Twenty-five Years of Endocrine Oncology with Analogs of Hypothalamic Peptides: An Overview

  • A. V. Schally
Conference paper


In this chapter I will try to report to you what I have been doing for the past 25 years and what advancements in oncology have emanated so far from the work on the hypothalamus. The discovery of hypothalamic hormones, especially luteinizing hormone-releasing hormone (LHRH) and somatostatin, has led to practical clinical use of their analogs in the field of cancer treatment. LHRH, somatostatin, growth hormone-releasing hormone (GHRH), their mRNAs and their receptors are found in diverse tumors (Schally et al., 2001a, Schally et al., 2001b). Mammalian bombesin-like peptides, such as gastrin-releasing peptide (GRP) and neuromedin B, are likewise present in various tumors, and appear to produce mitogenic effects (Cuttitta, 1985; Sunday et al., 1988; Schally et al., 2001a). Antagonists of bombesin/GRP can be also used for the development of new methods for treatment of various tumors. In addition we have synthesized and evaluated cytotoxic analogs of LHRH, somatostatin and bombesin that can be targeted to various tumors. Moreover, we have made antagonists of GHRH, not discussed here. This chapter reviews some selected experimental and clinical findings on the use of analogs of LHRH, somatostatin and bombesin for treatment of various cancers.


Nude Mouse Human Prostate Cancer Small Cell Lung Carcinoma LHRH Agonist Human Epithelial Ovarian Cancer 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Bajo A.M., Schally A.V., Krupa M., Hebert F., Groot K. and Szepeshazi K. (2002). Bombesin antagonists inhibit growth of MDA-MB-435 estrogen independent breast cancers and decrease the expression of ErbB-2/HER-2 oncoprotein and c-jun and c-fos oncogenes. Proc Nat Acad Sci NSA, 99, 3836–3841.CrossRefGoogle Scholar
  2. Bajusz S., Csernus V.J., Janaky T., Bokser L., Fekete M. and Schally A.V. (1988). New antagonists of LHRH: II. Inhibition and potentiation of LHRH by closely related analogues. Int J Peptide Prot Res, 32, 425–435.CrossRefGoogle Scholar
  3. Bauer W., Briner U., Doepfner W., Haller R., Huguenin R., Marbach P., Petcher T.J. and Pless J. (1982). SMS 201-995: a very potent and selective octapeptide analogue of somatostatin with prolonged action. Life Sci, 31,1133–1140.PubMedCrossRefGoogle Scholar
  4. Brazeau P., Vale W., Burgus R., Ling N., Butcher M., Rivier J. and Guillemin R. (1973). Hypothalamic polypeptide that inhibits the secretion of immunoreactive pituitary growth hormone. Science, 179, 77–79.PubMedCrossRefGoogle Scholar
  5. Buscail L, Saint-Laurent N., Chastre E., Vaillant J.C., Gespach C., Capella G., Kalthoff H., Lluis F., Vaysse N. and Susini C. (1996). Loss of sst2 somatostatin receptor gene expression in human pancreatic and colorectal cancer. Cancer Res, 56, 1823–1827.PubMedGoogle Scholar
  6. Cai R-Z, Reile H., Armatis P. and Schally A.V. (1994). Potent bombesin antagonists with C-terminal Leu ψ(CH2N)-Tac-NH2 or its derivatives. Proc Natl Acad Sci USA, 91,Google Scholar
  7. 12664–12668.Google Scholar
  8. Cai R-Z., Szoke B., Lu R., Fu D., Redding T.W. and Schally A.V. (1986). Synthesis and biological activity of highly potent octapeptide analogs of somatostatin. Proc Natl Acad Sci USA, 83, 1896–1900.PubMedCrossRefGoogle Scholar
  9. Chave H.S., Gough A.C., Palmer K., Preston S.R. and Primrose J.N. (2000). Bombesin family receptor and ligand gene expression in human colorectal cancer and normal mucosa. Br J Cancer, 82, 124–130.PubMedCrossRefGoogle Scholar
  10. Comaru-Schally A.M., Brannan W., Schally A.V, Colcolough M. and Monga M. (1998). Efficacy and safety of LHRH antagonist cetrorelix in the treatment of symptomatic benign prostatic hyperplasia. J Clin Endocrinol Metab, 83, 3826–3831.PubMedCrossRefGoogle Scholar
  11. Cuttitta F., Carney D.N., Mulshine J., Moody T.W., Fedorko J., Fischler A. and Minna J.D. (1985), Bombesin-like peptides can function as autocrine growth factors in human small-cell lung cancer. Nature, 316, 823–826PubMedCrossRefGoogle Scholar
  12. Dondi D., Limonta P., Moretti R.M., Marelli M.M., Garattini E. and Motta M. (1994). Antiproliferative effects of luteinizing hormone-releasing hormone (LHRH) agonists on human androgen-independent prostate cancer cell line DU 145: evidence for an autocrine-inhibitory LHRH loop. Cancer Res, 54, 4091–4095PubMedGoogle Scholar
  13. Emons G., Ortmann O., Becker M., Irmer G., Springer B., Laun R., Holzel F., Schulz K-D. and Schally A.V. (1993). High affinity binding and direct antiproliferative effects of LHRH analogues in human ovarian cancer cell lines. Cancer Res, 53, 5439–5446.PubMedGoogle Scholar
  14. Emons G., Ortmann O., Teichert H.M., Fassl H., Barreton G., Lohrs U., Kullander S., Kauppila A., Ayalon D., Schally A. V, Heinrich C, Schulz K.D. and Oberheuser F. (1996). Luteinizing hormone-releasing hormone agonist triptorelin in combination with cytotoxic chemotherapy in patients with advanced epithelial ovarian cancer — A prospective double blinded randomized trial. Cancer, 78, 1452–1460.PubMedCrossRefGoogle Scholar
  15. Emons G. and Schally A.V. (1994). The use of luteinizing hormone-releasing hormone agonists and antagonists in gynecological cancers. Hum Reprod, 9, 1364–1379.PubMedGoogle Scholar
  16. Gonzalez-Barcena D., Vadillo-Buenfil M., Cortez-Morales A., Fuentes-Garcia M., Cardenas-Cornejo I., Comaru-Schally A.M. and Schally A.V. (1995). Luteinizing hormone-releasing hormone antagonist cetrorelix as primary single therapy in patients with advanced prostatic cancer and paraplegia due to metastatic invasion of spinal cord. Urology, 45, 275–281.PubMedCrossRefGoogle Scholar
  17. Gonzalez-Barcena D., Vadillo-Buenfil M., Gomez-Orta F., Fuentes Garcia M., Cardenas-Cornejo I., Graef-Sanchez A., Comaru-Schally A.M. and Schally A.V. (1994). Responses to the antagonistic analog of LHRH (SB-75, cetrorelix) in patients with benign prostatic hyperplasia and prostatic cancer. Prostate, 24, 84–92.PubMedCrossRefGoogle Scholar
  18. Haimos G., Arenciba J.M., Schally A.V., Davis R. and Bostwick D.G. (2000a). High incidence of receptors for luteinizing hormone-releasing hormone (LHRH) and LHRH receptor gene expression in human prostate cancers. J Urol, 163, 623–629.CrossRefGoogle Scholar
  19. Haimos G, Schally A.V., Sun B., Davis R., Bostwick D.G. and Plonowski A. (2000b). High expression of somatostatin receptors and ribonucleic acid for its receptor subtypes in organ-confined and locally advanced human prostate cancers. J Clin Endocrinol Metab, 85, 2564–2571.CrossRefGoogle Scholar
  20. Huggins C. and Hodges C.V. (1941). Studies of prostatic cancer. I. Effect of castration, estrogens and androgen injections on serum phosphatases in metastatic carcinoma of the prostate. Cancer Res, 1, 293–295Google Scholar
  21. Jungwirth A., Schally A.V., Haimos G, Groot K., Szepeshazi K., Pinski J. and Armatis P. (1998). Inhibition of the growth of Caki-I human renal adenocarcinoma in vivo by LHRH antagonists cetrorelix, somatostatin analog RC-160 and bombesin antagonist RC-3940-II. Cancer, 82, 909–917.PubMedCrossRefGoogle Scholar
  22. Kahan Z., Nagy A., Schally A.V., Haimos G, Arencibia J.M. and Groot K. (1999a). Complete regression of MX- I human breast carcinoma xenografts after targeted chemotherapy with a cytotoxic analog of luteinizing hormone-releasing hormone, AN-207. Cancer, 85, 2608–2615.CrossRefGoogle Scholar
  23. Kahan Z., Nagy A., Schally A.V., Hebert F., Sun B., Groot K. and Haimos G (1999b). Inhibition of growth of MX- I, MCF-7, Mill and MDA-MB-23I human breast cancer xenografts after administration of a targeted cytotoxic analog of somatostatin, AN-238. Int J Cancer, 82, 592–598.CrossRefGoogle Scholar
  24. Kahan Z., Sum Sun B., Schally A.V., Arencibia J.M., Cal R-Z., Groot K. and Haimos G. (2000). Inhibition of growth of MDA-MB-468 estrogen-independent human breast cancers by bombesin/gastrin-releasing peptide (GRP) antagonists RC-3095 and RC-3940-II. Cancer, 88, 1384–1392.PubMedCrossRefGoogle Scholar
  25. Karten M.J. and Rivier J.E. (1986) Gonadotropin-releasing hormone analog design. Structure-function studies toward the development of agonists and antagonists: rationale and perspective. Endocr Rev, 7, 44–66PubMedCrossRefGoogle Scholar
  26. Kaufmann M., Jonat W., Kleeberg U., Eiermann W., Janicke F., Hilfrich J., Kreienberg R., Albrecht M., Weitzel H.K., Schmid H., Strunz P., Schachner-Wunschmann E., Bastert G and Maass H. (1989). Goserelin, a depot gonadotropin-releasing hormone agonist in the treatment of premenopausal patients with metastatic breast cancer. German Zoladex Trial Group. J Clin Oncol, 7, 1113–1119.PubMedGoogle Scholar
  27. Kiaris H., Schally A.V., Nagy A., Sun B., Armatis P. and Szepeshazi K. (1999). Targeted cytotoxic analog of bombesin/gastrin-releasing peptide inhibits the growth of H-69 human small-cell lung carcinoma in nude mice. Br J Cancer, 81, 966–971.PubMedCrossRefGoogle Scholar
  28. Kiaris H., Schally A.V., Nagy A., Sun B., Szepeshazi K. and Haimos G. (2000). Regression of U-87MG human glioblastomas in nude mice after treatment with a cytotoxic somatostatin analog AN-238. Clin Cancer Res, 6, 709–717.PubMedGoogle Scholar
  29. Kiaris H., Schally A.V., Nagy A., Szepeshazi K., Hebert F. and Haimos G (2001) A targeted cytotoxic somatostatin (SST) analogue AN-238 inhibits the growth of H-69 small cell lung carcinoma (SCLC) and H-157 non-SCLC in nude mice. Eur J Cancer, 37, 620–628.PubMedCrossRefGoogle Scholar
  30. Klijn J.G, Beex L.V., Mauriac L., van Zijl J.A., Veyret C, Wildiers J., Jassem J., Piccart M., Burghouts J., Becquart D., Seynaeve C, Mignolet F. and Duchateau L. (2000). Combined treatment with buserelin and tamoxifen in premenopausal metastatic breast cancer: a randomized study. J Natl Cancer Inst, 92, 903–911.PubMedCrossRefGoogle Scholar
  31. Koppan M., Haimos G, Arencibia J.M., Lamharzi N. and Schally A.V. (1998). Bombesin gastrin-releasing peptide antagonists RC-3095 and RC-3940-11 inhibit tumor growth and decrease the levels and mRNA expression of epidermal growth factor receptors in H-69 small cell lung carcinoma. Cancer, 83, 1335–1343.PubMedCrossRefGoogle Scholar
  32. Koppan M., Nagy A., Schally A.V., Plonowski A., Haimos G., Arencibia J.M. and Groot K. (1999). Targeted cytotoxic analog of luteinizing hormone-releasing hormone AN-207 inhibits the growth of PC-82 human prostate cancer in nude mice. Prostate, 38, 151–158.PubMedCrossRefGoogle Scholar
  33. Kovacs M., Schally A.V., Csernus B. and Rekasi Z. (2001). Luteinizing hormone-releasing hormone (LHRH) antagonist cetrorelix down regulates the mRNA expression of pituitary receptors for LHRH by counteracting the stimulatory effect of endogenous LHRH. Proc Natl Acad Sci USA, 98, 1829–1834.PubMedCrossRefGoogle Scholar
  34. Krenning E.P., Kwekkeboom D.J., Bakker W.H., Breeman W.A., Kooij P.P., Oei H.Y., van Hagen M., Postema P.T., de Jong M., Reubi J.C., Visser T.J., Reijs A.E.M., Hofland L.J, Koper J.W, Lamberts S.W.J. and Krenning E.P. (1993). Somatostatin receptor scintigraphy with [111In-DTPA-D-Phei] and [123I-Tyr3]-octreotide: the Rotterdam experience with more than 1000 patients. Eur J Nucl Med, 20, 716–731.PubMedCrossRefGoogle Scholar
  35. Lamberts S.W., Krenning E.P. and Reubi J.C. (1991). The role of somatostatin and its analogs in the diagnosis and treatment of tumors. Endocr Rev, 12, 450–82.PubMedCrossRefGoogle Scholar
  36. Limonta P., Dondi D., Moretti R.M., Maggi R. and Motta M. (1992). Antiproliferative effects of luteinizing hormone-releasing hormone agonists on the human prostatic cancer cell line LNCaP. J Clin Endocrinol Metab, 75, 207–212.PubMedCrossRefGoogle Scholar
  37. Markwalder R. and Reubi J.C. (1999). Gastrin-releasing peptide receptors in the human prostate: relation to neoplastic transformation. Cancer Res, 59, 1152–1159PubMedGoogle Scholar
  38. Miyazaki M., Lamharzi N., Schally A.V, Haimos G., Szepeshazi K., Groot K. and Cai R-Z. (1998). Inhibition of growth of MDA-MB-231 human breast cancer xenografts in nude mice by bombesin/gastrin releasing peptide (GRP) antagonists RC-3940-II and RC-3095. Eur J Cancer, 34, 710–717.PubMedCrossRefGoogle Scholar
  39. Miyazaki M., Nagy A., Schally A.V, Lamharzi N., Haimos G., Szepeshazi K., Groot K. and Armatis P. (1997). Growth inhibition of human ovarian cancers by cytotoxic analogues of luteinizing hormone-releasing hormone. J Natl Cancer Inst, 89, 1803–1809PubMedCrossRefGoogle Scholar
  40. Miyazaki M., Schally A.V, Nagy A., Lamharzi N., Haimos G., Szepeshazi K. and Armatis P (1999). Targeted cytotoxic analog of luteinizing hormone-releasing hormone AN-207 inhibits growth of OV-1063 human epithelial ovarian cancers in nude mice. Am J Obstet Gynecol, 180, 1095–1103PubMedCrossRefGoogle Scholar
  41. Molineaux C.J., Sluss P.M., Bree M.P., Gefter M.L., Sullivan L.M. and Garnie M.B. (1998). Suppression of plasma gonadtrophs by abrelix: a potent new LHRH antagonist. Mol Urol, 2, 265–268.Google Scholar
  42. Nagy A., Armatis P., Cai R-Z., Szepeshazi K., Haimos G. and Schally A.V. (1997). Design, synthesis and in vitro evaluation of cytotoxic analogs of bombesin-like peptides containing doxorubicin or its intensely potent derivative, 2-pyrrolinodoxorubicin. Proc Natl Acad Sci USA, 94, 652-656.PubMedCrossRefGoogle Scholar
  43. Nagy A., Plonowski A. and Schally A.V. (2000). Stability of cytotoxic hormone-releasing hormone conjugate (AN-152) containing doxorubicin-14-O-Hemiglutarate in mouse and human serum in vitro; implications for the design of preclinical studies. Proc Natl Acad Sci USA, 97, 829–834.PubMedCrossRefGoogle Scholar
  44. Nagy A., Schally A.V, Armatis P., Szepeshazi K., Haimos G., Kovacs M., Zarandi M., Groot K., Miyazaki M., Jungwirth A. and Horvath J. (1996). Cytotoxic analogs of luteinizing hormone-releasing hormone containing doxorubicin or 2-pyrrolinodoxorubicin, a derivative 500-1000 times more potent. Proc Natl Acad Sci USA, 93, 7269–7273.PubMedCrossRefGoogle Scholar
  45. Nagy A., Schally A.V, Haimos G., Armatis P., Cai R-Z., Csernus V, Kovacs M., Koppan M., Szepeshazi K. and Kahn Z. (1998). Synthesis and biological evaluation of cytotoxic analogs of somatostatin containing doxorubicin or its intensely potent derivative 2-pyrrolinodoxonubicin. Proc Natl Acad Sci USA, 95, 1794–1799.PubMedCrossRefGoogle Scholar
  46. Patel Y.C. (1997). Molecular pharmacology of somatostatin receptor subtypes. J Endocrinol Invest, 20, 348–367.PubMedGoogle Scholar
  47. Pinski J., Lamharzi N., Haimos G., Groot K., Jungwirth A., Vadillo-Buenfil M., Kakar S.S. and Schally A.V. (1996). Chronic administration of luteinizing hormone-releasing hormone (LHRH) antagonist Cetrorelix decreases gonadotrope responsiveness and pituitary LHRH receptor messenger ribonucleic acid levels in rats. Endocrinology, 137, 3430–3436.PubMedCrossRefGoogle Scholar
  48. Plonowski A., Nagy A., Schally A.V., Sun B., Groot K. and Haimos G. (2000a). In vivo inhibition of PC-3 human androgen-independent prostate cancer by a targeted cytotoxic bombesin analogue AN-215. Int J Cancer, 88, 652–657.CrossRefGoogle Scholar
  49. Plonowski A., Schally A.V., Nagy A., Kiaris H., Hebert F. and Haimos G. (2000b). Inhibition of metastatic renal cell carcinomas expressing somatostatin receptors by a targeted cytotoxic analog of somatostatin AN-238. Cancer Res, 60, 2996–3001.Google Scholar
  50. Plonowski A., Schally A.V., Nagy A., Sun B. and Szepeshazi K. (1999). Inhibition of PC-3 human androgen-independent prostate cancer and its metastases by cytotoxic somatostatin analogue AN-238. Cancer Res, 59, 1947–1953.PubMedGoogle Scholar
  51. Plonowski A., Schally A.V., Varga J.L., Rekasi Z., Hebert F., Haimos G. and Groot K. (2000c). Potentiation of the inhibitory effect of growth hormone-releasing hormone antagonists on PC-3 human prostate cancer by bombesin antagonists indicative of interference with both IGF and EGF pathways. Prostate, 44, 172–180.CrossRefGoogle Scholar
  52. Redding T.W. and Schally A.V. (1981). Inhibition of prostate tumor growth in two rat models by chronic administration of D-Trp6-LHRH. Proc Nat Acad Sci USA, 78, 6509–6512PubMedCrossRefGoogle Scholar
  53. Reubi J.C. and Kvols L. (1992). Somatostatin receptors in human renal cell carcinomas.Google Scholar
  54. Cancer Res, 52, 6074–6078.Google Scholar
  55. Santen R.J., Manni A., Harvey H. and Redmond C. (1990). Endocrine treatment of breast cancer in women. Endocr Rev, 11, 221–265.PubMedCrossRefGoogle Scholar
  56. Schally A.V. (1988). Oncological applications of somatostatin analogs. Cancer Res, 48, 6977–6985.PubMedGoogle Scholar
  57. Schally A.V. (1999). Luteinizing hormone-releasing hormone analogs: their impact on the control of tumorigenesis. Peptides, 20, 1247–1262.PubMedCrossRefGoogle Scholar
  58. Schally A.V, Arimura A., Baba Y., Nair R.M.G, Matsuo H., Redding T.W., Debeljuk L. and White W.F. (1971a). Isolation and properties of the FSH- and LH-releasing hormone. Biochem Biophys Res Commun, 43, 393–399.CrossRefGoogle Scholar
  59. Schally A.V, Arimura A., Kastin A.J., Matsuo H., Baba Y., Redding T.W, Nair R.M.G, Debeljuk L. and White W.F. (1971b). Gonadotropin-releasing hormone: one polypeptide regulates secretion of luteinizing and follicle-stimulating hormones. Science, 173, 1036–1038.CrossRefGoogle Scholar
  60. Schally A.V, Comaru-Schally A.M., Nagy A., Kovacs M., Szepeshazi K., Plonowski A., Varga J.L. and Haimos G (2001a). Hypothalamic hormones and cancer. Frontiers Neuroendocrinol, 22, 248–291.CrossRefGoogle Scholar
  61. Schally A.V, Comaru-Schally A.M., Plonowski A., Nagy A., Haimos G. and Rekasi Z. (2000). Peptide analogs in the Therapy of Prostate Cancer. Prostate, 45, 158–166.PubMedCrossRefGoogle Scholar
  62. Schally A.V, Haimos G, Rekasi Z. and Arencibia J.M. (2001b). The actions of LHRH agonists, antagonists, and cytotoxic analogs on the LHRH receptors on the pituitary and tumors. In Infertil Reprod Med Clin N Am, 12, 17–44.Google Scholar
  63. Schally A.V, Kastin A.J. and Arimura A. (1971c). Hypothalamic FSH and LH-regulating hormone, structure, physiology, and clinical studies. Fertil Steril, 22, 703–721.Google Scholar
  64. Schally A.V and Nagy A. (1999). Cancer chemotherapy based on targeting of cytotoxic peptide conjugates to their receptors on tumors. Eur J Endocrinol, 141, 1–14.PubMedCrossRefGoogle Scholar
  65. Shriver S.P., Bourdeau H.A., Gubish CT., Tirpak D.L., Davis A.L., Luketich J.D. and Siegfried J.M. (2000). Sex-specific expression of gastrin-releasing peptide receptor: relationship to smoking history and risk of lung cancer. J Natl Cancer Inst, 92, 24–33.PubMedCrossRefGoogle Scholar
  66. Sun B., Haimos G, Schally A.V, Wang X. and Martinez M. (2000). The presence of receptors for bombesin/gastrin-releasing peptide and mRNA for three receptor subtypes in human prostate cancers. Prostate, 42, 295–303.PubMedCrossRefGoogle Scholar
  67. Sunday M.E., Kaplan L.M., Motoyama E., Chin W.W. and Spindel E.R. (1988). Gastrin-releasing peptide (mammalian bombesin) gene expression in health and disease. Lab Invest, 59, 5–24.PubMedGoogle Scholar
  68. Szepeshazi K., Schally A.V., Haimos G., Armatis R, Hebert F., Sun B., Feil A., Kiaris H. and Nagy A. (2002). Targeted cytotoxic somatostatin analogue an-238 inhibits somatostatin receptor-positive experimental colon cancers independently of their pS3 status. Cancer Res, 62, 781–788.PubMedGoogle Scholar
  69. Szepeshazi K., Schally A.V., Haimos G., Sun B., Hebert F., Csernus B. and Nagy A. (2001). Targeting of cytotoxic somatostatin analog AN-238 to somatostatin receptor subtypes 5 and/or 3 in experimental pancreatic cancer. Clin Cancer Res, 7, 2854–2861.PubMedGoogle Scholar
  70. Szereday Z., Schally A. V., Nagy A., Plonowski A., Bajo A.M., Haimos G., Szepeshazi K. and Groot K. (2002). Effective treatment of experimental U-87MG human glioblastoma in nude mice with a targeted cytotoxic bombesin analogue, AN-215. Br J Cancer, 86, 1322–1327.PubMedCrossRefGoogle Scholar
  71. Tolis G., Ackman D., Stellos A., Mehta A., Labrie F., Fazekas A.T., Comaru-Schally A.M. and Schally A.V. (1982). Tumor growth inhibition in patients with prostatic carcinoma treated with luteinizing hormone-releasing hormone agonists. Proc Natl Acad Sci USA, 79, 1658–1662.PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Italia 2003

Authors and Affiliations

  • A. V. Schally

There are no affiliations available

Personalised recommendations