Breast Cancer Research and Treatment

, Volume 14, Issue 3, pp 307–314 | Cite as

Growth inhibition of MXT mammary carcinoma by enhancing programmed cell death (apoptosis) with analogs of LH-RH and somatostatin

  • Bela Szende
  • Karoly Lapis
  • Tommie W. Redding
  • Gordan Srkalovic
  • Andrew V. Schally


BDF female mice inoculated with MXT mammary adenocarcinoma were treated for 30 days with microcapsules of the luteinizing hormone-releasing hormone (LH-RH) agonist D-Trp-6-LH-RH (releasing 25µg/day for 30 days), microcapsules of the somatostatin agonist RC-160 (liberating 25µg/day for one month), or the combination of these peptides. Bilateral surgical ovariectomy was performed in one group which served as an additional control. Tumor volume was measured weekly during the treatment period of 30 days. When tumor volume changes in the treated groups were compared to the corresponding changes in controls, the combination of D-Trp-6-LH-RH and RC-160 was the most effective in inhibiting tumor growth and approached the effect of surgical ovariectomy. At the conclusion of the experiment, tumor weights were also measured. All peptide analogs inhibited tumor weight by 42 to 63%. In the D-Trp-6-LH-RH treated group, ovarian weights and uterine weights decreased by 48% and 52%, respectively, as compared to controls. Histologically, the regressive changes in tumors caused by the treatment with RC-160, D-Trp-6-LH-RH and their combination were characterized by the coexistence of apoptosis (programmed cell death) and coagulation necrosis. The transition of apoptosis into coagulation necrosis was a common finding. The term ‘apoptotic index’ is proposed for the ratio of tumorous glands containing apoptotic cells. The apoptotic index was higher in the treated groups than in the control.

Key words

luteinizing hormone-releasing hormone (LH-RH) MXT mammary tumor D-Trp-6-LH-RH somatostatin analog RC-160 apoptosis programmed cell death 


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  1. 1.
    Schally AV, Comaru-Schally AM: Use of Luteinizing Hormone-Releasing Hormone analogs in the treatment of hormone dependent tumors. Semin Reprod Endocrinol 5: 389–398, 1987Google Scholar
  2. 2.
    Schally AV: Oncological applications of somatostatin analogs. Cancer Res 48: 6977–6985, 1988PubMedGoogle Scholar
  3. 3.
    Schally AV, Bajusz S, Redding TW, Zalatnai A, Comaru-Schally AM: Analogs of LH-RH. The present and the future. In: Vickery BH, Luenefeld B: GnRH analogues in cancer and human reproduction. MTP Press, Lancaster/Boston, 1989Google Scholar
  4. 4.
    Gonzalez-Barcena D, Rangel-Garcia N, Perez-Sanchez PL, Gutierrez-Damperio C, Garcia-Carrasco R, Comaru-Schally AM, Schally AV: Response of advanced adenocarcinoma of pancreas to D-Trp-6-LH-RH. Lancet ii, 154, 1989Google Scholar
  5. 5.
    Schally AV, Redding TW: Somatostatin analogs as adjuncts to agonists of luteinizing hormone-releasing hormone in the treatment of experimental prostate cancer. Proc Natl Acad Sci USA 84: 7275–7279, 1987PubMedGoogle Scholar
  6. 6.
    Fekete M, Zalatnai A, Comaru-Schally AM, Schally AV: Membrane receptors for peptides in experimental and human pancreatic cancers. Pancreas 4: 521–528, 1989PubMedGoogle Scholar
  7. 7.
    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, 1985PubMedGoogle Scholar
  8. 8.
    Scambia G, Benedetti-Panici P, Baiocchi G, Perrone L, Iacobelli S, Mancuso S: Antiproliferative effects of somatostatin analogs SMS 201-995 on three human breast cancer cell lines. J Cancer Res Clin Oncol 114: 306–308, 1988PubMedGoogle Scholar
  9. 9.
    Seytono-Han B, Henkelman MS, Foekens JA, Klijn JGM: Direct inhibitory effects of somatostatin (analogues) on the growth of human breast cancer cells. Cancer Res 47: 1566–1570, 1987PubMedGoogle Scholar
  10. 10.
    Redding TW, Fekete M, Schally AV: Direct inhibition of the MT-5 rat mammary tumor cell line by somatostatin analog RC-160. Abstract, Endocrine Society meeting, New Orleans, June, 1988, No. 603, p 171Google Scholar
  11. 11.
    Sharoni Y, Basin 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: 1989, in pressGoogle Scholar
  12. 12.
    Gullino PM: The regression process in hormone-dependent mammary carcinomas. In: Iacobelli S,et al.: Hormones and Cancer. Raven Press, New York, 1980, pp 271–279Google Scholar
  13. 13.
    Szende B, Zalatnai A, Schally AV: Programmed cell death (apoptosis) in pancreatic cancers of hamsters after treatment with analogs of both luteinizing hormone-releasing hormone and somatostatin. Proc Natl Acad Sci USA 86: 1643–1647, 1989PubMedGoogle Scholar
  14. 14.
    Watson C, Medina D, Clark JH: Estrogen receptor characterization in a transplantable mouse mammary tumor. Cancer Res 37: 3344–3348, 1977PubMedGoogle Scholar
  15. 15.
    Srkalovic G, Szende B, Redding TW, Groot K, Schally AV: Receptors for D-Trp-6-luteinizing hormone-releasing hormone, somatostatin and insulin-like growth factor-I in MXT mouse mammary carcinoma. Proc Soc Exp Biol Med 192: dec 1989Google Scholar
  16. 16.
    Schally AV, Redding TW, Comaru-Schally AM: Inhibition of prostate tumors by agonistic and antagonistic analogs of LH-RH. Prostate 4: 545–552, 1983PubMedGoogle Scholar
  17. 17.
    Redding TW, Schally AV: Inhibition of prostate tumor growth in two rat models by chronic administration of D-Trp-6-LH-RH. Proc Natl Acad Sci USA 80: 6509–6512, 1983Google Scholar
  18. 18.
    Redding TW, Schally AV: Inhibition of growth of the transplantable rat chondrosarcoma by analogs of hypothalamic hormones. Proc Natl Acad Sci USA 80: 1078–1082, 1983PubMedGoogle Scholar
  19. 19.
    Redding TW, Schally AV: Inhibition of growth of pancreatic carcinomas in animal models by analogs of hypothalamic hormones. Proc Natl Acad Sci USA 81: 248–252, 1984PubMedGoogle Scholar
  20. 20.
    Redding TW, Schally AV: Inhibition of mammary tumor growth in rats and mice by administration of agonistic and antagonistic analogs of luteinizing hormone-releasing hormone. Proc Natl Acad Sci USA 80: 1459–1462, 1983PubMedGoogle Scholar
  21. 21.
    Gullino PM, Grantham FH, Losonczy I, Berghoffer B: Mammary tumor regression, I. Physiopathologic characteristics of hormone-dependent tissue. J Natl Cancer Inst 49: 1333–1348, 1972PubMedGoogle Scholar
  22. 22.
    Gullino PM, Lanzerotti RH: Mammary tumor regression, II. Autophagy of neoplastic cells. J Natl Cancer Inst 49: 1349–1356, 1972PubMedGoogle Scholar
  23. 23.
    Kerr JFR, Wyllie AH, Currie AR: Apoptosis: basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer 26: 239–257, 1972PubMedGoogle Scholar
  24. 24.
    Searle J, Lawson TA, Abbott PJ, Harmon B, Kerr JFR: An electron-microscope study of the mode of cell death induced by cancer-chemotherapeutic agents in populations of proliferating normal and neoplastic cells. J Pathol 116: 129–138, 1975PubMedGoogle Scholar
  25. 25.
    Wyllie AH: The biology of cell death in tumors. Anticancer Res 5: 131–136, 1985PubMedGoogle Scholar
  26. 26.
    Wyllie AH: What is apoptosis? Histopathology 10: 995–998, 1986PubMedGoogle Scholar
  27. 27.
    Crass RA, Morgan RGH: The effects of long-term feeding of soybean flour diets on pancreatic growth in the rat. Br J Nutr 47: 119–126, 1982PubMedGoogle Scholar
  28. 28.
    Oates PS, Bruce NB, Morgan RGH: Pancreatic blood flow in the rat during enlargement, involution and cholecystokinin treatment. Am J Physiol 247: G457-G462, 1984PubMedGoogle Scholar
  29. 29.
    Oates PS, Morgan RGH, Light AM: Cell death (apoptosis) during pancreatic involution after raw soya flour feeding in the rat. Am J Physiol 198: G9-G14, 1986Google Scholar
  30. 30.
    Evans GS, Chandler JA: Cell proliferation studies in the rat prostate: II. The effects of castration and androgen-induced regeneration upon basal and secretory cell proliferation. Prostate 11: 339–351, 1987PubMedGoogle Scholar

Copyright information

© Kluwer Academic Publishers 1989

Authors and Affiliations

  • Bela Szende
    • 2
    • 3
  • Karoly Lapis
    • 1
    • 2
    • 3
  • Tommie W. Redding
    • 2
    • 3
  • Gordan Srkalovic
    • 2
    • 3
  • Andrew V. Schally
    • 2
    • 3
  1. 1.1st Institute of Pathology and Experimental Cancer ResearchSemmelweis University Medical SchoolBudapestHungary
  2. 2.Endocrine, Polypeptide and Cancer InstituteVeterans Administration Medical CenterUSA
  3. 3.Department of MedicineTulane University Medical SchoolNew OrleansUSA

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