ertl, Tibor; Cai, Ren Zhi; Halmos, Gabor; Schally, Andrew V.

In: Cancer Research, Vol. 54, No. 4, 15.02.1994, p. 1035-1041.

Research output: Contribution to journalArticle

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title = "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 μg 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 μM) 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 μM 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 μM) 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 (K(d) = 4.25 ± 0.77 nM) and low capacity (B(max) = 0.268 ± 0.052 pmol/106 cells) and the other with low affinity (K(d) = 321.70 ± 68.46 nM) and high capacity (B(max) = 3.991 ± 0.374 pmol/106 cells). Antagonist RC-3095 inhibited the binding of 125I-Tyr4-bombesin to CFPAC-1 cell membranes in a dose-dependent manner. These observations suggest that bombesin acts as a growth factor and stimulates proliferation of CFPAC-1 human pancreatic cancer through specific receptors for bombesin/GRP present on the cells. RC-3095 appears to inhibit the growth of CFPAC-1 cells by blocking the interaction of bombesin with its receptors. Bombesin/GRP receptor antagonist RC-3095 could be considered for the development of new approaches for treatment of human pancreatic cancers.",
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T1 - Inhibitory effect of bombesin receptor antagonist RC-3095 on the growth of human pancreatic cancer cells in vivo and in vitro

AU - Qin, Yunfeng

AU - Ertl, Tibor

AU - Cai, Ren Zhi

AU - Halmos, Gabor

AU - Schally, Andrew V

PY - 1994/2/15

Y1 - 1994/2/15

N2 - 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 μg 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 μM) 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 μM 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 μM) 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 (K(d) = 4.25 ± 0.77 nM) and low capacity (B(max) = 0.268 ± 0.052 pmol/106 cells) and the other with low affinity (K(d) = 321.70 ± 68.46 nM) and high capacity (B(max) = 3.991 ± 0.374 pmol/106 cells). Antagonist RC-3095 inhibited the binding of 125I-Tyr4-bombesin to CFPAC-1 cell membranes in a dose-dependent manner. These observations suggest that bombesin acts as a growth factor and stimulates proliferation of CFPAC-1 human pancreatic cancer through specific receptors for bombesin/GRP present on the cells. RC-3095 appears to inhibit the growth of CFPAC-1 cells by blocking the interaction of bombesin with its receptors. Bombesin/GRP receptor antagonist RC-3095 could be considered for the development of new approaches for treatment of human pancreatic cancers.

AB - 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 μg 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 μM) 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 μM 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 μM) 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 (K(d) = 4.25 ± 0.77 nM) and low capacity (B(max) = 0.268 ± 0.052 pmol/106 cells) and the other with low affinity (K(d) = 321.70 ± 68.46 nM) and high capacity (B(max) = 3.991 ± 0.374 pmol/106 cells). Antagonist RC-3095 inhibited the binding of 125I-Tyr4-bombesin to CFPAC-1 cell membranes in a dose-dependent manner. These observations suggest that bombesin acts as a growth factor and stimulates proliferation of CFPAC-1 human pancreatic cancer through specific receptors for bombesin/GRP present on the cells. RC-3095 appears to inhibit the growth of CFPAC-1 cells by blocking the interaction of bombesin with its receptors. Bombesin/GRP receptor antagonist RC-3095 could be considered for the development of new approaches for treatment of human pancreatic cancers.

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