Summary
Human breast carcinoma (MCF-7 MIII), which exhibits an estrogen-independent but estrogenresponsive phenotype, was xenografted in 8–9-week-old intact female athymic nude mice without estrogen supplementation. In this model, we investigated inhibitory effects of the modern luteinizing hormonereleasing hormone (LH-RH) antagonist SB-75 and the agonist D-Trp6-LH-RH. The analogs were administered in the form of sustained delivery systems (microcapsules and microgranules). In the first experiment, treatment lasted 10 weeks. After 9 weeks of treatment, a significant inhibition of tumor volume was first found only in the group treated with SB-75, but the final tumor volume was significantly suppressed both by D-Trp6-LH-RH and SB-75. In the second experiment, treatment was started 70 days after tumor transplantation and was continued for 6 weeks. Chronic treatment with SB-75 or D-Trp6-LH-RH appeared to completely arrest tumor growth as measured by tumor volume, percentage change in tumor volume, and tumor weight. Serum estradiol was suppressed to undetectable levels and LH levels were also diminished. Histologically, the regressive changes in the treated tumors were due to the enhancement of apoptosis (programmed cell death) of tumor cells. Membrane receptor assays showed that LH-RH binding sites were down-regulated in tumor cells after treatment with SB-75 or D-Trp6-LH-RH.
The results indicate that the antagonist SB-75, released from sustained delivery systems, can inhibit the growth of MCF-7 MIII tumors as effectively as the agonist D-Trp6-LH-RH, but more rapidly. In view of its immediate blockade of the pituitary-gonadal axis and the absence of side effects, the LH-RH antagonist SB-75 might be considered as a possible new hormonal agent for the treatment of breast cancer.
Abbreviations
- LH-RH:
-
luteinizing hormone-releasing hormone
- LH:
-
luteinizing hormone
- FSH:
-
follicle-simulating hormone
- D-Trp6-LH-RH:
-
D-tryptophan-6-luteinizing hormone-releasing hormone
- IGF-I:
-
insulin-like growth factor I
- EGF:
-
epidermal growth factor
- Ac:
-
acetyl
- Nal(2):
-
3-(2-naphthyl)alanine
- Phe(4C1):
-
4-chlorophenylalanine
- Pal(3):
-
3-(3-pyridyl)alanine
- Cit:
-
citrulline
References
Boring CC, Squires TS, Tong T: Cancer Statistics, 1991. Ca-A Cancer Journal for Clinicians 41:19–36, 1991
Beatson GT: On the treatment of inoperable cases of carcinoma of the mamma: suggestion for a new method of treatment with illustrative cases. Lancet 2:104–107, 1896
Santen RJ, Manni A, Harvey H, Redmond C: Endocrine treatment of breast cancer in women. Endocr Rev 11:221–265, 1990
Schally AV, Bajusz S, Redding TW, Zalatnai A, Comaru-Schally AM: Analogs of LHRH: The present and the future. In: Vickery BH, Lunenfeld B (eds) GnRH Analogues in Cancer and Human Reproduction, Basic Aspects. Kluwer Academic Publishers, Dordrecht/Boston/London, Vol. 1, pp. 5–31, 1989
Schally AV: The use of LHRH analogs in gynecology and tumor therapy. In: Belfort P, Pinotti JA, Eskes TKAB (eds) General Gynecology. Parthenon Publishing, Carnforth, England, Vol. 6, pp. 3–22, 1989
Bokser L, Srkalovic G, Szepeshazi K, Schally AV: Recovery of pituitary-gonadal function in male and female rats after prolonged administration of a potent antagonist of luteinizing hormone-releasing hormone (SB-75). Neuroendocrinology 54:136–145, 1991
De Sombre ER, Johnson ES, White WF: Regression of rat mammary tumors effected by a gonadoliberin analog. Cancer Res 36:3830–3833, 1976
Klijn JGM, De Jong FH: Treatment with a luteinising-hormone-releasing-hormone analogue (Buserelin) in premenopausal patients with metastatic breast cancer. Lancet 2:1213–1216, 1982
Manni A, Santen R, Harvey H, Lipton A, Max D: Treatment of breast cancer with gonadotropin-releasing hormone. Endocr Rev 7:89–94, 1986
Williams MR, Walker KJ, Turkes A, Blamey RW, Nicholson RI: The use of an LH-RH agonist (ICI 118630, Zoladex) in advanced premenopausal breast cancer. Br J Cancer 53:629–636, 1986
Mathe G, Keiling R, Prevot G, Vo Van ML, Gastiaburu J, Vannetzel JM, Despax R, Jasmin C, Levi F, Musset M, Machover D, Ribaud P, Misset JL: LH-RH agonist: Breast and prostate cancer. In: Klijn JGM, Paridaens R, Foekens JA (eds) Hormonal Manipulation of Cancer: Peptides, Growth Factors, and New (Anti) Steroidal Agents. Raven Press, New York, pp. 315–319, 1987
Kaufmann M: Zoladex in the treatment of premenopausal metastatic breast cancer patients. Hormone Res 32 (Suppl 1):202–205, 1989
Plowman PN, Nicholson RI, Walker KJ: Remission of postmenopausal breast cancer during treatment with the luteinizing hormone releasing hormone agonist ICI 118630. Br J Cancer 54:903–909, 1986
Schwartz L, Guiochet N, Keiling R: Two partial remissions induced by an LHRH analogue in two postmenopausal women with metastatic breast cancer. Cancer 62:2498–2500, 1988
Harris AL, Carmichael J, Cantwell BMJ, Dowsett M: Zoladex: Endocrine and therapeutic effects in postmenopausal breast cancer. Br J Cancer 59:97–99, 1989
Bajusz S, Csernus VJ, Janaky T, Bokser L, Fekete M, Schally AV: New antagonists of LH-RH: II. Inhibition and potentiation by closely related analogues. Int J Peptide Protein Res 32:425–435, 1988
Csernus VJ, Szende B, Groot K, Redding TW, Schally AV: Development of radioimmunoassay for a potent luteinizing hormone-releasing hormone antagonist: Evaluation of serum levels after injection of [Ac-3-(2-naphthyl)-D-Ala1, D-Phe(pCl)2,3-(3-pyridyl)-D-Ala3, D-Cit6, D-Ala10]-LH-RH. Arzneimittel-Forschung/Drug Res 40:111–118, 1990
Redding TW, Schally AV, Tice TR, Meyers WE: Long-acting delivery systems for peptides: inhibition of rat prostate tumors by controlled release of [D-Trp6]-luteinizing hormone-releasing hormone from injectable microcapsules. Proc Natl Acad Sci USA 81:5845–5848, 1984
Szende B, Srkalovic G, Groot K, Lapis K, Schally AV: Growth inhibition of mouse MXT mammary tumor by the luteinizing hormone-releasing hormone antagonist SB-75. J Natl Cancer Inst 82:513–517, 1990
Gonzalez-Barcena D, Perez-Sanchez PL, Graef A, Gomez AM, Berea H, Comaru-Schally AM, Schally AV: Inhibition of the pituitary-gonadal axis by a single intramuscular administration of D-Trp-6-LH-RH (Decapeptyl) in a sustained-release formulation in patients with prostatic carcinoma. Prostate 14:291–300, 1989
Szepeshazi K, Korkut E, Szende B, Lapis K, Schally AV: Histological changes in Dunning prostate tumors and testes of rats treated with LH-RH antagonist SB-75. Prostate 18:255–270, 1991
Shafie SM, Grantham FH: Role of hormones in the growth and regression of human breast cancer cells (MCF-7) transplanted into athymic nude mice. J Natl Cancer Inst 67:51–56, 1981
Clarke R, Brunner N, Katzenellenbogen BS, Thompsor EW, Norman MJ, Koppi C, Paik S, Lippman ME. Dickson RB: Progression of human breast cancer cells from hormone-dependent to hormone-independent growth both in vitro and in vivo. Proc Natl Acad Sc USA 86:3649–3653, 1989
Clarke R, Brunner N, Thompson EW, Glanz P, Katz D, Dickson RB, Lippman ME: The inter-relationships between ovarian-independent growth, tumorigenicity, invasiveness and antioestrogen resistance in the malignant progression of human breast cancer. J. Endocrinology 122:331–340, 1989
Osborne CK, Clemmons DR, Arteaga CL: Regulation of breast cancer growth by insulin-like growth factors. J Steroid Biochem Molec Biol 37:805–809, 1990
Bonneterre J, Peyrat JP, Beuscart R, Demaille A: Prognostic significance of insulin-like growth factor l receptors in human breast cancer. Cancer Res 50:6931–6935, 1990
Tomayko MM, Reynolds CP: Determination of subcutaneous tumor size in athymic (nude) mice. Cancer Chemother Pharmacol 24:148–154, 1989
Csernus V: Antibodies of high affinity and specificity for radioimmunological determination of progesterone, testosterone and estradiol-17ß. Proc of the Symp on the Analysis of Steroids. Eger, Hungary, pp. 171–177, 1981
Srkalovic G, Szende B, Redding TW, Groot K, Schally AV: Receptors for D-Trp6-luteinizing hormone-releasing hormone, somatostatin, and insulin-like growth factor I in MXT mouse mammary carcinoma. Proc Soc Exp Biol Med 192:209–218, 1989
Munson PJ, Rodbard D: Ligand: A versatile computerized approach for characterization of ligandbinding systems. Anal Biochem 107:220–239, 1980
Seibert K, Shafie SM, Triche TJ, Whang-Peng JJ, O'Brien SJ, Toney JH, Huff KK, Lippman ME: Clonal variation of MCF-7 breast cancer cells in vitro and in athymic nude mice. Cancer Res 43:2223–2239, 1983
Kyprianou N, English HF, Davidson NE, Isaacs JT: Programmed cell death during regression of the MCF-7 human breast cancer following estrogen ablation. Cancer Res 51:162–166, 1991
Miller WR, Scott WN, Morris R, Fraser HM, Sharpe RM: Growth of human breast cancer cells inhibited by a luteinizing hormone-releasing hormone agonist. Nature 313:231–233, 1985
Foekens JA, Henkelman MS, Fukkink JF, Blankenstein MA, Klijn JGM: Combined effects of buserelin, estradiol and tamoxifen on the growth of MCF-7 human breast cancer cells in vitro. Biochem Biophys Res Commun 140:550–556, 1986
Néri C, Berthois Y, Schatz B, Drieu K, Martin PM: Compared effects of GnRH analogs and 4-hydroxytamoxifen on growth and steroid receptor in antiestrogen sensitive and resistant MCF-7 breast cancer cell sublines. Breast Cancer Res Treat 15:85–93, 1990
Eidne KA, Flanagan CA, Millar RP: Gonadotropinreleasing releasing hormone binding sites in human breast carcinoma. Science 229:989–991, 1985
Fekete M, Bajusz S, Groot K, Csernus VJ, Schally AV: Comparison of different agonists and antagonists of luteinizing hormone-releasing hormone for receptorbinding ability to rat pituitary and human breast cancer membranes. Endocrinology 124:946–955, 1989
Néri C, Blangy D, Schatz B, Drieu K, Berebbi M, Martin PM: Direct inhibiting effects of [D-Trp6] gonadotropin-releasing hormone on the estrogensensitive progression of polyoma virus-induced mammary tumors in athymic mice. Cancer Res 50:5892–5897, 1990
Sharoni Y, Bosin E, Miinster A, Levy J, Schally AV: Inhibition of growth of human mammary tumor cells by potent antagonists of luteinizing hormone-releasing hormone. Proc Natl Acad Sci USA 86:1648–1651, 1989
Dickson RB: Stimulatory and inhibitory growth factors and breast cancer. J Steroid Biochem Molec Biol 37:795–803, 1990
Pollak MN, Perdue JF, Margolese RG, Baer K, Richard M: Presence of somatomedin receptors on primary human breast and colon carcinomas. Cancer Lett 38:223–230, 1987
Fekete M, Wittliff JL, Schally AV: Characteristics and distribution of receptors for [D-Trp6]-luteinizing hormone-releasing hormone, somatostatin, epidermal growth factor, and sex steroids in 500 biopsy samples of human breast cancer. J Clin Lab Anal 3:137–147, 1989
Fitzpatrick SL, LeChance MP, Schultz GS: Characterization of epidermal growth factor receptor and action on human breast cancer cells in culture. Cancer Res 44:3442–3447, 1984
Pollak MN, Polychronakos C, Yousefi S, Richard M: Characterization of insulin-like growth factor I (IGF-I) receptors of human breast cancer cells. Biochem Biophys Res Commun 154:326–331, 1988
Arteaga CL, Kitten LJ, Coronado EB, Jacobs S, Kull FC Jr, Allred DC, Osborne CK: Blockade of the type I somatomedin receptor inhibits growth of human breast cancer cells in athymic mice. J Clin Invest 84:1418–1423, 1989
Gonzalez-Barcena D, Vadillo-Buenfil M, Guerra-Arguero L, Carreno J, Comaru-Schally AM, Schally AV: Potent antagonistic analog of LH-RH (SB-75) inhibits LH, FSH and testosterone levels in human beings. Abstracts, 72nd Annual Meeting, Endocrine Society, Atlanta, GA, June 20–23, 1990, Abstr. No. 1318, p. 354
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Yano, T., Korkut, E., Pinski, J. et al. Inhibition of growth of MCF-7 MIII human breast carcinoma in nude mice by treatment with agonists or antagonists of LH-RH. Breast Cancer Res Tr 21, 35–45 (1992). https://doi.org/10.1007/BF01811962
Issue Date:
DOI: https://doi.org/10.1007/BF01811962