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  • 1
    Electronic Resource
    Electronic Resource
    Antagonists of growth hormone-releasing hormone arrest the growth of MDA-MB-468 estrogen-independent human breast cancers in nude mice (2000)
    Springer
    Breast cancer research and treatment 60 (2000), S. 71-79 
    Details
    ISSN: 1573-7217
    Keywords: breast cancer ; growth hormone-releasing hormone (GH-RH) antagonists ; IGF-I ; IGF-I receptor ; GH-RH
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Since antagonists of growth hormone-releasing hormone (GH-RH) inhibit proliferation of various tumors, in this study we investigated the effects of GH-RH antagonists MZ-5-156 or JV-1-36 on growth of estrogen-independent MDA-MB-468 human breast cancers xenografted into nude mice. Both GH-RH antagonists administered at a dose of 20 μg/day induced regression of some and growth-arrest of other tumors, while control tumors continued to grow. After 5 weeks of therapy with MZ-5-156 or JV-1-36, final volume and weight of MDA-MB-468 tumors were significantly decreased (all p values 〈0.001) and serum IGF-I levels as well as tumor IGF-I mRNA expression were reduced as compared with controls. High affinity binding sites for IGF-I were detected by the ligand binding method. Gene expression of human IGF-I receptors, as measured by the RT-PCR, was not significantly different in control and treated MDA-MB-468 tumors. In cell culture, IGF-I did not stimulate, GH-RH slightly stimulated, while MZ-5-156 and JV-1-36 inhibited proliferation of MDA-MB-468 cells known to possess defective insulin and IGF-I receptor signaling. The expression of mRNA for human GH-RH was found in five of 8 tumors treated with GH-RH antagonists, and in one of the five control tumors. These results suggest that GH-RH antagonists inhibit MDA-MB-468 breast cancers possibly through mechanisms involving interference with locally produced GH-RH.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006363230990
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  • 2
    Electronic Resource
    Electronic Resource
    Effect of a cytotoxic analog of LH-RH (T-98) on the growth of estrogendependent MXT mouse mammary cancers: Correlations between growth characteristics and EGF receptor content of tumors (1996)
    Springer
    Breast cancer research and treatment 40 (1996), S. 129-139 
    Details
    ISSN: 1573-7217
    Keywords: experimental breast cancer ; LH-RH agonist ; cytotoxic compounds ; EGF receptors ; organ distribution ; AgNOR ; apoptosis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Female BDF mice bearing estrogen-dependent MXT mouse mammary cancers were treated for 4 weeks with a cytotoxic analog of luteinizing hormone-releasing hormone (LH-RH), T-98 (agonist [D-Lys6]LH-RH linked to glutaryl-2(hydroxymethyl)anthraquinone). The effects of T-98 were compared to those of equimolar amounts of the cytotoxic moiety 2-(hydroxymethyl)anthraquinone hemiglutarate (G-HMAQ) and carrier LH-RH agonist [D-Lys6]LH-RH. Both T-98 and [D-Lys6]LH-RH significantly inhibited the growth of MXT cancers, but G-HMAQ had only a minor non-significant effect. Cytotoxic analog T-98 and the carrier [D-Lys6]LH-RH had similar inhibitory hormonal activities on the pituitary-gonadal axis, but T-98 caused a larger reduction in tumor volume and decreased proliferation characteristics such as mitotic activity and AgNOR numbers in tumor cells to a greater extent than the carrier. Tumor inhibition by T-98, [D-Lys6]LH-RH, and ovariectomy was connected with a significant decrease in binding capacity of EGF receptors in tumor cell membranes. The concentration of EGF receptors remained high in tumors that continued to enlarge in spite of treatment and in all control untreated tumors, even those of small size. Thus, the changes in EGF receptors are likely to be the result of the therapy. Treatment with T-98 caused a greater reduction in the binding capacity of EGF receptors in tumors than [D-Lys6]LH-RH. This could explain the higher inhibitory effect of the cytotoxic analog on tumor growth. Since radiolabeled T-98 was shown to accumulate in MXT cancers 3 hours after a subcutaneous injection, this indicates that specific targeting might play a role in the antitumor effect exerted by this cytotoxic analog.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01806208
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  • 3
    Electronic Resource
    Electronic Resource
    Bombesin antagonists inhibit in vitro and in vivo growth of human gastric cancer and binding of bombesin to its receptors (1994)
    Springer
    Journal of cancer research and clinical oncology 120 (1994), S. 519-528 
    Details
    ISSN: 1432-1335
    Keywords: Bombesin ; gastrin-releasing peptide ; bombesin receptor ; bombesin antagonist ; gastric carcinoma
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract We investigated the effect of bombesin/gastrinreleasing peptide (GRP) antagonist RC-3095 and other analogs on the growth of Hs746T human gastric cancer cells implanted in nude mice or culturedin 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 μg 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 (K d=0.24±0.07 nM) and a low binding capacity (B max=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 cellsin vitro as shown by an increase in the uptake of [3H]thymidine. Bombesin antagonist RC-3095 could effectively inhibit the bombesinstimulated 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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01221028
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  • 4
    Electronic Resource
    Electronic Resource
    Growth inhibition of experimental pancreatic cancers and sustained reduction in epidermal growth factor receptors during therapy with hormonal peptide analogs (1999)
    Springer
    Journal of cancer research and clinical oncology 125 (1999), S. 444-452 
    Details
    ISSN: 1432-1335
    Keywords: Key words Experimental pancreatic cancer ; Hormonal therapy ; Bombesin antagonist ; Somatostatin analog ; LH-RH antagonist ; EGF receptor ; Apoptosis ; AgNOR
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Reduction in receptors for epidermal growth factor (EGF) in cancers appears to be one of the principal mechanisms through which peptide hormone analogs can inhibit tumor growth. In this study, hamsters with nitrosamine-induced pancreatic cancers were treated for 8 weeks with bombesin/gastrin-releasing peptide (GRP) antagonist RC-3095, somatostatin analog RC-160 or the luteinizing hormone-releasing hormone antagonist Cetrorelix, using sustained delivery systems releasing 20, 35 and 20 μg analog/ day respectively. To establish the pattern of changes in the number and affinity of EGF receptors on tumors, groups of animals were sacrificed at regular intervals during therapy. Chronic treatment with RC-3095 or Cetrorelix resulted in an early (day 10) and sustained reduction (71% or 69% respectively) in EGF receptors on pancreatic tumors. In contrast, RC-160 decreased receptor concentration by 60% only after 20 days. Among the histological characteristics of proliferation, the decrease in argyrophilic nucleolar organizer regions, but not apoptotic and mitotic indices, showed a correlation with the fall in EGF receptors. The concentration of the receptors returned to the control level 4 days after cessation of chronic treatment with RC-3095. The effect of single injections of RC-3095, RC-160 and Cetrorelix on EGF receptors was also investigated. RC-160 decreased the number of EGF receptors on pancreatic cancers by 31% 3 h after administration, but the receptors had returned to normal level at 6 h. RC-3095 and Cetrorelix caused a 67% and 59% decline, respectively, in EGF receptors only 6 h after injection and the concentration of receptors remained low for 24 h. Thus, the pattern of down-regulation of EGF receptors in pancreatic cancers appears to depend on the peptide used for therapy. Since the antitumor effect may be the result of the fall in EGF receptors in cancers, information on the time course of changes in these receptors during treatment with these analogs may lead to an improvement in therapeutic regimens.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s004320050301
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  • 5
    Electronic Resource
    Electronic Resource
    Administration of a targeted cytotoxic analog of luteinizing hormone-releasing hormone inhibits growth of estrogen-independent MDA-MB-231 human breast cancers in nude mice (2000)
    Springer
    Breast cancer research and treatment 59 (2000), S. 255-262 
    Details
    ISSN: 1573-7217
    Keywords: cytotoxic LH-RH analog ; estrogen-independent breast cancer ; LH-RH receptors ; MDA-MB-231 xenografts ; receptor targeted chemotherapy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Receptor targeted chemotherapy is less toxic and more effective than conventional chemotherapy. Receptors for luteinizing hormone-releasing hormone (LH-RH) are found in about 50% of human breast cancers. Highly potent cytotoxic radical 2-pyrrolinodoxorubicin (AN-201) was linked to the agonistic analog [D-Lys6]LH-RH to form cytotoxic LH-RH analog AN-207. We evaluated whether AN-207 could be targeted to the hormone-independent MDA-MB-231 human breast cancers. Nude mice bearing MDA-MB-231 tumors were injected i.v. with 250 nmol/kg doses of cytotoxic radical AN-201, cytotoxic LH-RH analog AN-207, the unconjugated mixture of AN-201 and carrier [D-Lys6]LH-RH, [D-Lys6]LH-RH alone and vehicle (control). The growth of MDA-MB-231 tumors in animals given a single dose of AN-207 was inhibited significantly (p=0.01) for 3 weeks after injection, whereas tumors in all the other groups grew steadily. All cytotoxic compounds produced leukopenia, but the strongest lymphocyte suppression was caused by cytotoxic radical AN-201. Three weeks after treatment, the presence of mRNA for LH-RH receptors was demonstrated by RT-PCR in all the groups and radioreceptor assays demonstrated high-affinity binding sites for LH-RH on tumor cell membranes of control animals and those treated with AN-201, the carrier peptide alone or in combination with AN-201. At this time point binding assays did not reveal the expression of membrane proteins in tumors treated with AN-207, but 60 days after administration of AN-207, high affinity LH-RH binding sites were found again in MDA-MB-231 tumors. These results indicate that cytotoxic LH-RH analog AN-207 could be utilized for receptor targeted chemotherapy of breast cancers expressing receptors for LH-RH.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006352401912
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