Abstract
We investigated the effects of our synthetic bombesin/gastrin-releasing peptide (GRP) antagonists and somatostatin analogue RC-160 on the growth of human small-cell lung carcinoma (SCLC) and non-small-cell lung carcinoma (non-SCLC) lines in nude mice. Athymic nude mice bearing xenografts of the SCLC NCl-H69 line or non-SCLC NCl-H157 line were treated for 5 and 4 weeks, respectively, with somatostatin analogue RC-160 or various bombesin/GRP antagonists. RC-160, administered s.c. peritumorally at a dose of 100 micrograms per animal per day, inhibited the growth of H69 SCLC xenografts as shown by more than 70% reduction in tumour volumes and weights, as compared with the control group. Bombesin/GRP antagonists, RC-3440, RC-3095 and RC-3950-II, given s.c. peritumorally at a dose of 20 micrograms per animal per day, also inhibited the growth of H69 SCLC tumours. RC-3950-II had the greatest inhibitory effect and decreased tumour volume and weights by more than 80%. The growth of H-157 non-SCLC xenografts was significantly reduced by treatment with RC-160, but not with bombesin/GRP antagonist RC-3095. In mice bearing either tumour model, administration of RC-160 significantly decreased serum growth hormone and gastrin levels. Specific high-affinity receptors for bombesin and somatostatin were found on membranes of SCLC H69 tumours, but not on non-SCLC H157 tumours. Receptor analyses demonstrated high-affinity binding sites for epidermal growth factor (EGF) and insulin-like growth factor I (IGF-I) on the membranes of H69 and H157 tumours. EGF receptors were down-regulated on H69 tumours after treatment with RC-160 and bombesin/GRP antagonists. The concentration of binding sites for EGF and IGF-I on the H157 tumours was decreased after treatment with RC-160, but bombesin/GRP antagonist RC-3095 had no effect. These results demonstrate that bombesin/GRP antagonists inhibit the growth of H-69 SCLC, but not of H-157 non-SCLC xenografts in nude mice, whereas somatostatin analogue RC-160 is effective in both tumour models. This raises the possibility that these peptide analogues could be used selectively in the treatment of various subclasses of lung cancer.
Highlights
We have evaluated the effects of somatostatin analogue RC-160 and three bombesin/gastrin-releasing peptide (GRP) antagonists, including RC-3095, on the growth of xenografts of the human small-cell lung carcinoma (SCLC) cell line NCI-H69 and the non-SCLC cell line NC1H 157 in athymic nude mice
In view of the presence of oestrogen and progesterone receptors in human lung cancer (Cagle et al, 1990), we examined whether castration or administration of the luteinising hormone-releasing hormone (LH-RH) antagonist SB-75 (Cetrorelix) can affect the growth of non-SCLC H 157 tumours
The present study demonstrates a significant inhibitory effect of bombesin/GRP antagonists RC-3095, RC-3440 and RC-3950-II on the growth of the SCLC H69 cell line xenografted into nude mice
Summary
Val-Cys-Trp-NH2) originally synthesised by us (Cai et al, 1986) was made by classical synthesis and supplied by Debiopharm, Lausanne, Switzerland). GRP(14-27)) and RC-3009 (D-Trp, D-Phe, Leu27GRP(14-27)) were synthesised in our laboratory (Radulovic et al, 1991a; Cai et al, 1992, 1994). NCI-Navy Medical Oncology Branch, Bethesda, MD, USA These cell lines were cultured in RPMI-1640 medium supplemented with 4 mM L-glutamine, 50 units ml-I penicilln G sodium, SOigml-' streptomycin sulphate, 0.125pgml-'. Radioiodination of other peptides and receptor binding of EGF, IGF-I, somatostatin and bombesin/GRP were performed as previously described (Srkalovic et al, 1989; Szepeshazi et al, 1992). In order to determine the specificity of the binding sites for radiolabelled EGF, IGF-I, somatostatin and bombesin to lung cancer membranes, various structuraly related and unrelated peptides were tested for their ability to inhibit the binding of the tracers
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