Review of the Endocrine Actions of Luteinising Hormone-Releasing Hormone Analogues in Premenopausal Women with Breast Cancer

Nicholson, Robert Ian; Walker, Kate; Walker, R.F.; Read, G F; Turkes, A.; Robertson, J.F.R.; Blamey, R.W.

doi:10.1159/000181345

Cited by 13 publications

(5 citation statements)

References 11 publications

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“…Experimental studies in rat and mouse models of mammary tumors showed that analogs of LH-RH, by creating a state of sex-steroid deficien-cy, might be useful for treatment of estrogen-dependent breast cancer [4,5]. Clinical trials conducted since 1982 with the LH-RH agonists Decapeptyl, Buserelin, Zoladex, or Leuprolide in premenopausal women with metastatic breast cancer have shown about 40% objective response rate in unsetected patients and 50% in women with estrogen-receptor (ER)-positive tumors [1,2,[6][7][8]. Responses to LH-RH analogs in a small percentage of postmenopausal women [8][9][10] are incompletely understood but tentatively explained by a hypothesis of direct effects ofLH-RH agonists on tumors, since LH-RH agonists inhibit human breast cancer cell lines in vitro and receptors for LH-RH are present in cell lines and in primary breast tumors [11][12][13][14].…”

Section: Introductionmentioning

confidence: 99%

Growth inhibition of estrogen independent MXT mouse mammary carcinomas in mice treated with an agonist or antagonist of LH-RH, an analog of somatostatin, or a combination

Szepesházi

Milovanović

Lapis

et al. 1992

Breast Cancer Res Tr

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Female BDF1 mice inoculated with MXT (3.2) estrogen independent mouse mammary carcinoma were treated for three weeks with microcapsules of the luteinizing hormone-releasing hormone (LH-RH) agonist [D-Trp6]LH-RH, the antagonist SB-75, the somatostatin analog RC-160, or combinations. The lack of estrogen dependence of the tumor was proved by bilateral surgical ovariectomy, which had no effect. In two experiments, treatment with 25 micrograms/day doses of each analog alone resulted in a significant inhibition of tumor growth as shown by a 40-53% inhibition of tumor volumes, 38-43% decrease in tumor weights, and histological signs of tumor regression. However, the combination of SB-75 or [D-Trp6]LH-RH with somatostatin analog RC-160 caused greater reduction of tumor volume (68 and 61%) or tumor weights (59 and 56%), than single analogs, and histologically the occurrence of apoptosis and decrease in AgNOR numbers was more pronounced in the groups receiving combination therapy. Specific binding sites for [D-Trp6]LH-RH, EGF, and IGF-I were demonstrated in the tumor membranes. The binding capacity of LH-RH receptors was decreased by treatment with the analogs, the greatest down-regulation being caused by combination therapy. A significant decrease in EGF binding capacity was observed after treatment with the LH-RH analogs, alone or especially in combination with somatostatin analog RC-160. The combination of these analogs also caused a reduction in IGF-I receptors. The finding that LH-RH agonists and antagonists and somatostatin analogs inhibit the growth of estrogen independent mammary tumors, and that combinations are more effective than single analogs, might be of practical importance in human breast cancer therapy.

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Section: Introductionmentioning

confidence: 99%

Growth inhibition of estrogen independent MXT mouse mammary carcinomas in mice treated with an agonist or antagonist of LH-RH, an analog of somatostatin, or a combination

Szepesházi

Milovanović

Lapis

et al. 1992

Breast Cancer Res Tr

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“…Das Tetradecapeptid Bombesin wurde 1970 zuerst aus der Haut des Frosches Bombina isoliert [2,4,8,9]. Im Anschluss daran wurde ein dem Bombesin ähnliches Peptid im Säugetier charakterisiert,das Gastrinreleasing peptide [8].…”

Section: Bombesin-und Gastrin-releasingpeptide-antagonistenunclassified

“…Da die antiöstrogene Wirkung des Tamoxifens bei prämenopausalen Frauen nicht ausreicht und ein Zusammenhang zwischen der Einnahme dieses Wirkstoffs und einer erhöhten Inzidenz von Endometriumkarzinomen vermutet wird [29],ist die Suche nach alternativen Therapien sinnvoll. Im Ratten-und Mausmodell erwiesen sich LHRH-Agonisten als wirksam beim rezeptorpositiven Mammakarzinom [1,2,4,9].Daraufhin durchgeführte klinische Studien konnten die Wirksamkeit von LHRH-Agonisten beim rezeptorpositiven Mammakarzinom prämenopau-saler Frauen bestätigen [29,30,31].…”

Section: Mammakarzinomunclassified

Experimentelle Therapie gyn�kologischer Tumoren mit Peptidanaloga

2003

Gyn�kologische Endokrinologie

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Di e bisherige medikamentöse Therapie von Mamma-, Endometrium-, und Ovarialkarzinom ist unbefriedigend.Chemotherapien schränken durch eine hohe Rate an Nebenwirkungen, die Lebensqualität des Patienten massiv ein und können oft, wie z. B. beim metastasierten Mammakarzinom keine definitive Heilung erzielen. Es besteht ein großer Bedarf an wirksamen medikamentösen Therapien, die mit einer geringeren Rate an Nebenwirkungen belastet sind und so die Lebensqualität der Patientin in geringerem Maße einschränken.Die Wirksamkeit verschiedener Wirkstoffe,die sich von hypothalamischen Hormonen herleiten und die zum Teil als Vektoren für an sie gekoppelte zytotoxische Substanzen dienen, wurde an verschiedenen Tumoren in vitro und im Tiermodell untersucht. Hier soll zunächst ein kurzer Überblick über die verwendeten Substanzklassen gegeben werden. Danach wird im Einzelnen auf potenzielle Therapieoptionen dieser Substanzen im Endometrium-, Ovarial-und Mammakarzinom eingegangen. Hypothalamische PeptihormonanalogaLuteinising-Hormone-releasingHormone-(LHRH-)Antagonisten LHRH-Antagonisten, wie z. B.Cetrorelix, wirken nach dem Prinzip der klassischen kompetitiven Hemmung sowohl am hypophysären als auch an lokalen LHRH- Originalarbeit

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“…Several clinical and experimental studies have shown that chronic administration of LH-RH agonists or antagonists inhibits the growth of estrogen dependent and independent mammary tumors by inducing a state of pituitary desensitization and ovarian hormone ablation [1][2][3][4][5][6][7][8]. Recent evidence suggests that, in addition to inhibitory effects on the pituitary-gonadal axis, LH-RH analogs also exert a direct effect on tumor cells [1,3,9,[10][11][12][13][14][15].…”

Section: Introductionmentioning

confidence: 99%

Evaluation of binding of cytotoxic analogs of luteinizing hormone-releasing hormone to human breast cancer and mouse MXT mammary tumor

Milovanović

Radulović

Schally

1992

Breast Cancer Res Tr

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The binding characteristics of several cytotoxic analogs of luteinizing hormone-releasing hormone (LH-RH) developed in our laboratory were examined in membranes from human breast cancer and estrogen independent MXT mammary cancer. Specific binding of [125I]D-Trp6-LH-RH and the cytotoxic LH-RH analog [125I]T-98 ([D-Lys6]LH-RH coupled to glutaryl-2-(hydroxymethyl)anthraquinone) (HMAQG) was demonstrated in membrane preparations from human breast and MXT mammary tumor cells. Ligand binding of T-98 was specific, saturable, and dependent on temperature, time, and plasma membrane concentration. Analysis of the binding data showed that in human breast cancer, interaction of [125I]T-98 was consistent with the presence of two classes of LH-RH receptors, one class showing high affinity and low capacity, and the other class showing low affinity and high capacity binding. In membranes from MXT mammary cancer, T-98 bound to one class of saturable, specific, noncooperative binding sites with high affinity and low capacity. The rates of association and dissociation for [125I]T-98 were calculated to be 4.757 x 10(8) M-1 min-1 and 0.016 min-1 (t1/2 = 38.7) in membranes from MXT mammary cancer. In human breast cancer, association rate constants (K1a and K1b) were 2.3 x 10(6) M-1 min-1 for binding to high affinity and 1.8 x 10(4) M-1 min-1 for binding to low affinity binding sites. Dissociation rate constants were K-1a = 0.0801 min-1 (t1/2a = 63.4 min) and K-1b = 0.0467 min-1 (t1/2b = 23.5 min), respectively. [125I]T-98 was not displaced by either unlabeled somatostatin or epidermal growth factor, but was displaced completely by unlabeled T-98 or [D-Trp6]LH-RH. The analysis of displacement curves of [D-Trp6]LH-RH by cytotoxic agonists and antagonists of LH-RH synthesized in our laboratory showed that T-121, AJ-11, T-120, T-133, and T-98 were the most potent in displacing [125I]D-Trp6-LH-RH from breast and MXT cancer membranes. Binding kinetics and analyses of displacement curves of [125I]D-Trp6-LH-RH and [125I]T-98 in membranes of human breast cancer and estrogen independent MXT mouse mammary cancer suggest that binding of the cytotoxic analog T-98 to the LH-RH receptor proceeds reversibly like that of its congeners without cytotoxic radicals. Our findings may provide a stimulus for further studies with LH-RH analogs carrying cytotoxic radicals.(ABSTRACT TRUNCATED AT 400 WORDS)

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Review of the Endocrine Actions of Luteinising Hormone-Releasing Hormone Analogues in Premenopausal Women with Breast Cancer

Cited by 13 publications

References 11 publications

Growth inhibition of estrogen independent MXT mouse mammary carcinomas in mice treated with an agonist or antagonist of LH-RH, an analog of somatostatin, or a combination

Growth inhibition of estrogen independent MXT mouse mammary carcinomas in mice treated with an agonist or antagonist of LH-RH, an analog of somatostatin, or a combination

Experimentelle Therapie gyn�kologischer Tumoren mit Peptidanaloga

Evaluation of binding of cytotoxic analogs of luteinizing hormone-releasing hormone to human breast cancer and mouse MXT mammary tumor

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