The biology of gonadotropin hormone-releasing hormone: Role in the control of tumor growth and progression in humans

Frontiers in Neuroendocrinology

Volumn 24, Issue 4, 2003, Pages 279-295

  Limonta, Patrizia ^a   Moretti, Roberta M ^a   Marelli, Marina Montagnani ^a   Motta, Marcella ^a  

^a Center for Endocrinological Oncology   (Italy)

Author keywords

[No Author keywords available]

Indexed keywords

ABARELIX; AZALINE B; BUSERELIN; CETRORELIX; GANIRELIX; GONADORELIN; GONADORELIN ANTAGONIST; GOSERELIN; GROWTH HORMONE RELEASING FACTOR; LEUPRORELIN; NAFARELIN; PEPTIDE HORMONE; RELEASING FACTOR; TRIPTORELIN; UNCLASSIFIED DRUG;

BINDING AFFINITY; BIOACCUMULATION; CANCER CELL; CELL ADHESION; CHICKEN; DISEASE COURSE; EXTRACELLULAR MATRIX; GENITAL SYSTEM; GONADOTROPIN RELEASE; HORMONE SYNTHESIS; HUMAN; MAMMAL; MELANOMA CELL; MEMBRANE POTENTIAL; METASTASIS; MOLECULAR WEIGHT; NONHUMAN; PRIMATE; PRIORITY JOURNAL; PROTEIN ANALYSIS; PROTEIN DEGRADATION; PROTEIN DOMAIN; PROTEIN EXPRESSION; PROTEIN SECRETION; REGULATORY MECHANISM; REVIEW; SIGNAL TRANSDUCTION; TUMOR GROWTH; VERTEBRATE;

EID: 0347320615     PISSN: 00913022     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.yfrne.2003.10.003     Document Type: Article

References (200)

1. Arencibia J.M., Schally A.V. Luteinizing hormone-releasing hormone as an autocrine growth factor in ES-2 ovarian cancer cell line. Int. J. Oncol. 16:2000;1009-1013.
2. Bahk J.Y., Hyun J.S., Lee H., Kim M.O., Cho G.J., Lee B.H., Choi W.S. Expression of gonadotropin-releasing hormone (GnRH) and GnRH receptor mRNA in prostate cancer cells and effect of GnRH on the proliferation of prostate cancer cells. Urol. Res. 26:1998;259-264.
3. Baumann K.H., Kiesel L., Kaufmann M., Bastert G., Runnebaum B. Characterization of binding sites for a GnRH-agonist (buserelin) in human breast cancer biopsies and their distribution in relation to tumor parameters. Breast Cancer Res. Treat. 25:1993;37-46.
4. Becker J.C., Kampgen E., Brocker E. Classical chemotherapy for metastatic melanoma. Clin. Exp. Dermatol. 25:2000;503-508.
5. Belsham D.D., Evangelou A., Roy D., Duc V.L., Brown T.J. Regulation of gonadotropin-releasing hormone (GnRH) gene expression by 5alpha- dihydrotestosterone in GnRH-secreting GT1-7 hypothalamic neurons. Endocrinology. 139:1998;1108-1114.
6. Burfeind P., Chernicky C.L., Rininsland F., Ilan J. Antisense-RNA to the type I insulin-like growth factor receptor suppresses tumor growth and prevents invasion by rat prostate cancer cells in vivo. Proc. Soc. Natl. Acad. Sci. USA. 93:1996;7263-7268.
7. Chatzaki E., Bax C.M., Eidne K.A., Anderson L., Grudzinskas J.G., Gallagher C.J. The expression of gonadotropin-releasing hormone and its receptor in endometrial cancer, and its relevance as an autocrine growth factor. Cancer Res. 56:1996;2059-2065.
8. Chen A., Ganor Y., Rahimipour S., Ben-Aroya N., Koch Y., Levite M. The neuropeptides GnRH-II and GnRH-I are produced by human T cells and trigger laminin receptor gene expression, adhesion, chemiotaxis and homing to specific organs. Nat. Med. 8:2002;1421-1426.
9. Chen A., Yahalom D., Ben-Aroya N., Kaganovsky E., Okon E., Koch Y. A second isoform of gonadotropin-releasing hormone is present in the brain of human and rodents. FEBS Lett. 435:1998;199-203.
10. Cheon K.W., Lee H.S., Parhar I.S., Kang I.S. Expression of the second isoform of gonadotropin hormone (GnRH-II) in human endometrium throughout the menstrual cycle. Mol. Hum. Reprod. 7:2001;447-452.
11. Choi K.-C., Auersperg N., Leung P.C.K. Expression and anti-proliferative effect of a second form of gonadotropin-releasing hormone in normal and neoplastic ovarian surface epithelial cells. J. Clin. Endocrinol. Metab. 86:2001;5075-5078.
12. Chou C.S., MacCalman C.D., Leung P.C. Differential effects of gonadotropin-releasing hormone I and II on the urokinase-type plasminogen activator/plasminogen activator inhibitor system in human decidual stromal cell in vitro. J. Clin. Endocrinol. Metab. 88:2003;3806-3815.
13. Chou C.S., Zhu H., Shalev E., MacCalman C.D., Leung P.C. The effects of gonadotropin-releasing hormone (GnRH) I and II on the urokinase-type plasminogen activator/plasminogen inhibitor system in human extravillous cytotrophoblasts in vitro. J. Clin. Endocrinol. Metab. 87:2002;5594-5603.
14. Clayton R.N. Gonadotropin-releasing hormone: its actions and receptors. J. Endocrinol. 120:1989;11-19.
15. Conn P.M., Crowley W.F. Jr. Gonadotropin-releasing hormone and its analogues. Annu. Rev. Med. 45:1994;391-405.
16. Connolly J.M., Rose D.P. Autocrine regulation of DU145 human prostate cancer cell growth by epidermal growth factor-related polypeptides. Prostate. 19:1991;173-180.
17. Connolly J.M., Rose D.P. Regulation of DU145 human prostate cancer cell proliferation by insulin-like growth factors and its interaction with the epidermal growth factor autocrine loop. Prostate. 24:1994;167-175.
18. Densmore V.S., Urbanski H.F. Relative effect of gonadotropin-releasing hormone (GnRH)-I and GnRH-II on gonadotropin release. J. Clin. Endocrinol. Metab. 88:2003;2126-2134.
19. Dondi D., Limonta P., Moretti R.M., Montagnani Marelli M., Garattini E., Motta M. Antiproliferative effects of luteinizing hormone-releasing hormone (LHRH) agonists on human androgen-independent prostate cancer cell line DU 145: evidence for an autocrine-inhibitory GnRH loop. Cancer Res. 54:1994;4091-4095.
20. Dondi D., Moretti R.M., Montagnani Marelli M., Pratesi G., Polizzi D., Milani M., Motta M., Limonta P. Growth inhibitory effects of luteinizing hormone-releasing hormone (LHRH) agonists on xenografts of the DU 145 human androgen-independent prostate cancer cell line in nude mice. Int. J. Cancer. 76:1998;506-511.
21. Dubois E.A., Zandbergen M.A., Peute J., Goos H.J.Th. Evolutionary development of three gonadotropin-releasing hormone (GnRH) systems in vertebrates. Brain Res. Bull. 57:2002;413-418.
22. Emons G., Muller V., Ortmann O., Grossmann G., Tautner U., von Stuckrad B., Schulz K.-D., Schally A.V. Luteinizing hormone-releasing hormone agonist triptorelin antagonizes signal transduction and mitogenic activity of epidermal growth factor in human ovarian and endometrial cancer cell lines. Int. J. Oncol. 9:1996;1129-1137.
23. Emons G., Muller V., Ortmann O., Schulz K.-D. Effects of GnRH-analogues on mitogenic signal transduction in cancer cells. J. Steroid Biochem. Mol. Biol. 65:1998;199-206.
24. Emons G., Ortmann O., Becker M., Irmer G., Springer B., Laun R., Holzel F., Schulz K.-D., Schally A.V. High affinity binding and direct antiproliferative effects of GnRH analogues in human ovarian cancer cell lines. Cancer Res. 53:1993;5439-5446.
25. Emons G., Ortmann O., Schulz K.-D. GnRH analogues in ovarian, breast and endometrial cancers. GnRH Analogues. The State of the Art. 1996;13-26 Parthenon Publishing Group, Carnforth, UK.
26. Emons G., Ortman O., Schulz K.-D., Schally A.V. Growth inhibitory actions of analogs of luteinizing hormone releasing on tumor cells. Trends Endocrinol. Metab. 8:1997;355-362.
27. Emons G., Pahwa G.S., Ortmann O., Knuppen R., Oberheuser F., Schulz K.-D. GnRH-receptors and GnRH-agonist treatment in ovarian cancer: an overview. J. Steroid Biochem. Mol. Biol. 37:1990;1003-1006.
28. Emons G., Schally A.V. The use of luteinizing hormone-releasing hormone agonists and antagonists in gynecological cancers. Hum. Reprod. 9:1994;1364-1379.
29. Emons G., Schroder B., Ortmann O., Westphalen S., Schulz K.-D., Schally A.V. High affinity binding and direct antiproliferative effects of luteinizing hormone-releasing hormone analogs in human endometrial cancer cell lines. J. Clin. Endocrinol. Metab. 77:1993;1458-1464.
30. Emons G., Weiss S., Ortmann O., Grundker C., Schulz K.-D. Luteinizing hormone-releasing hormone (LHRH) might act as a negative autocrine regulator of proliferation of human ovarian cancer. Eur. J. Endocrinol. 142:2000;665-670.
31. Fan N.C., Peng C., Krisinger J., Leung P.C. The human gonadotropin-releasing hormone receptor gene: complete structure including multiple promoters, transcription initiation sites and polyadenylation signals. Mol. Cell. Endocrinol. 107:1995;R1-R8.
32. Felberbaum R.E., Ludwig M., Diedrich K. Clinical application of GnRH-antagonists. Mol. Cell. Endocrinol. 166:2000;9-14.
33. Fernald R.D., White R.B. Gonadotropin-releasing hormone genes: phylogeny, structure, and functions. Front. Neuroendocrinol. 20:1999;224-240.
34. Fink G. Gonadotropin secretion and its control. Neill J.D. The Physiology of Reproduction. 1988;1349-1377 Raven Press, New York.
35. Furui T., Imai A., Takagi H., Horibe S., Fuseya T., Tamaya T. Phosphotyrosine phosphatase activity in membranes from endometrial carcinoma. Oncol. Rep. 2:1995;1055-1057.
36. Gore A.C., Roberts J.L. Regulation of gonadotropin-releasing hormone gene expression in vivo and in vitro. Front. Neuroendocrinol. 18:1997;209-245.
37. Grosse R., Schmid A., Schoneberg T., Herrlich A., Muhn P., Schultz G., Gudermann T. Gonadotropin-releasing hormone receptor initiate multiple signaling pathways by exclusively coupling to Gq/11 proteins. J. Biol. Chem. 275:2000;9193-9200.
38. Grundker C., Gunthert A.R., Westphalen S., Emons G. Biology of the gonadotropin-releasing hormone system in gynecological cancers. Eur. J. Endocrinol. 146:2002;1-14.
39. Grundker C., Schulz K.-D., Gunthert A.R., Emons G. Luteinizing hormone-releasing hormone induces nuclear factor kappaB-activation and inhibits apoptosis in ovarian cancer cells. J. Clin. Endocrinol. Metab. 85:2000;3815-3820.
40. Grundker C., Volker P., Schulz K.D., Emons G. Luteinizing hormone-releasing hormone agonist triptorelin and antagonist cetrorelix inhibit EGF-induced c-fos expression in human gynecological cancers. Gynecol. Oncol. 78:2000;194-202.
41. Halmos G., Arencibia J.M., Schally A.V., Davis R., Bostwick D.G. High incidence of receptors for luteinizing hormone-releasing hormone (GnRH) and GnRH receptor gene expression in human prostate cancers. J. Urol. 163:2000;623-629.
42. Halmos G., Schally A.V., Kahan Z. Down-regulation and change in subcellular distribution of receptors for luteinizing hormone-releasing hormone in OV-1063 human epithelial ovarian cancers during therapy with LH-RH antagonist Cetrorelix. Int. J. Oncol. 17:2000;367-373.
43. Harris N., Dutlow C., Eidne K., Dong K.W., Roberts J., Millar R.P. Gonadotropin-releasing hormone gene expression in MDA-MB-231 and ZR-75-1 breast carcinoma cell lines. Cancer Res. 51:1991;2577-2581.
44. Harris D., Reiss N., Naor Z. Differential activation of protein kinase C delta and epsilon gene expression by gonadotropin-releasing hormone in alphaT3-1 cells: autoregulation of protein kinase C. J. Biol. Chem. 272:1997;13534-13540.
45. Haviv F., Bush E.N., Knittle J., Greer J. GnRH antagonists. Pharm. Biotechnol. 11:1998;131-149.
46. Hayflick J.S., Adelman J.P., Seeburg P.H. The complete nucleotide sequence of the human gonadotropin-releasing hormone gene. Nucleic Acids Res. 17:1989;6403-6404.
47. Herbison A.E., Pape J.-R. New evidence for estrogen receptors in gonadotropin-releasing hormones neurons. Front. Neuroendocrinol. 22:2001;292-308.
48. Hofmann U.B., Westphal J.R., Waas E.T., Zendman A.J.W., Cornelissen I.M.H.A., Ruiter D.J., van Muijen G.N.P. Matrix metalloproteinases in human melanoma cell lines and xenografts: increased expression of activated matrix metalloproteinase-2 (MMP-2) correlates with melanoma progression. Br. J. Cancer. 81:1999;774-782.
49. 125I-estrogen binding sites in luteinizing hormone-releasing hormone neurons of the rat brain. Endocrinology. 141:2000;3506-3509.
50. Huang Y.T., Huang J.J., Lee L.T., Liebow C., lee P.P., Ke F.C., Lo T.B., Schally A.V., Lee M.T. Inhibitory effects of luteinizing hormone-releasing hormone agonist on basal and epidermal growth factor-induced cell proliferation and metastasis-associate properties in human epidermoid carcinoma A431 cells. Int. J. Cancer. 99:2002;505-513.
51. Huirne J.A., Lambalk C.B. Gonadotropin-releasing-hormone-receptor antagonists. Lancet. 358:2001;1793-1803.
52. Illing N., Troskie B.E., Nahorniak C.S., Hapgood J.P., Peter R.E., Millar R.P. Two gonadotropin-releasing hormone receptor subtypes with distinct ligand selectivity and differential distribution in brain and pituitary in the goldfish (Carassius auratus). Proc. Natl. Acad. Sci. USA. 96:1999;2526-2531.
53. Imai A., Horibe S., Takagi H., Fuseya T., Tamaya T. Signal transduction of GnRH receptor in the reproductive tract tumor. Endocrinol. J. 43:1996;249-260.
54. Imai A., Horibe S., Takagi A., Tamaya T. Gi protein activation of gonadotropin-releasing hormone-mediated protein dephosphorylation in human endometrial carcinoma. Am. J. Obstet. Gynecol. 176:1997;371-376.
55. Imai A., Ohno T., Iida K., Fuseya T., Furui T., Tamaya T. Gonadotropin-releasing hormone receptors in gynecological tumors. Cancer. 74:1994;2555-2561.
56. Imai A., Ohno T., Iida K., Fuseya T., Furui T., Tamaya T. Presence of gonadotropin-releasing hormone receptor and its messenger ribonucleic acid in endometrial carcinoma and endometrium. Gynecol. Oncol. 55:1994;144-148.
57. Imai A., Takagi H., Furui T., Horibe S., Fuseya T., Tamaya T. Evidence for coupling of phosphotyrosine phosphatase to a gonadotropin-releasing hormone receptor in ovarian carcinoma membrane. Cancer. 77:1996;132-137.
58. Imai A., Takagi H., Horibe S., Fuseya T., Tamaya T. Coupling of gonadotropin-releasing hormone receptor to Gi protein in human reproductive tract tumors. J. Clin. Endocrinol. Metab. 81:1996;3249-3253.
59. Imai A., Takagi A., Horibe S., Takagi H., Tamaya T. Evidence for tight coupling of gonadotropin-releasing hormone receptor to stimulated Fas ligand expression in reproductive tract tumors: Possible mechanism for hormonal control of apoptotic cell death. J. Clin. Endocrinol. Metab. 83:1998;427-431.
60. Imai A., Takagi A., Horibe S., Takagi H., Tamaya T. Fas and Fas ligand system may mediate antiproliferative activity of gonadotropin-releasing hormone receptor in endometrial cancer cells. Int. J. Oncol. 13:1998;97-100.
61. Imai A., Tamaya T. GnRH receptor and apoptotic signaling. Vitam. Horm. 59:2000;1-33.
62. Irmer G., Burger C., Muller R., Ortmann O., Peter U., Kakar S.S., Neill J.D., Schulz K.-D., Emons G. Expression of the messenger RNAs for luteinizing hormone-releasing hormone (LHRH) and its receptor in human ovarian epithelial carcinoma. Cancer Res. 55:1995;817-822.
63. Irmer G., Burger C., Ortmann O., Shulz K.-D., Emons G. Expression of luteinizing hormone-releasing hormone and its mRNA in human endometrial cancer cell lines. J. Clin. Endocrinol. Metab. 79:1994;916-919.
64. Iwamura M., Sluss P.M., Casamento J.B., Cockett A.T.K. Insulin-like growth factor I: action and receptor characterization in human prostate cancer cell lines. Prostate. 22:1993;243-252.
65. Jungwirth A., Galvan G., Pinski J., Halmos G., Szepeshazi K., Cai R.Z., Groot K., Schally A.V. Luteinizing hormone-releasing hormone antagonist Cetrorelix (SB-75) and bombesin antagonist RC-3940-II inhibit the growth of androgen-independent PC3 prostate cancer in nude mice. Prostate. 32:1997;164-172.
66. Jungwirth A., Pinski J., Galvan G., Halmos G., Szepeshazi K., cai R.Z., Groot K., Vadillo-Buenfil M., Schally A.V. Inhibition of growth of androgen-independent DU-145 prostate cancer in vivo by luteinising hormone-releasing hormone antagonist Cetrorelix and bombesin antagonists RC-3940-II and RC-3950-II. Eur. J. Cancer. 33:1997;1141-1148.
67. Kaiser U.B., Conn P.M., Chin W.W. Studies of gonadotropin-releasing hormone (GnRH) action using GnRH receptor-expressing pituitary cell lines. Endocrinol. Rev. 18:1997;46-70.
68. Kakar S.S. Molecular structure of the human gonadotropin-releasing hormone receptor gene. Eur. J. Endocrinol. 137:1997;183-192.
69. Kakar S.S., Grizzle W.E., Neill J.D. The nucleotide sequences of human GnRH receptors in breast and ovarian tumors are identical with that found in pituitary. Mol. Cell. Endocrinol. 106:1994;145-149.
70. Kakar S.S., Musgrove L.C., Devor D.C., Sellers J.C., Neill J.D. Cloning, sequencing, and expression for human gonadotropin releasing hormone (GnRH) receptor. Biochem. Biophys. Res. Commun. 189:1992;289-295.
71. Kalra S.P. Mandatory neuropeptide-steroid signaling for the preovulatory luteinizing hormone-releasing hormone discharge. Endocrinol. Rev. 14:1993;507-538.
72. Kalra S.P., Kalra P.S. Regulation of gonadotropin secretion: emerging new concepts. Imura H. The Pituitary Gland. second ed. 1994;285-308 Raven Press, New York.
73. Kalra S.P., Horvath T., Naftolin F., Xu B., Pu S., Kalra P.S. The interactive language of the hypothalamus for the gonadotropin releasing hormone (GnRH) system. J. Neuroendocrinol. 9:1997;569-576.
74. Kang S.K., Choi K.-C., Cheng K.W., Nathwani P.S., Auersperg N., Leung P.C.K. Role of gonadotropin-releasing hormone as an autocrine growth factor in human ovarian surface epithelium. Endocrinology. 141:2000;72-80.
75. Kang S.K., Choi K.-C., Yang H.-S., Leung P.C.K. Potential role of gonadotrophin-releasing hormone (GnRH)-I and GnRH-II in the ovary and ovarian cancer. Endocr. Rel. Cancer. 10:2003;169-177.
76. Kang S.K., Tai C.-J., Cheng K.W., Leung P.C.K. Gonadotropin-releasing hormone activates mitogen-activated protein kinase in human ovarian and placental cells. Mol. Cell. Endocrinol. 170:2000;143-151.
77. Kang S.K., Tai C.-J., Nathwani P.S., Leung P.C.K. Differential regulation of two forms of gonadotropin-releasing hormone messenger ribonucleic acid in human granulosa-luteal cells. Endocrinology. 142:2001;182-192.
78. Karande A.A., Rajeshwari K., Schol D.J., Hilgers J.H.M. Establishment of immunological probes to study human gonadotropin-releasing hormone receptors. Mol. Cell. Endocrinol. 114:1995;51-56.
79. Karten M.J., Rivier J.E. Gonadotropin-releasing hormone analog design. Structure-function studies toward the development of agonists and antagonists: rationale and perspectives. Endocr. Rev. 7:1986;44-66.
80. Kasten T.L., White S.A., Norton T.T., Bond C.T., Adelman J.P., Fernald R.D. Characterization of two new prepro-GnRH mRNAs in the tree shrew: First direct evidence for mesencephalic GnRH gene expression in a placental mammal. Gen. Comp. Endocrinol. 104:1996;7-19.
81. Keri G., Balogh A., Szoke B., Teplan I., Csuka O. Gonadotropin-releasing hormone analogues inhibit cell proliferation and activate signal transduction pathways in MDA-MB-231 human breast cancer cell line. Tumour Biol. 12:1991;61-67.
82. Khosravi S., Leung P.C.K. Differential regulation of gonadotropin- releasing hormone (GnRH)I and GnRHII messenger ribonucleic acid by gonadal steroids in human granulosa luteal cells. J. Clin. Endocrinol. Metab. 88:2003;663-672.
83. Kiesel L.A., Rody A., Greb R.R., Szilagy A. Clinical use of GnRH analogues. Clin. Endocrinol. 56:2002;677-687.
84. Kimura G., Kasuya J., Giannini S., Honda Y., Mohan S., Kawachi M., Akimoto M., Fujita-Yamaguchi Y. Insulin-like growth factor (IGF) system components in human prostatic cancer cell lines: LNCaP, DU145, and PC3 cells. Int. J. Urol. 3:1996;39-46.
85. Kimura A., Ohmichi M., Kurachi H., Ikegami H., Hayakawa J., Tasaka K., Kanda Y., Nishio Y., Jikihara H., Matsuura N., Murata Y. Role of mitogen-activated protein kinase/extracellular signal-regulated kinase cascade in gonadotropin-releasing hormone-induced growth inhibition of a human ovarian cancer cell line. Cancer Res. 59:1999;5133-5142.
86. King J.A., Millar R.P. Heterogeneity of vertebrate luteinizing hormone. Science. 206:1979;67-69.
87. King J.A., Millar R.P. Structure of chicken hypothalamic GnRH I. Structural determination on partially purified material. J. Biol. Chem. 257:1982;10722-10728.
88. King J.A., Millar R.P. Structure of chicken hypothalamic GnRH II. Isolation and characterization. J. Biol. Chem. 257:1982;10729-10732.
89. King J.A., Millar R.P. Evolution of gonadotropin-releasing hormone. Trends Endocrinol. Metab. 3:1992;339-346.
90. King J.A., Millar R.P. Evolutionary aspects of gonadotropin-releasing hormone and its receptor. Cell. Mol. Neurobiol. 15:1995;5-23.
91. Kleinman D., Douvdevani A., Scahhly A.V., Levi J., Sharoni Y. Direct growth inhibition of human endometrial cancer cells by the gonadotropin- releasing hormone antagonist SB-75: role of apoptosis. Am. J. Obstet. Gynecol. 170:1994;96-102.
92. Kniewald Z., Massa R., Motta M., Martini L. Feedback mechanisms and the control of the hypothalamohypophysial complex. UCLA Forum Med. Sci. 15:1972;289-299.
93. Kottler M.L., Starzec A., Carre M.C., Lagarde J.P., Martin A., Counis R. The genes for gonadotropin-releasing hormone and its receptor are expressed in human breast with fibrocystic disease and cancer. Int. J. Cancer. 71:1997;595-599.
94. Kraus S., Naor Z., Seger R. Intracellular signaling pathways mediated by the gonadotropin-releasing hormone (GnRH) receptor. Arch. Med. Res. 32:2001;499-509.
95. Krsmanovic L.Z., Stojilkovic S.S., Mertz L.M., Tomic M., Catt K.V. Expression of gonadotropin-releasing hormone receptors and autocrine regulation of neuropeptide release in immortalized hypothalamic neurons. Proc. Natl. Acad. Sci. USA. 90:1993;3908-3912.
96. Latimer V.S., Kohama S.G., Garyfallou V.T., Urbanski H.F. A developmental increase in the expression of messenger ribonucleic acid encoding a second form of gonadotropin-releasing hormone in the rhesus macaque hypothalamus. J. Clin. Endocrinol. Metab. 86:2001;324-329.
97. Lee M.T., Liebow C., Kramer A.R., Schally A.V. Effects of epidermal growth factor and analogues of luteinizing hormone-releasing hormone and somatostatin on phosphorylation of tyrosine residues of specific substrates in various tumors. Proc. Natl. Acad. Sci. USA. 88:1991;1656-1660.
98. Lescheid D.W., Terasawa E., Abler L.A., Urbansky H.F., Warby C.M., Millar R.P., Sherwood N.M. A second form of gonadotropin-releasing hormone (GnRH) with characteristics of chicken GnRH-II is present in the primate brain. Endocrinology. 138:1997;5618-5629.
99. Liebow C., Lee M.T., Kramer A.R., Schally A.V. Regulation of luteinizing hormone-releasing hormone receptor binding by heterologous receptor-stimulated tyrosine phosphorylation. Proc. Natl. Acad. Sci. USA. 88:1991;2244-2248.
100. Limonta P., Dondi D., Moretti R.M., Fermo D., Garattini E., Motta M. Expression of luteinizing hormone-releasing hormone mRNA in the human prostatic cancer cell line LNCaP. J. Clin. Endocrinol. Metab. 76:1993;797-800.
101. Limonta P., Dondi D., Moretti R.M., Maggi R., Motta M. Antiproliferative effects of luteinizing hormone-releasing hormone agonists on the human prostatic cancer cell line LNCaP. J. Clin. Endocrinol. Metab. 75:1992;207-212.
102. Limonta P., Montagnani Marelli M., Moretti R.M. GnRH analogues as anticancer agents: pituitary and extrapituitary sites of action. Exp. Opin. Invest. Drugs. 10:2001;709-720.
103. Limonta P., Moretti R.M., Dondi D., Montagnani Marelli M., Motta M. The EGF/TGFα system as an autocrine growth stimulatory loop in LNCaP cells. Endocr. Rel. Cancer. 1:1994;5-13.
104. Limonta P., Moretti R.M., Montagnani Marelli M., Dondi D., Motta M. GnRH as a growth-inhibitory factor in prostatic tumor cells: possible mechanism of action. Endocr. Rel. Cancer. 3:1996;211-216.
105. Limonta P., Moretti R.M., Montagnani Marelli M., Dondi D., Parenti M., Motta M. The luteinizing hormone-releasing hormone receptor in human prostate cancer cells: messenger ribonucleic acid expression, molecular size and signal transduction pathway. Endocrinology. 140:1999;5250-5256.
106. P. Limonta, G. Pratesi, R.M. Moretti, M. Montagnani Marelli, M. Motta, D. Dondi, in: A. Jungwirth et al. (Ed.), Comments on: Inhibition of Growth of Androgen Independent DU-145 Prostate Cancer in vivo by Luteinising Hormone-releasing Hormone Antagonist Cetrorelix and Bombesin Antagonists RC-3940-II and RC-3950-II, Eur. J. Cancer 33 (1997) 1141-1148', Br. J. Cancer. 34 (1998) 1134-1135.
107. Lin X.-W., Otto C.J., Peter R.E. Evolution of neuroendocrine peptide systems: gonadotropin-releasing hormone and somatostatin. Comp. Biochem. Physiol. Part C. 119:1998;375-388.
108. Ma Y.J., Berg-von der Emde K., Rage F., Wetsel W.C., Ojeda S.R. Hypothalamic astrocytes respond to transforming growth factor-alpha with the secretion of neuroactive substances that stimulate the release of luteinizing hormone-releasing hormone. Endocrinology. 138:1997;19-25.
109. Ma Y.J., Junier M.P., Costa M.E., Ojeda S.R. Transforming growth factor-alpha gene expression in the hypothalamus is developmentally regulated and linked to sexual maturation. Neuron. 9:1992;657-670.
110. MacKie R.M. Incidence, risk factors and prevention of melanoma. Eur. J. Cancer. 34:1998;S3-S6.
111. Maney D.L., Richardson J.C., Wingfield J.C. Central administration of chicken gonadotropin-releasing-II enhances courtship behavior in a female sparrow. Horm. Behav. 32:1997;11-18.
112. Mangia A., Tommasi S., Reshkin S.J., Simone G., Stea B., Schittulli F., Paradiso A. Gonadotropin releasing hormone receptor expression in primary breast cancer: comparison of immunohistochemical, radioligand and Western blot analyses. Oncol. Rep. 9:2002;1127-1132.
113. Martinez de la Escalera G., Clapp C. Regulation of gonadotropin- releasing hormone secretion: insights from GT1 immortal GnRH neurons. Arch. Med. Res. 32:2001;486-498.
114. Matsuo H., Baba Y., Nair R.M.G., Arimura A., Schally A.V. Structure of the porcine LH- and FSH-releasing hormone. I. The proposed aminoacid sequence. Biochem. Biophys. Res. Commun. 43:1971;1334-1339.
115. McCann S.M., Porter J.C. Hypothalamic pituitary stimulating and inhibiting hormones. Physiol. Rev. 49:1969;240-284.
116. Melcangi R.C., Cavarretta I., Magnaghi V., Martini L., Galbiati M. Interactions between growth factors and steroids in the control of GnRH-secreting neurons. Brain Res. Rev. 37:2001;223-234.
117. Melcangi R.C., Galbiati M., Messi E., Magnaghi V., Cavarretta I., Riva M.A., Zanisi M. Astrocyte-neuron interactions in vitro: role of growth factors and steroids on GnRH dynamics. Brain Res. Bull. 44:1997;465-469.
118. Melcangi R.C., Galbiati M., Messi E., Piva F., Martini L., Motta M. Type I astrocytes influence luteinizing hormone-releasing hormone release from the hypothalamic cell line GT1-1: is transforming growth factor-beta the principle involved? Endocrinology. 136:1995;679-686.
119. Melcangi R.C., Martini L., Galbiati M. Growth factors and steroid hormones: a complex interplay in the hypothalamic control of reproductive functions. Prog. Neurobiol. 67:2002;421-429.
120. Mellon P.L., Windle J.J., Goldsmith P.C., Padula C.A., Roberts J.L., Wiener R.I. Immortalization of hypothalamic GnRH neurons by genetically targeted tumorigenesis. Neuron. 5:1990;1-10.
121. Millar R.P. Gonadotropin releasing hormones and their receptors. Fauser B.C.J.M. Molecular Biology in Clinical Reproductive Medicine. second ed. 2002;199-224 Parthenon Publishing Group, Carnforth, UK.
122. Millar R.P. GnRH II and type II GnRH receptors. Trends Endocrinol. Metab. 14:2003;35-43.
123. Millar R.P., Conklin D., Lofton-Day C., Hutchinson E., Troskie B., Illing N., Sealfon S.C., Hapgood J. A novel human GnRH receptor gene: abundant and wide tissue distribution of the antisense transcript. J. Endocrinol. 162:1999;117-126.
124. Millar R.P., Lowe S., Conklin D., Pawson A., Maudsley S., Troskie B., Ott T., Millar M., Lincoln G., Sellar R., Faurholm B., Scobie G., Kuestner R., Terasawa E., Katz A. A novel mammalian receptor for the evolutionarily conserved type II GnRH. Proc. Natl. Acad. Sci. USA. 98:2001;9636-9641.
125. Miller W.R., Scott W.N., Morris R., Fraser H.M., Sharpe R.M. Growth of human breast cancer cells inhibited by a luteinizing hormone-releasing hormone agonist. Nature. 313:1985;231-233.
126. Miyamoto K., Hasegawa Y., Nomura M., Igarashi M., Kanagawa K., Matsuo H. Identification of a second gonadotropin-releasing hormone in chicken hypothalamus: evidence that gonadotropin secretion is probably controlled by two distinct gonadotropin-releasing hormones in avian species. Proc. Natl. Acad. Sci. USA. 81:1984;3874-3878.
127. Molineaux C.J., Lasdun A., Michaud C., Orlowski M. Endopeptidase 24.15 is the primary enzyme that degrades GnRH both in vitro and in vivo. J. Neurochem. 51:1988;624-633.
128. Montagnani Marelli M., Moretti R.M., Dondi D., Motta M., Limonta P. Luteinizing hormone-releasing hormone agonists interfere with the mitogenic activity of the insulin-like growth factor system in androgen-independent prostate cancer cells. Endocrinology. 140:1999;329-334.
129. Moretti R.M., Montagnani Marelli M., Dondi D., Poletti A., Martini L., Motta M., Limonta P. Luteinizing hormone-releasing hormone agonists interfere with the stimulatory actions of epidermal growth factor in human prostatic cancer cell lines, LNCaP and DU 145. J. Clin. Endocrinol. Metab. 81:1996;3930-3937.
130. Moretti R.M., Montagnani Marelli M., van Groeninghen J.C., Limonta P. Locally expressed GnRH receptors mediate the oncostatic and antimetastatic activity of GnRH agonists on melanoma cells. J. Clin. Endocrinol. Metab. 87:2002;3791-3797.
131. Moretti R.M., Montagnani Marelli M., van Groeninghen J.C., Motta M., Limonta P. Inhibitory activity of luteinizing hormone-releasing hormone on tumor growth and progression. Endocr. Rel. Cancer. 10:2003;161-167.
132. Motta M., Dondi D., Moretti R.M., Montagnani Marelli M., Pimpinelli F., Maggi R., Limonta P. Role of growth factors, steroid and peptide hormones in the regulation of human prostatic tumor growth. J. Steroid Biochem. Mol. Biol. 56:1996;107-111.
133. Motta M., Piva F., Martini L. New findings on the control of gonadotrophin secretion. J. Reprod. Fertil. 20:1973;27-52.
134. Muske L.E. Evolution of gonadotropin-releasing hormone (GnRH) neuronal systems. Brain Behav. Evol. 42:1993;215-230.
135. Nagai N., Oshita T., Mukai K., Shiroyama Y., Shigemasa K., Ohama K. GnRH agonist inhibits human telomerase reverse transcriptase mRNA expression in endometrial cancer cells. Int. J. Mol. Med. 10:2002;593-597.
136. Nagata S. Apoptosis by death factor. Cell. 88:1997;355-365.
137. Naor Z., Benard O., Seger R. Activation of MAPK cascades by G-protein-coupled receptors: the case of gonadotropin-releasing hormone receptor. Trends Endocrinol. Metab. 11:2002;91-99.
138. Navarro C.E., Abdul Saeed S., Murdock C., Martinez-Fuentes A.J., Arora K.K., Krsmanovic L.Z., Catt K.J. Regulation of cyclic AMP signaling and pulsatile neurosecretion by Gi-coupled plasma membrane estrogen receptors in immortalized GnRH neurons. Mol. Endocrinol. 17:2003;1792-1804.
139. Neill J.D. Minireview: GnRH and GnRH receptor genes in the human genome. Endocrinology. 143:2002;737-743.
140. Neill J.D., Duck L.W., Sellers J.C., Musgrove L.C. A gonadotropin- releasing hormone (GnRH) receptor specific for GnRH II in primates. Biochem. Biophys. Res. Commun. 282:2001;1012-1018.
141. Nelson S.B., Eraly S.A., Mellon P.L. The GnRH promoter: target of transcription factors, hormones, and signaling pathways. Mol. Cell. Endocrinol. 140:1998;151-155.
142. Norwitz E.R., Jeong K.-H., Chin W.W. Molecular mechanisms of gonadotropin-releasing hormone receptor gene regulation. J. Soc. Gynecol. Invest. 6:1999;169-178.
143. Ohno T., Imai A., Furui T., Takahashi K., Tamaya T. Presence of gonadotropin-releasing hormone and his messenger ribonucleic acid in human ovarian epithelial carcinoma. Am. J. Obstet. Gynecol. 169:1993;605-610.
144. Oka Y. Physiology and release activity of GnRH neurons. Prog. Brain Res. 141:2002;259-281.
145. Parkin D.M., Pisani P., Ferlay J. Global cancer statistics. CA Cancer J. Clin. 49:1999;33-64.
146. Peng C., Fang N.C., Ligier M., Vaannanen J., Leung P.C.K. Expression and regulation of gonadotropin-releasing hormone (GnRH) and GnRH receptor messenger ribonucleic acids in human granulosa-luteal cells. Endocrinology. 135:1994;1740-1746.
147. Perrin M.H., Bilezikjian L.M., Hoeger C., Donaldson C.J., Rivier J., Haas Y., Vale W.W. Molecular and functional characterization of GnRH receptors cloned from rat pituitary and a mouse pituitary tumor cell line. Biochem. Biophys. Res. Commun. 191:1993;1139-1144.
148. Poletti A., Rampoldi A., Piccioni F., Volpi S., Simeoni S., Zanisi M., Martini L. 5Alpha-reductase type 2 and androgen receptor expression in gonadotropin releasing hormone GT1-1 cells. J. Neuroendocrinol. 13:2001;353-357.
149. Prager D., Weber M.M., Herman-Bonert V. Placental growth factors and releasing/inhibiting peptides. Semin. Reprod. Endocrinol. 10:1992;83-91.
150. Prevot V. Glial-neuronal-endothelial interactions are involved in the control of GnRH secretion. J. Neuroendocrinol. 14:2002;247-255.
151. Qayum A., Gullick W.J., Mellon K., Krausz T., Neal D., Sikora K., Waxman J. The partial purification and characterization of GnRH-like activity from prostatic biopsy specimens and prostatic cancer cell lines. J. Steroid Biochem.
152. Radovick S., Wray S., Lee E., Nicols D.K., Nakayama Y., Weintraub B.D., Westfal H., Cutler G.B., Wondisford F.E. Migratory arrest of gonadotropin-releasing hormone neurons in transgenic mice. Proc. Natl. Acad. Sci. USA. 88:1991;3402-3406.
153. Rissman E.F. Behavioral regulation of gonadotropin-releasing hormone. Biol. Reprod. 54:1996;413-419.
154. Rivier J.E. Novel antagonists of GnRH: a compendium of their physicochemical properties, activities, relative potencies and efficacy in humans. GnRH Analogues: The State of the Art. 1993;13-26 Parthenon Publishing Group, Carnford, UK.
155. Rivier J.E. GnRH analogues towards the next millennium. GnRH Analogues: The State of the Art at the Millennium. 1999;31-45 Parthenon Publishing Group, Carnford, UK.
156. Roy D., Angelini N.L., Belsham D.D. Estrogen directly represses gonadotropin-releasing hormone (GnRH) gene expression in estrogen receptor-alpha (Eralpha)- and Erbeta-expressing GT1-7 GnRH neurons. Endocrinology. 140:1999;5045-5053.
157. Schally A.V. LH-RH analogues: I. Their impact on reproductive medicine. Gynecol. Endocrinol. 13:1999;401-409.
158. Schally A.V. Luteinizing hormone-releasing hormone analogs: their impact on the control of tumorigenesis. Peptides. 20:1999;1247-1262.
159. Schally A.V., Comaru-Schally A.M., Nagy A., Kovacs M., Szepeshazi K., Plonowski A., Varga J.L., Halmos G. Hypothalamic hormones and cancer. Front. Neuroendocrinol. 22:2001;248-291.
160. Schwanzel-Fukuda M. Origin and migration of luteinizing hormone-releasing hormone neurons in mammals. Microsc. Res. Tech. 44:1999;2-10.
161. Sealfon S.C., Weinstein H., Millar R.P. Molecular mechanisms of ligand interaction with the gonadotropin-releasing hormone receptor. Endocr. Rev. 18:1997;180-205.
162. Seeburg P.H., Adelman J.P. Characterization of cDNA for precursor of human luteinizing hormone releasing hormone. Nature. 311:1984;666-668.
163. Seftor R.E.B., Seftor E.A., Hendrix M.J.C. Molecular role(s) for integrins in human melanoma invasion. Cancer Metastasis Rev. 18:1999;359-375.
164. Segal-Abramson T., Kitroser H., Levy J., Schally A.V., Sharoni Y. Direct effects of luteinizing hormone-releasing hormone agonists and antagonists on MCF-7 mammary cancer cells. Proc. Natl. Acad. Sci. USA. 89:1992;2336-2339.
165. Shacham S., Cheifetz M.N., Lewy H., Ashkenazi I.E., Becker O.M., Seger R., Naor Z. Mechanism of GnRH receptor signaling: from the membrane to the nucleus. Ann. Endocrinol. 60:1999;79-88.
166. Shen E.S., Meade E.H., Perez M.C., Deecher D.C., Negro-Vilar A., Lopez F.J. Expression of functional estrogen receptors and galanin messenger ribonucleic acid in immortalized luteinizing hormone-releasing hormone neurons: estrogenic control of galanin gene expression. Endocrinology. 139:1998;939-948.
167. Sherwood N.M., Lovejoy D.A., Coe I.R. Origin of mammalian gonadotropin-releasing hormones. Endocrinol. Rev. 14:1993;241-254.
168. Sherwood N.M., Parker D.B., McRory J.E., Lescheid D.W. Molecular evolution of growth hormone-releasing hormone and gonadotropin-releasing hormone. Randall D.J., Farrell A.P. Fish Physiology. vol. III:1994;3-66 Academic Press, San Diego.
169. Shih I.M., Herlyn M. Role of growth factors and their receptors in the development and progression of melanoma. J. Invest. Dermatol. 100:1993;S196-S203.
170. Siler-Khodr T.M., Grayson M. Action of chicken II GnRH on the human placenta. J. Clin. Endocrinol. Metab. 86:2001;804-810.
171. Somoza G.M., Miranda L.A., Strobl-Mazzulla P., Guilgur L.G. Gonadotropin-releasing hormone (GnRH): from fish to mammalian brains. Cell. Mol. Neurobiol. 22:2002;589-609.
172. Stojilkovic S.S., Catt K.J. Expression and signal transduction pathways of gonadotropin releasing hormone receptors. Rec. Prog. Horm. Res. 30:1995;161-205.
173. Stojilkovic S.S., Reinhart J., Catt K.J. Gonadotropin-releasing hormone receptors. Structure and signal transduction pathways. Endocr. Rev. 15:1994;462-499.
174. Straub B., Muller M., Krause H., Schrader M., Goessl C., Miller K. Receptor gene messenger RNA expression in metastatic lesions of prostate cancer. J. Urol. 168:2002;1212-1214.
175. Takeuchi S., Futamura N., Minoura H., Toyoda N. Possible direct effect of gonadotropin releasing hormone on human endometrium and decidua. Life Sci. 62:1998;1187-1194.
176. Terasawa E. Luteinizing Hormone-releasing hormone (LHRH) neurons: mechanism of pulsatile LHRH release. Vitam. Horm. 63:2001;91-129.
177. Thompson M.A., Adelson M.D., Kaufman L.M. Lupron retards proliferation of ovarian tumor cell cultured in serum-free medium. J. Clin. Endocrinol. Metab. 72:1991;1036-1041.
178. Tieva A., Stattin P., Wikstrom P., Bergh A., Damber J.E. Gonadotropin-releasing hormone receptor expression in the human prostate. Prostate. 47:2001;276-284.
179. Troskie B., King J.A., Millar R.P., peng Y.Y., Kim J., Figueras H., Illing N. Chicken GnRH II-like peptides and a GnRH receptor selective for chicken GnRH in amphibian sympathetic ganglia. Neuroendocrinology. 65:1997;396-402.
180. Tsutsumi M., Zhou W., Millar R.P., Mellon P.L., Roberts J.L., Flanagan C.A., Dong K., Gillo B., Sealfon S.C. Cloning and functional expression of a mouse gonadotropin-releasing hormone receptor. Mol. Endocrinol. 6:1992;1163-1169.
181. Urbanski H.F., White R.B., fernald R.D., Kohama S.G., Garyfallou V.T., Densmore V.S. Regional expression of mRNA encoding a second form of gonadotropin-releasing hormone in the macaque brain. Endocrinology. 140:1999;1945-1948.
182. van Groeninghen J.C., Kiesel L., Winkler D., Zwirner M. Effects of luteinizing hormone-releasing hormone on nervous-system tumours. Lancet. 352:1998;372-373.
183. Vincze B., Palyi I., Daubner D., Kremmer T., Szamel I., Bodrogi I., Sugar J., Seprodi J., Mezo I., Teplan I., Eckhardt S. Influence of luteinizing hormone-releasing hormone agonists on human mammary carcinoma cell lines and their xenografts. J. Steroid Biochem. Mol. Biol. 38:1991;119-126.
184. Volker P., Grundker C., Schmidt O., Schulz K.-D., Emons G. Expression of receptors for luteinizing hormone-releasing hormone in human ovarian and endometrial cancers: Frequency, autoregulation, and correlation with direct antiproliferative activity of luteinizing hormone-releasing hormone analogues. Am. J. Obst. Gynecol. 186:2002;171-179.
185. Wang L., Bogerd J., Choi H.S., Seong J.Y., Soh J.M., Chun S.Y., Blomenrohr M., Troskie B.E., Millar R.P., Yu W.H., McCann S.M., Kwon H.B. Three distinct types of GnRH receptor characterized in the bullfrog. Proc. Natl. Acad. Sci. USA. 98:2001;361-366.
186. Wang Y., Matsuo H., Kurachi O., Maruo T. Down-regulation of proliferation and up-regulation of apoptosis by gonadotropin-releasing hormone agonist in cultured uterine leiomyoma cells. Eur. J. Endocrinol. 146:2002;447-456.
187. Weiner R.I., Westel W., Goldsmith P., Martinez de la Escalera G., Windle J., Padula C., Choi A., Negro-Vilar A., Mellon P. Gonadotropin-releasing hormone neuronal cell lines. Front. Neuroendocrinol. 13:1992;95-119.
188. Westel W.C., Valenca M.M., Merchenthaler I., Liposits Z., Lopez F.J., Weiner R.I., Mellon P.L., Negro-Vilar A. Intrinsic pulsatile secretory activity of immortalized luteinizing hormone-releasing hormone secreting neurons. Proc. Natl. Acad. Sci. USA. 89:1992;4149-4153.
189. White R.B., Eisen J.A., Kasten T.L., Fernald R.D. Second gene for gonadotropin-releasing hormone in humans. Proc. Natl. Acad. Sci. USA. 95:1998;305-309.
190. Witkin J.W. Synchronized neuronal networks: the GnRH system. Microsc. Res. Tech. 44:1999;11-18.
191. Wolfe A., Kim H.H., Radovick S. The GnRH neuron: molecular aspects of migration, gene expression and regulation. Prog. Brain Res. 141:2002;243-257.
192. Wormald P.J., Eidne K.A., Millar R.P. Gonadotropin-releasing hormone receptors in human pituitary: ligand structural requirements, molecular size, and cationic effects. J. Clin. Endocrinol. Metab. 61:1985;1190-1194.
193. Wray S. Development of gonadotropin-releasing hormone-1 neurons. Front. Neuroendocrinol. 23:2002;292-316.
194. Yano T., Pinski J., Halmos G., Szepeshazi K., Schally A.V. Inhibition of growth of OV-1063 human epithelial ovarian cancer xenografts in nude mice by treatment with luteinizing hormone-releasing hormone antagonist SB-75. Proc. Natl. Acad. Sci. USA. 91:1994;7090-7094.
195. Yano T., Pinski J., Radulovic S., Schally A.V. Inhibition of human epithelial ovarian cancer cell growth in vitro by agonistic and antagonistic analogues of luteinizing hormone-releasing hormone. Proc. Natl. Acad. Sci. USA. 91:1994;1701-1704.
196. Yin H., Cheng K., Hwah H., Peng C., Auersperg N., Leung P.C.K. Expression of the messenger RNA for gonadotropin-releasing hormone and its receptor in human cancer cell lines. Life Sci. 62:1998;2015-2023.
197. Yu W.H., Karanth S., Mastronardi C.A., Sealfon S., Dean C., Dees W.L., McCann S.M. Lamprey GnRH-III acts on its putative receptor via nitric oxide to release follicle-stimulating hormone specifically. Exp. Biol. Med. 227:2002;786-793.
198. Yu W.H., Karanth S., Sower S.A., Parlow A.F., McCann S.M. The similarity of FSH-releasing factor to lamprey gonadotropin-releasing hormone III (GnRH-III). Proc. Soc. Exp. Biol. Med. 224:2000;87-92.
199. Yu W.H., Seeburg P.H., Nicolics K., McCann S.M. Gonadotropin-releasing hormone-associated peptide exerts a prolactin-inhibiting and weak gonadotropin-releasing activity in vivo. Endocrinology. 123:1988;390-395.
200. Zanisi M., Messi E., Motta M., Martini L. Ultrashort feedback control of luteinizing hormone-releasing hormone secretion in vitro. Endocrinology. 121:1987;2199-2204.