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

The National Academy of Sciences of the USA
Publication Date
  • Biological Sciences
  • Biology


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 H-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 (Kd) = 6.55 ± 0.93 nM and maximal binding capacity (Bmax) = 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 Kd = 1.78 ± 0.26 nM and Bmax = 216.8 ± 19.6 fmol/mg membrane protein were also found on the untreated H-128 SCLC tumors. Treatment with RC-3095 significantly decreased Bmax 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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