Reduction in receptors for bombesin and epidermal growth factor in xenografts of human small-cell lung cancer after treatment with bombesin antagonist RC-3095

Gabor Halmos, Andrew V Schally

Research output: Contribution to journalArticle

52 Citations (Scopus)

Abstract

Antagonists of bombesin/gastrin-releasing peptide (BN/GRP) have been developed to inhibit the stimulatory effects of BN/GRP on the mitogenesis of tumor cells such as human small-cell lung carcinoma (SCLC). The mode of action of these antagonists is not completely understood. In this study, we evaluated the effect of BN/GRP antagonist RC-3095 on receptors for BN/GRP and epidermal growth factor (EGF) in II-128 human SCLC line xenografted into nude mice. Treatment with RC-3095, administered s.c. at a dose of 20 μg/day per animal for 4 weeks caused a 70% reduction in tumor volume and weight. Membrane receptors for BN/GRP and EGF were characterized in untreated and treated animals. In the control group, [125I-Tyr4]BN was bound to a single class of specific, high affinity binding sites with a dissociation constant (K(d)) = 6.55 ± 0.93 nM and maximal binding capacity (B(max)) = 512.8 ± 34.8 fmol/mg membrane protein. Therapy with RC-3095 decreased the concentration of BN/GRP receptors on H-128 SCLC tumor membranes. Specific, high affinity binding sites for EGF with K(d) = 1.78 ± 0.26 nM and B(max) = 216.8 ± 19.6 fmol/mg membrane protein were also found on the untreated H- 128 SCLC tumors. Treatment with RC-3095 significantly decreased B(max) of receptors for EGF. Our results indicate that the suppression of growth of H- 128 SCLC by BN antagonist RC-3095 is accompanied by a decrease in the number of receptors for both BN/GRP and EGF. These observations are in agreement with the results obtained in other experimental cancers. The findings on antagonist RC-3095 reinforce the view that both BN/GRP and EGF receptors participate in a cascade of events involved in the growth of SCLC and other cancers. Although the complete mechanisms of action of antagonist RC-3095 remain to be elucidated, the antitumor effect could be the result of the fall in the EGF receptor number, which might lead to a decrease in EGF receptor autophosphorylation.

Original languageEnglish
Pages (from-to)956-960
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume94
Issue number3
DOIs
StatePublished - Feb 4 1997
Externally publishedYes

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Bombesin
Small Cell Lung Carcinoma
Gastrin-Releasing Peptide
Heterografts
Bombesin Receptors
Epidermal Growth Factor
Neoplasms
Tumor Burden
Epidermal Growth Factor Receptor
Membrane Proteins
Binding Sites
Membranes
Growth
ErbB Receptors
Tpi(6)-Leu(13)-psi(CH2NH)-Leu(14)-bombesin (6-14)
Nude Mice
Control Groups

Keywords

  • down-regulation of binding sites
  • lung carcinoma
  • tumor regression

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

@article{ac5f62a9e6184867a9a4b9832aae1aa0,
title = "Reduction in receptors for bombesin and epidermal growth factor in xenografts of human small-cell lung cancer after treatment with bombesin antagonist RC-3095",
abstract = "Antagonists of bombesin/gastrin-releasing peptide (BN/GRP) have been developed to inhibit the stimulatory effects of BN/GRP on the mitogenesis of tumor cells such as human small-cell lung carcinoma (SCLC). The mode of action of these antagonists is not completely understood. In this study, we evaluated the effect of BN/GRP antagonist RC-3095 on receptors for BN/GRP and epidermal growth factor (EGF) in II-128 human SCLC line xenografted into nude mice. Treatment with RC-3095, administered s.c. at a dose of 20 μg/day per animal for 4 weeks caused a 70{\%} reduction in tumor volume and weight. Membrane receptors for BN/GRP and EGF were characterized in untreated and treated animals. In the control group, [125I-Tyr4]BN was bound to a single class of specific, high affinity binding sites with a dissociation constant (K(d)) = 6.55 ± 0.93 nM and maximal binding capacity (B(max)) = 512.8 ± 34.8 fmol/mg membrane protein. Therapy with RC-3095 decreased the concentration of BN/GRP receptors on H-128 SCLC tumor membranes. Specific, high affinity binding sites for EGF with K(d) = 1.78 ± 0.26 nM and B(max) = 216.8 ± 19.6 fmol/mg membrane protein were also found on the untreated H- 128 SCLC tumors. Treatment with RC-3095 significantly decreased B(max) of receptors for EGF. Our results indicate that the suppression of growth of H- 128 SCLC by BN antagonist RC-3095 is accompanied by a decrease in the number of receptors for both BN/GRP and EGF. These observations are in agreement with the results obtained in other experimental cancers. The findings on antagonist RC-3095 reinforce the view that both BN/GRP and EGF receptors participate in a cascade of events involved in the growth of SCLC and other cancers. Although the complete mechanisms of action of antagonist RC-3095 remain to be elucidated, the antitumor effect could be the result of the fall in the EGF receptor number, which might lead to a decrease in EGF receptor autophosphorylation.",
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T1 - Reduction in receptors for bombesin and epidermal growth factor in xenografts of human small-cell lung cancer after treatment with bombesin antagonist RC-3095

AU - Halmos, Gabor

AU - Schally, Andrew V

PY - 1997/2/4

Y1 - 1997/2/4

N2 - Antagonists of bombesin/gastrin-releasing peptide (BN/GRP) have been developed to inhibit the stimulatory effects of BN/GRP on the mitogenesis of tumor cells such as human small-cell lung carcinoma (SCLC). The mode of action of these antagonists is not completely understood. In this study, we evaluated the effect of BN/GRP antagonist RC-3095 on receptors for BN/GRP and epidermal growth factor (EGF) in II-128 human SCLC line xenografted into nude mice. Treatment with RC-3095, administered s.c. at a dose of 20 μg/day per animal for 4 weeks caused a 70% reduction in tumor volume and weight. Membrane receptors for BN/GRP and EGF were characterized in untreated and treated animals. In the control group, [125I-Tyr4]BN was bound to a single class of specific, high affinity binding sites with a dissociation constant (K(d)) = 6.55 ± 0.93 nM and maximal binding capacity (B(max)) = 512.8 ± 34.8 fmol/mg membrane protein. Therapy with RC-3095 decreased the concentration of BN/GRP receptors on H-128 SCLC tumor membranes. Specific, high affinity binding sites for EGF with K(d) = 1.78 ± 0.26 nM and B(max) = 216.8 ± 19.6 fmol/mg membrane protein were also found on the untreated H- 128 SCLC tumors. Treatment with RC-3095 significantly decreased B(max) of receptors for EGF. Our results indicate that the suppression of growth of H- 128 SCLC by BN antagonist RC-3095 is accompanied by a decrease in the number of receptors for both BN/GRP and EGF. These observations are in agreement with the results obtained in other experimental cancers. The findings on antagonist RC-3095 reinforce the view that both BN/GRP and EGF receptors participate in a cascade of events involved in the growth of SCLC and other cancers. Although the complete mechanisms of action of antagonist RC-3095 remain to be elucidated, the antitumor effect could be the result of the fall in the EGF receptor number, which might lead to a decrease in EGF receptor autophosphorylation.

AB - Antagonists of bombesin/gastrin-releasing peptide (BN/GRP) have been developed to inhibit the stimulatory effects of BN/GRP on the mitogenesis of tumor cells such as human small-cell lung carcinoma (SCLC). The mode of action of these antagonists is not completely understood. In this study, we evaluated the effect of BN/GRP antagonist RC-3095 on receptors for BN/GRP and epidermal growth factor (EGF) in II-128 human SCLC line xenografted into nude mice. Treatment with RC-3095, administered s.c. at a dose of 20 μg/day per animal for 4 weeks caused a 70% reduction in tumor volume and weight. Membrane receptors for BN/GRP and EGF were characterized in untreated and treated animals. In the control group, [125I-Tyr4]BN was bound to a single class of specific, high affinity binding sites with a dissociation constant (K(d)) = 6.55 ± 0.93 nM and maximal binding capacity (B(max)) = 512.8 ± 34.8 fmol/mg membrane protein. Therapy with RC-3095 decreased the concentration of BN/GRP receptors on H-128 SCLC tumor membranes. Specific, high affinity binding sites for EGF with K(d) = 1.78 ± 0.26 nM and B(max) = 216.8 ± 19.6 fmol/mg membrane protein were also found on the untreated H- 128 SCLC tumors. Treatment with RC-3095 significantly decreased B(max) of receptors for EGF. Our results indicate that the suppression of growth of H- 128 SCLC by BN antagonist RC-3095 is accompanied by a decrease in the number of receptors for both BN/GRP and EGF. These observations are in agreement with the results obtained in other experimental cancers. The findings on antagonist RC-3095 reinforce the view that both BN/GRP and EGF receptors participate in a cascade of events involved in the growth of SCLC and other cancers. Although the complete mechanisms of action of antagonist RC-3095 remain to be elucidated, the antitumor effect could be the result of the fall in the EGF receptor number, which might lead to a decrease in EGF receptor autophosphorylation.

KW - down-regulation of binding sites

KW - lung carcinoma

KW - tumor regression

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