Biomedical subjects

G Halmos

Publications and source records attributed to G Halmos.

At least 91 records · Page 5Linked to original sources

PubMed1994

Inhibitory effects of analogs of luteinizing hormone-releasing hormone on the growth of the androgen-independent Dunning R-3327-AT-1 rat prostate cancer.

The effects of treatment with the luteinizing hormone-releasing hormone (LH-RH) antagonist SB-75 and agonist [D-Trp6] LH-RH were investigated in Copenhagen rats bearing the anaplastic, androgen-independent Dunning R-3327-AT-1 prostatic adenocarcinoma implanted orthotopically into the ventral lobes of prostate glands. The LH-RH antagonist SB-75 and the LH-RH agonist [D-Trp6] LH-RH were administered from osmotic minipumps and the survival time of animals bearing this cancer was evaluated. Treatment with SB-75 and [D-Trp6] LH-RH significantly prolonged the mean survival time of rats by 4.1 days and 4.5 days, respectively. In cell cultures, proliferation of the AT-1 cell line was strongly inhibited by the antagonist SB-75, but only a moderate suppression of tumor cell growth in vitro was observed with the agonist [D-Trp6] LH-RH. Receptor assays on Dunning R-3327-AT-1 tumor membranes showed high-affinity binding sites for LH-RH, epidermal growth factor (EGF) and insulin-like growth factor-1 (IGF-1). Receptors for EGF were significantly down-regulated by treatment with SB-75. Therapy with SB-75 also decreased EGF levels in tumor tissue to non-detectable levels, as measured by specific RIA. Our results demonstrate that the LH-RH antagonist SB-75 and agonist [D-Trp6] LH-RH inhibit the growth of androgen-independent Dunning R-3327-AT-1 prostatic cancer in vivo and in vitro.

Androgens↗

PubMed1994

Characterization of bombesin/gastrin-releasing peptide receptors in membranes of MKN45 human gastric cancer.

Binding of the radiolabeled bombesin analog [125I-Tyr4]bombesin to crude cell membranes of MKN45 human gastric cancer grown in nude mice was investigated in vitro. Scatchard analyses of multipoint binding data, performed by complete displacement method demonstrated the presence of two classes of [Tyr4]bombesin binding sites. The high-affinity binding sites had a mean dissociation constant (Kd1) of 2.75 nM with a mean maximal binding capacity (Bmax1) of 492 fmol/mg membrane protein, while the low-affinity binding sites showed a mean dissociation constant (Kd2) of 0.41 microM with a mean maximal binding capacity (Bmax2) of 41.4 pmol/mg membrane protein. Binding of [125(1)-Tyr4]bombesin was specific, reversible and linearly related to the protein concentration of tumor membrane. In displacement studies, the binding of radiolabeled [Tyr4]bombesin was inhibited in a dose-dependent manner by gastrin releasing peptide (GRP)(14-27) and two synthetic antagonists of bombesin/GRP, RC-3095 and RC-3950-II. Both antagonists exhibited high affinity in nearly the same concentration range as GRP(14-27). The presence of receptors for bombesin/GRP on human gastric cancer membranes suggests that bombesin-like peptides may play a role in growth of gastric cancer.

Adenocarcinoma↗

PubMed1994

Inhibition of growth of OV-1063 human epithelial ovarian cancer xenografts in nude mice by treatment with luteinizing hormone-releasing hormone antagonist SB-75.

Female athymic nude mice bearing xenografts of OV-1063 human epithelial ovarian cancer cell line were treated with potent luteinizing hormone (LH)-releasing hormone (LH-RH) antagonist SB-75 (Cetrorelix; [Ac-D-Nal(2)1, D-Phe(4 CI)2, D-Pal(3)3, D-Cit6, D-Ala10]LH-RH in which Ac-D-Nal(2) = N-acetyl-3-(2-naphthyl)-D-alanine, D-Phe(4CI) = 4-chloro-D-phenylalanine, D-Pal(3) = 3-(3-pyridyl)-D-alanine, and D-Cit = D-Citrulline) or with the agonist [D-Trp6]LH-RH. In the first experiment, SB-75 and [D-Trp6]LH-RH were administered in the form of microcapsules releasing 60 and 25 micrograms/day, respectively. In the second study, the analogs were given by daily s.c. injections in doses of 100 micrograms/day. In both experiments, tumor growth, as measured by reduction in tumor volume, percentage change in tumor volume, tumor burden, and increase in tumor doubling time, was significantly inhibited by treatment with SB-75 but not with [D-Trp6]LH-RH. Uterine and ovarian weights were reduced and serum LH levels decreased by administration of either analog. Chronic treatment with SB-75 greatly reduced the concentration of receptors for epidermal growth factor and insulin-like growth factor I in tumor cell membranes, a phenomenon that might be related to tumor growth inhibition. It is possible that the antitumoral effects of SB-75 on OV-1063 ovarian cancers are exerted not only through the suppression of the pituitary-gonadal axis, but also directly. In view of its strong inhibitory effect on the growth of OV-1063 ovarian cancers in vivo, the potent LH-RH antagonist SB-75 might be considered for possible hormonal therapy of advanced epithelial ovarian carcinoma.

Animals↗

PubMed1994

Inhibition of growth of MKN45 human gastric-carcinoma xenografts in nude mice by treatment with bombesin/gastrin-releasing-peptide antagonist (RC-3095) and somatostatin analogue RC-160.

Nude mice bearing xenografts of the gastrin-responsive human gastric carcinoma MKN45 cell line were treated for 4 to 5 weeks with bombesin/gastrin-releasing-peptide(GRP) antagonist (RC-3095), somatostatin analogues RC-160 and SMS 201-995, or the combination of RC-3095 and RC-160. Tumor volumes and weights were reduced significantly to a similar extent by RC-160 and SMS 201-995, administered by daily s.c. injections at a dose of 100 micrograms/day. Bombesin/GRP antagonist RC-3095, given s.c. at a dose of 20 micrograms/day, had the greatest inhibitory effect on tumor growth. The combination of RC-3095 with RC-160 did not further potentiate the suppression of tumor growth. Histologically, the number of mitotic cels decreased significantly in the groups treated with RC-160 or the combination of RC-3095 with RC-160. Serum gastrin levels were significantly diminished in all treated groups. Therapy with RC-160 or the combination also significantly decreased levels of serum growth hormone. Receptor assays on tumor membranes showed that bombesin was bound to 2 classes of receptor sites, one with high affinity and low capacity, the other with low affinity and high capacity. Binding sites for epidermal growth factor (EGF) were down-regulated in tumor cells after treatment with RC-3095, RC-160 or the combination of RC-3095 with RC-160. In studies in vitro, both RC-160 and RC-3095 significantly inhibited the proliferation of MKN45 cells in culture as measured by cell number. These data demonstrate, for the first time, that the growth of human gastric cancer in nude mice can be inhibited not only by somatostatin analogues, but also by administration of modern bombesin/GRP antagonists, such as RC-3095.

Adenocarcinoma↗

PubMed1994

Inhibitory effect of bombesin/gastrin-releasing peptide antagonist RC-3095 and luteinizing hormone-releasing hormone antagonist SB-75 on the growth of MCF-7 MIII human breast cancer xenografts in athymic nude mice.

BACKGROUND: The results of several clinical trials using various luteinizing hormone-releasing hormone agonists for treatment of advanced breast cancer are encouraging. However, only about 30% of breast cancers are estrogen-dependent and can be treated by hormonal manipulation. New therapeutic approaches combining estrogen ablation therapy with other compounds must be explored. Various studies suggest that bombesin or gastrin-releasing peptide acts as an autocrine growth factor and may play a role in the initiation and progression of some cancers, including that of the breast. METHODS: Female athymic nude mice bearing xenografts of the MCF-7 MIII human breast cancer cell line were treated for 7 weeks with bombesin/gastrin-releasing peptide antagonist (D-Tpi6, Leu13 psi[CH2NH]-Leu14) bombesin(6-14) (RC-3095) injected subcutaneously daily at a dose of 20 micrograms and luteinizing hormone-releasing hormone antagonist SB-75 (Cetrorelix) administered biweekly in the form of microgranules releasing 45 micrograms/day. RESULTS: After 2 weeks of treatment, a significant inhibition of tumor volume was observed in the groups treated with RC-3095 alone or in combination with SB-75 but not in those treated with SB-75 as a single agent. After 7 weeks, tumor growth as measured by tumor volume and percentage changes in tumor volume and tumor weight was greatly inhibited in all of the treated groups. Uterine and ovarian weights were reduced and serum luteinizing hormone levels decreased by administration of SB-75 alone or in combination with RC-3095. Histologically, a significant decrease in argyrophilic nucleolar organizer region count in tumor cell nuclei was observed in all of the treated groups, indicating a lower proliferation of these cells. High-affinity binding sites for bombesin were detected in cultured MCF-7 MIII cells. Chronic treatment with RC-3095 caused a significant down-regulation of epidermal growth factor receptors in tumor cell membranes, which might be related to tumor inhibition. In studies in vitro, SB-75 inhibited proliferation of MCF-7 cells in culture but not proliferation of MCF-7 MIII cells. CONCLUSIONS: Because previously we demonstrated that RC-3095 inhibits the proliferation of MCF-7 MIII cells in vitro, it appears that the major antitumoral effect of RC-3095 on the MCF-7 MIII cancer line is direct, whereas that of SB-75 is indirect, and that it is mediated by suppression of the pituitary-gonadal axis. In view of its immediate and powerful inhibitory effect on MCF-7 MIII tumors, bombesin/gastrin-releasing peptide antagonist RC-3095 might be considered as a possible new agent for the treatment of breast cancer.

Animals↗

PubMed1994

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

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)

Animals↗

PubMed1994

Inhibitory effects of somatostatin analogue RC-160 and bombesin/gastrin-releasing peptide antagonist RC-3095 on the growth of the androgen-independent Dunning R-3327-AT-1 rat prostate cancer.

The effects of somatostatin analogue RC-160 and bombesin/gastrin releasing-peptide (GRP) antagonist RC-3095 were evaluated in Copenhagen rats bearing the anaplastic, androgen-independent Dunning R3327-AT-1 prostatic adenocarcinoma. In the first experiment, RC-160 was given in the form of microcapsules releasing 60 micrograms/day/rat. RC-3095 was administered from implanted Alzet osmotic minipumps liberating 100 micrograms/day/rat. After 32 days, tumor volumes and weights were significantly reduced by RC-160 as compared with the control group. Tumor doubling time in rats treated with RC-160 was significantly longer than in controls. Bombesin/GRP antagonist RC-3095 also significantly reduced tumor volume after 7 days of treatment, but after 18 days the inhibition in tumor volume was no longer significant. Tumor growth was not suppressed by castration. In the second experiment, 3-mm3 fragments of Dunning R-3327-AT-1 tumor were implanted orthotopically into the prostates of Copenhagen rats in order to evaluate the survival time of animals bearing this cancer during treatment with RC-160 released from Alzet osmotic minipumps at a dose of 100 micrograms/day/rat. Treatment with RC-160 significantly (P < 0.05) prolonged the mean survival time of rats by 5.3 days as compared to control animals. In both experiments, therapy with RC-160 significantly decreased serum growth hormone or insulin-like growth factor I levels. In the first experiment, receptor assays on R-3327-AT-1 tumor membranes showed high affinity binding sites for somatostatin, bombesin, and epidermal growth factor. At the end of the treatment, receptors for epidermal growth factor were significantly down-regulated by treatment with RC-160 but not with RC-3095. The binding capacity of bombesin receptors was reduced to nondetectable levels after the treatment with RC-3095. In cell cultures, high affinity binding sites for bombesin/GRP were found on intact Dunning R-3327-AT-1 cells, but receptors for somatostatin could not be detected. Proliferation of the AT-1 cell line was significantly inhibited by antagonist RC-3095. However, no effect on tumor cell growth in vitro was observed with analogue RC-160. Our results demonstrate that somatostatin analogue RC-160 and bombesin/GRP antagonist RC-3095 can inhibit the growth of the androgen-independent Dunning R-3327-AT-1 prostatic cancer in rats, although the remission produced by RC-3095 may be of short duration due to a down-regulation of bombesin receptors. Our work suggests the merit of further investigation as to whether these analogues can induce a possible delay in relapse and prolong survival in prostate cancer.

Amino Acid Sequence↗

PubMed1994

Bombesin antagonists inhibit in vitro and in vivo growth of human gastric cancer and binding of bombesin to its receptors.

We investigated the effect of bombesin/gastrin-releasing peptide (GRP) antagonist RC-3095 and other analogs on the growth of Hs746T human gastric cancer cells implanted in nude mice or cultured in vitro and on the binding of bombesin to its receptors. Nude mice bearing xenografts of the Hs746T cell line received s.c. injections of RC-3095 (10 micrograms twice daily) or the vehicle (control) for 21 days. Administration of antagonist RC-3095 inhibited the growth of Hs746T tumors. Treatment with RC-3095 produced a significant decrease in tumor volume, prolonged the tumor volume doubling time from 3.6 days to 5.1 days, and decreased the tumor growth rate by 76.9%. The tumor growth delay time in mice treated with RC-3095 was 2.8 days. Treatment with RC-3095 also decreased the final tumor weight by 88.3% and reduced DNA and protein contents in tumors by 91.5% and 89.5%, respectively, as compared to controls. The presence of specific receptors for bombesin/GRP was investigated on the crude membranes of implanted tumors of Hs746T cells. Saturation binding assays showed that the binding of [125I-Tyr4]bombesin to the membranes was saturable and reversible. Scatchard analysis indicated the presence of a single class of binding sites with a high affinity (Kd = 0.24 +/- 0.07 nM) and a low binding capacity (Bmax = 57.0 +/- 0.9 fmol/mg protein). In displacement studies, the binding of [125I-Tyr4]bombesin was inhibited in a dose-dependent manner by unlabelled bombesin(1-14), [Tyr4]-bombesin and GRP (14-27), but not by structurally unrelated peptides. Synthetic bombesin/GRP antagonists RC-3095, RC-3110, and RC-3950-II were all able to inhibit effectively the binding of [125I-Tyr4]bombesin to the membranes of Hs746T cells. RC-3950-II showed a higher binding affinity for bombesin receptors than RC-3095 or RC-3110. Addition of the non-hydrolyzable guanine-nucleotide analog GTP [S] to the binding buffer caused a significant reduction in the amount of [125I-Tyr4]bombesin bound to the cells, indicating that the bombesin receptor is coupled to a G-protein. In cell cultures, bombesin significantly stimulated the growth of Hs746T cells in vitro as shown by an increase in the uptake of [3H]thymidine. Bombesin antagonist RC-3095 could effectively inhibit the bombesin-stimulated growth of Hs746T cells in cultures. These observations suggest that bombesin/GRP may act as growth factors through specific receptors present on the membranes of Hs746T cells. Bombesin/GRP antagonists appear to nullify the effects of bombesin/GRP and may be useful for the treatment of gastric cancers.

Animals↗

PubMed1994

LH-RH analogue carrying a cytotoxic radical is internalized by rat pituitary cells in vitro.

The binding and internalization of a cytotoxic analogue of luteinizing hormone-releasing hormone (LH-RH), T-98 (agonist [D-Lys6]LH-RH linked to glutaryl-2-(hydroxymethyl)anthraquinone), by rat anterior pituitary cells was investigated. Analogue T-98 was bound to pituitary membrane binding sites for LH-RH with a high affinity (Kd = 1.2 nM) and was 17 times more potent in releasing luteinizing hormone (LH) from superfused rat pituitary cells than LH-RH. The labeling of this cytotoxic LH-RH analogue was carried out both with radioactive (125I) and nonradioactive iodine. Monoiodination of the Tyr5 residue of T-98 did not significantly affect its binding affinity but greatly decreased its LH-releasing activity to about 3% of the original value. Di-iodination in the same position lowered binding affinity twenty-threefold and further diminished LH-releasing potency. [125I]T-98 was found to bind very strongly to polystyrene, which precluded the use of regular tissue culture plasticware in our experiments. In pituitary cells cultured in glass vials, binding and internalization of [125I]T-98 were observed, which were time and temperature dependent, and which could be inhibited by excess unlabeled analogue. No enzymatic degradation of labeled T-98 was detected in the culture medium during the incubation. Our results indicate that T-98 is internalized by pituitary gonadotropes through receptor-mediated endocytosis. Because this new class of compounds was designed as anticancer drugs, our findings also suggest that this cytotoxic LH-RH agonist may also be internalized by LH-RH receptors present in breast, prostate, ovarian, and other tumors.

Animals↗

PubMed1994

Inhibitory effect of bombesin/gastrin-releasing peptide (GRP) antagonists RC-3950-II and RC-3095 on MCF-7 MIII human breast cancer xenografts in nude mice.

Bombesin/gastrin-releasing peptide (GRP) may be involved in the growth of human breast cancers. Nude mice bearing xenografts of MCF-7 MIII human breast cancer cell line were treated for 7 weeks with bombesin/GRP antagonists RC-3950-II and RC-3095. RC-3950-II, administered sc twice daily at a dose of 10 micrograms, produced significant inhibitory effects on tumor growth after 2 weeks of administration. RC-3095 acetate (D 22213), injected sc twice daily at the same dose of 10 micrograms, suppressed tumor growth after 4 weeks. Both RC-3950-II and RC-3095 significantly decreased the final tumor volume and tumor weights. RC-3950-II appeared to be somewhat more efficacious than RC-3095 in inhibiting the growth of MCF-7 MIII breast cancers. Chronic treatment with either bombesin/GRP antagonist caused down-regulation of receptors for epidermal growth factor (EGF) in tumor cell membranes, which might be related to inhibition of tumor growth. These findings suggest that bombesin/GRP antagonists should be considered for a new endocrine therapy of breast cancer.

Animals↗

PubMed1994

Somatostatin receptor expression in lung cancer.

Experimental evidence suggests that somatostatin analogues may have a role to play in the management of lung tumours. We evaluated membrane preparations of nine small cell lung cancer (SCLC) cell lines and of tumour samples from 3 patients with non-small cell lung cancer (NSCLC), 1 patient with an atypical carcinoid and another with a bronchial carcinoid for the presence of specific binding sites for RC-160, a potent growth inhibitory octapeptide analogue of somatostatin. Specific binding was noted on six of nine SCLC lines. Radio-receptor assay on the cell line NCI H 69 showed evidence of two specific binding sites for RC-160, one with high affinity and the other with low affinity. Binding sites were also found on all five tumour samples. Scatchard analysis indicated the presence of a single class of receptors with high affinity in each case. Histological assessment of the resected specimens before binding assay showed them to be comprised of tumour cells and necrotic tissue, stroma and/or inflammatory cells. Therefore, the specific binding of RC-160 may be to tissues other than the tumour cells. In 3 patients, from whom the tumour samples were obtained, radiolabelled somatostatin analogue scintigraphy using [111In] pentetreotide was performed prior to surgery. In all cases, the radiolabel localised the disease. This study demonstrates the presence of specific binding sites for RC-160 in SCLC. Furthermore, the detection of specific binding in vitro and in vivo in NSCLC and intrapulmonary carcinoids demonstrates that these tumours contain cells which express specific binding sites for somatostatin. These results suggest that RC-160 may have a role to play as a therapeutic agent in lung cancer.

Carcinoma, Non-Small-Cell Lung↗

PubMed1994

Effects of somatostatin analogue RC-160 and bombesin/gastrin-releasing peptide antagonists on the growth of human small-cell and non-small-cell lung carcinomas in nude mice.

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.

Amino Acid Sequence↗

PubMed1994

Inhibitory effects of antagonists of bombesin/gastrin releasing peptide (GRP) and somatostatin analog (RC-160) on growth of HT-29 human colon cancers in nude mice.

Nude mice bearing xenografts of HT-29 human colon cancer cell line were treated for 4 weeks with somatostatin analog (RC-160), bombesin/gastrin releasing peptide (GRP) antagonists (RC-3095 and RC-3440). In three separate experiments somatostatin analog RC-160 (50 micrograms/day) released from microgranules significantly reduced tumor growth. Bombesin/GRP antagonists, RC-3095 and RC-3440 injected subcutaneously (s.c.) twice daily at a dose of 10 micrograms had the greatest and consistently significant inhibitory effect on tumor growth. RC-3095 given once daily s.c. at a dose of 20 micrograms was less effective. RC-3095 also inhibited metastatic tumor growth after intrasplenic injection of HT-29 cells in nude mice. Specific binding sites of somatostatin, bombesin and epidermal growth factor (EGF) were detected on intact HT-29 cells or on the membranes from HT-29 tumor xenografts. The inhibitory effects of bombesin antagonists on tumor growth were consistently linked with a significant down-regulation of EGF receptors. Bombesin/GRP antagonists and somatostatin analogs could be considered for the development of new hormonal therapies for colon cancer.

Adenocarcinoma↗

PubMed1994

The concentration of LH-RH receptors in the nuclei of pancreatic cancer cells. Effect of (D-Trp6)LH-RH on tumor-bearing Syrian golden hamsters.

LH-RH analogs cause some inhibition of growth of pancreatic cancers. Syrian golden hamsters bearing chemically induced pancreatic cancers were treated with [D-Trp6]LH-RH for 3 d before sacrifice. LH-RH receptors were localized by electron-microscopic immunohistochemistry in the tumor cells of both treated and untreated hamsters. [D-Trp6]LH-RH treatment resulted in a marked increase in the concentration of LH-RH receptors in the nuclei. The dissociation constants (Kd) and the maximal binding capacity of the LH-RH receptors (Bmax), measured by radioreceptor assay, were higher in the nuclei of the pancreatic tumor cells of hamsters treated with [D-Trp6]LH-RH than in the untreated controls. Pancreatic cells of tumor-free hamsters did not show immunostaining for LH-RH receptors. A possible correlation between the increase in the concentration of the LH-RH receptors in the nuclei and the tumor growth-inhibiting activity of [D-Trp6]LH-RH is suggested.

Animals↗

PubMed1993

Effect of somatostatin analog RC-160 and bombesin/gastrin releasing peptide antagonist RC-3095 on growth of PC-3 human prostate-cancer xenografts in nude mice.

Nude mice bearing xenografts of the androgen-independent human prostate-cancer cell line PC-3 were treated for 4 weeks with somatostatin analog RC-160, bombesin/gastrin-releasing peptide (GRP) antagonist (RC-3095), or the combination of both peptides. In the first experiment, treatment was started when the tumors measured approximately 10 mm3. Tumor volumes and weights were reduced by about 40% by RC-160 or RC-3095 administered by s.c. injections at doses of 100 micrograms/day/animal and 20 micrograms/day/animal respectively. The combination of RC-3095 with RC-160 did not further potentiate suppression of tumor growth, but histologically the ratio of apoptotic and mitotic indices was significantly higher in the groups treated with the combination than in the other groups. Serum gastrin levels were significantly reduced in all treated groups. Therapy with RC-160 or the combination also significantly decreased serum growth-hormone levels. Specific high-affinity binding sites for bombesin, somatostatin and epidermal growth factor (EGF) were found on the tumor membranes. Receptors for EGF were significantly down-regulated by treatment with RC-3095, RC-160 and a combination of both analogs. Tumors from mice treated with RC-160 showed a significant increase in maximal binding capacity for somatostatin as compared with control tumors, demonstrating the absence of down-regulation. In the second experiment, treatment was started when the tumors were well developed and measured approximately 90 mm3. No significant reduction in volume, weight and growth rate of tumors was found in the groups treated with RC-160 or RC-3095. Our results suggest that somatostatin analog RC-160 and bombesin/GRP antagonist RC-3095 can inhibit the growth of androgen-independent prostate cancer when the therapy is started at an early stage of tumor development.

Animals↗

PubMed1993

Antagonists of bombesin/gastrin-releasing peptides as adjuncts to agonists of luteinizing hormone-releasing hormone in the treatment of experimental prostate cancer.

BACKGROUND: Palliative methods for treatment of advanced prostatic carcinoma, including those based on luteinizing hormone-releasing hormone (LH-RH) agonists, cannot prevent the ultimate growth of hormone-independent cells, and the duration of disease remission in patients with prostate cancer is limited. New therapeutic approaches combining androgen ablation therapy with other compounds must be explored. Various studies suggest that bombesin or gastrin-releasing peptide (GRP) act as autocrine growth factors and may play a role in the initiation and progression of some cancers, including those of the prostate. METHODS: The effects of treatment with bombesin/gastrin-releasing peptide (GRP) receptor antagonist [D-Tpi6, Leu13 psi(CH2NH)Leu14]BN(6-14)(RC-3095), an agonist of LH-RH [D-Lys6]-LH-RH and their combination were investigated in the androgen-dependent Dunning R-3327H rat prostate cancer model. Both analogs were administered by continuous subcutaneous infusion from osmotic minipumps for 7 weeks. RESULTS: Tumor volumes and weights were significantly reduced by treatment with RC-3095, compared with those of controls. In rats that received [D-Lys6]-LH-RH, there was a greater decrease in tumor weight and volume than that produced by RC-3095, and the weights of testes, ventral prostate, and seminal vesicles also were reduced. The combination of RC-3095 and [D-Lys6]-LH-RH had the greatest inhibitory effect on tumor growth. Histologic parameters demonstrated a significant increase of the ratio of apoptotic to mitotic indices in the groups treated with [D-Lys6]-LH-RH or the combination. Serum LH and testosterone levels were greatly depressed by [D-Lys6]-LH-RH or the combination. Specific high-affinity binding sites for bombesin/GRP, epidermal growth factor (EGF), and insulin-like growth Factor I (IGF-I) were found on the tumor membranes. The concentration of receptors for EGF was significantly reduced by treatment with the bombesin/GRP antagonist RC-3095. CONCLUSIONS: Combination therapy of LH-RH analogs with bombesin antagonists such as RC-3095 might be considered for improvement of hormonal therapy of prostate cancer.

Adenocarcinoma↗

PubMed1993

Somatostatin analog RC-160 and bombesin/gastrin-releasing peptide antagonist RC-3095 inhibit the growth of androgen-independent DU-145 human prostate cancer line in nude mice.

Nude mice bearing xenografts of the androgen-independent human prostate cancer DU-145 were treated for 4-5 weeks with somatostatin analog RC-160 or the bombesin/gastrin-releasing peptide (GRP) antagonist RC-3095. Tumor growth in animals treated with somatostatin analog RC-160 at a dose of 100 micrograms/day s.c. was significantly inhibited within 14 days of the start of the experiment. At necropsy, in mice given RC-160, tumor weight and volume were significantly decreased compared with control mice. Treatment with RC-3095 at a dose of 20 micrograms/day s.c. also suppressed tumor growth, the inhibition being significant after 2 weeks, but the reduction in tumor volume and weight was smaller than that produced by RC-160. Therapy with RC-160 significantly decreased serum growth hormone and gastrin levels. Specific binding sites for bombesin, somatostatin and epidermal growth factor (EGF) were found in the DU-145 tumor membranes. Receptors for EGF were significantly down-regulated after therapy with RC-3095 and RC-160. The finding that somatostatin analog RC-160 and bombesin/GRP antagonist RC-3095 inhibit the growth of androgen-independent prostate tumors in mice might be of practical importance for human prostate cancer therapy.

Amino Acid Sequence↗

PubMed1993

Effect of bombesin, gastrin-releasing peptide (GRP)(14-27) and bombesin/GRP receptor antagonist RC-3095 on growth of nitrosamine-induced pancreatic cancers in hamsters.

Female Syrian golden hamsters with N-nitroso-bis (2-oxopropyl) amine (BOP)-induced pancreatic cancers were treated for 2 months with bombesin/gastrin-releasing peptide (GRP) antagonist D-Tpi6,Leu13 psi(CH2NH)Leu14 bombesin(6-14) (RC-3095). Bombesin and GRP(14-27) were also administered alone and in combination with the antagonist RC-3095. RC-3095 exerted a dose-dependent inhibitory effect on growth of pancreatic cancers. The number of animals with pancreatic cancers was significantly lower in the group treated with 60 micrograms/day of RC-3095 and the weight of tumorous pancreata was reduced. Administration of bombesin or GRP alone did not stimulate the growth of pancreatic tumors and, in fact, had a slightly suppressive effect on cancers which was significant only in Experiment I. Bombesin and GRP (14-27) given together with RC-3095 did not nullify the inhibitory effect of the antagonist on pancreatic cancer growth. Actually, a greater inhibition of pancreatic tumors was observed after administration of RC-3095 together with bombesin or GRP, than with RC-3095 alone. The mechanism of action of bombesin, GRP, and bombesin antagonists on pancreatic cancers appears to be complex. The inhibitory effect of bombesin antagonists on pancreatic cancer growth was accompanied by a decrease in the binding capacity of EGF receptors in tumor membranes. Administration of bombesin also caused a down-regulation of EGF receptors and the greatest decrease in binding capacity of EGF receptors was observed after treatment with RC-3095 in combination with GRP. Inhibition of pancreatic cancer can thus be tentatively explained by some common pathways in the action of bombesin, GRP and their antagonists, that could be mediated by interference with EGF-receptor mechanisms.

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