2003, Number s4
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Gac Med Mex 2003; 139 (s4)
New Strategies for Treatment of Various Cancers with LH-RH, Somatostatin and Bombesin Cytotoxic Analogs.
Schally AV, Nagy A
Language: Spanish
References: 66
Page: 33-44
PDF size: 110.63 Kb.
ABSTRACT
The development of targeted cytotoxic analogs of hypothalamic peptides for the therapy of various cancers is reviewed and various oncological studies on experimental tumors are summarized. Novel therapeutic modalities for breast, prostate and ovarian cancer consist of the use of targeted cytotoxic analogs of LH-RH containing doxorubicin (DOX) or 2-pyrrolino-DOX. The same radicals have been incorporated into cytotoxic analogs of somatostatin which can be also targeted to receptors for this peptide in prostatic, mammary, ovarian, renal cancers, brain tumors and their metastases, A targeted cytotoxic analog of bombesin containing 2-pyrrolino-DOX has been also synthesized and succesfully tried in experimental models of prostate cancer, small cell lung carcinoma and brain tumors. The development of these new classes of peptide analogs should lead to a more effective tratment for various cancers.
REFERENCES
Chabner B. Cancer chemotherapy. Principles and practice. Philadelphia, J.B. Lippincott 1990.
Schally AV, Nagy A. Cancer chemotherapy based on targeting of cytotoxic peptide conjugates to their receptors on tumors. Eur J Endocrinol 1999;141:1-14.
Nagy A, Schally AV, Armatis P, Szepeshazi K, Halmos G, Kovacs M, Zarandi M, Groot K, Miyazaki M, Jungwirth A, Horvath J. Cytotoxic analogs of luteinizing hormone-releasing hormone containing doxorubicin or 2-pyrrolinodoxorubicin, a derivative 500-1000 times more potent. Proc. Natl. Acad. Sci. USA 1996;93:7269-7273.
Nagy A, Armatis P, Cai R-Z, Szepeshazi K, Halmos G, Schally AV. 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 1997;94:652-656.
Nagy A, Schally AV, Halmos G, Armatis P, Cai R-Z, Csernus V, Kovacs M, Koppan M, Szepeshazi K, Kahan Z. Synthesis and biological evaluation of cytotoxic analogs of somatostatin containing doxorubicin or its intensely potent derivative 2- pyrrolinodoxonubicin. Proc Natl Acad Sci USA 1998;95:1794-1799.
Nagy A and Schally AV. Targeted cytotoxic somatostatin analogs: A modern approach to the therapy of various cancers. Drugs of the Future 2001;26:261-270.
Nagy A, Schally AV. Cytotoxic analogs of luteinizing hormone-releasing hormone (LHRH); A new approach to targeted chemotherapy. Drugs of the Future. 2002;27:359-370.
Karten MJ, Rivier JE.Gonadotropin-releasing hormone analog design. Structure-function studies toward the development of agonists and antagonists: rationale and perspective. Endocr Rev 1986;7:44-66.
Schally AV. Luteinizing hormone-releasing hormone analogs: Their impact on the control of tumorigenesis. Peptides 1999;20:1247-1262.
Schally AV, Comaru-Schally AM, Nagy A, Kovacs M, Szepeshazi K, Plonowski A, Varga JL, Halmos G. Hypothalamic hormones and cancer.. Frontiers in Neuroendocrinology 2001;22:248-291.
Schally AV, Comaru-Schally AM, Plonowski A, Nagy A, Halmos G, Rekasi Z. Peptide analogs in the Therapy of Prostate Cancer. The Prostate 2000;5:158-166.
Schally AV, Halmos G, Rekasi Z, Arencibia JM. The actions of LH-RH agonists, antagonists, and cytotoxic analogs on the LH-RH receptors on the pituitary and tumors. In: Devroey P. Ed. Infertility and Reproductive Medicine Clinics of North America 2001;12:17-44.
Emons G, Schally AV. The Use of Luteinizing Hormone-Releasing Hormone Agonists and Antagonists in Gynecological Cancers. Human Reproduction 1994 ;9:1364-1379.
Irmer G, Bürger C, Muller R, Ortmann O, Peter U, Kakar SS, Neill JD, Schulz KD, Emons G. Expression of the messenger RNAs for luteinizing hormone-releasing hormone (LHRH) and its receptor in human ovarian epithelial carcinoma. Cancer Res 1995;55:817-822.
Emons G, Ortmann O, Becker M, Irmer G, Springer B, Laun R, Holzel F, Schulz K-D, Schally AV. High affinity binding and direct antiproliferative effects of LHRH analogues in human ovarian cancer cell lines. Cancer Res 1993;53:5439-5446.
Dondi D, Limonta P, Moretti RM, Marelli MM, 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 LHRH loop. Cancer Res 1994;54:4091-4095 .
Limonta P, Dondi D, Moretti RM, Maggi R, Motta M. Antiproliferative effects of luteinizing hormone-releasing hormone agonists on the human prostatic cancer cell line LNCaP. J Clin Endocrinol Metab 1992;75:207-212.
Halmos G, Arenciba JM, Schally AV, Davis R, Bostwick DG. High incidence of receptors for luteinizing hormone-releasing hormone (LH-RH) and LH-RH receptor gene expression in human prostate cancers. J Urology 2000;163:623-629.
Fekete M, Wittliff JL, Schally AV. Characteristics and distribution of receptors for peptide hormones and sex steroids in 500 biopsy samples of human breast cancer. J Clin Lab Anal 1989;3:137-141.
Srkalovic G, Schally AV, Wittliff JL, Day G, Jenison EL. Presence and characteristics of receptors for [D-Trp6] luteinizing hormone-releasing hormone and epidermal growth factor in human ovarian cancer. Int J Oncol 1998;12:489-498.
Srkalovic G, Wittliff JL, Schally AV. Detection and partial characterization of receptors for [D-Trp6]-luteinizing hormone-releasing hormone and epidermal growth factor in human endometrial carcinoma. Cancer Res 1990;50:1841-1846.
Jungwirth A, Schally AV, Nagy A, Pinski J, Groot K, Galvan G, Szepeshazi K, Halmos G. Regression of Rat Dunning R-3327-H Prostate Carcinoma by Treatment with Targeted Cytotoxic Analog of Luteinizing Hormone-Releasing Hormone AN-207 Containing 2-Pyrrolinodoxorubicin. Int. J. Oncology 1997;10:877-884.
Koppan M, Nagy A, Schally AV, Plonowski A, Halmos G, Arencibia JM, Groot K. Targeted cytotoxic analog of luteinizing hormone-releasing hormone AN-207 inhibits the growth of PC-82 human prostate cancer in nude mice. Prostate 1999;38:151-158.
Plonowski A, Schally AV, Nagy A, Groot K, Krupa M, Navone NM, Logothetis C. Inhibition of in vivo proliferation of MDA-PCa-2b human prostate cancer by a targeted cytotoxic analog of luteinizing hormone-releasing hormone AN-207. Cancer Letters 2002;176:57-63.
Klijn JG, Beex LV, Mauriac L, van Zijl JA, Veyret C, Wildiers J, Jassem J, Piccart M, Burghouts J, Becquart D, Seynaeve C, Mignolet F, Duchateau L. Combined treatment with buserelin and tamoxifen in premenopausal metastatic breast cancer: a randomized study. J Natl Cancer Inst 2000;92:903-911.
Kahan Z, Nagy A, Schally AV, Halmos G, Arencibia JM, Groot K. Complete regression of MX- 1 human breast carcinoma xenografts after targeted chemotherapy with a cytotoxic analog of luteinizing hormone-releasing hormone, AN-207. Cancer 1999;85:2608-2615.
Chatzistamou I, Schally AV, Nagy A, Armatis P, Szepeshazi K, Halmos G. Effective treatment of metastatic MDA-MD-435 human estrogen independent breast carcinomas with a targeted cytotoxic analog of luteinizing hormone-releasing hormone, AN-207. Clinical Cancer Research 2000;6:4158-4165.
Halmos G, Nagy A, Lamharzi N, Schally AV. Cytotoxic analogs of luteinizing hormone-releasing hormone bind with high-affinity to human breast cancers. Cancer Lett 1999;136:129-136. 29 Szepeshazi K, Schally AV, Nagy A. Effective treatment of advanced estrogen-independent MXT mouse mammary cancers with targeted cytotoxic LH-RH analogs. Breast Cancer Res Treat 1999;56:267-276.
Kahan Z, Nagy A, Schally AV, Halmos G, Arencibia JM, Groot K. Administration of a targeted cytotoxic analog of luteinizing hormone-releasing hormone inhibits growth of estrogen-independent MDA-MB-231 human breast cancers in nude mice. Breast Cancer Res Treat 2000;59:255-262.
Miyazaki M, Nagy A, Schally AV, Lamharzi N, Halmos G, Szepeshazi K, Groot K, Armatis P. Growth inhibition of human ovarian cancers by cytotoxic analogues of luteinizing hormone-releasing hormone. J Natl Cancer Inst 1997;89:1803-1809.
Gründker C, Völker P, Griesinger F, Ramaswamy A, Nagy A, Schally AV, Emons G. Antitumor effects of cytotoxic LHRH analog AN-152 on human endometrial and ovarian cancers xenografted into nude mice. Am J Ob Gyn. 2002;187:528-537.
Miyazaki M, Schally AV, Nagy A, Lamharzi N, Halmos G, Szepeshazi K, Armatis P. Targeted cytotoxic analog of luteinizing hormone-releasing hormone AN-207 inhibits growth of OV-1063 human epithelial ovarian cancers in nude mice. Am J Ob Gyn 1999;180:1095-1103.
Arencibia JM, Bajo AM, Schally AV, Krupa M, Chatzistamou I, Nagy A. Effective treatment of experimental ES-2 human ovarian cancers with cytotoxic analog of luteinizing hormone-releasing hormone AN-207. Anti-Cancer Drugs 2002;13:949-956.
Kovacs M, Schally AV, Nagy A, Koppan M, Groot K. Recovery of pituitary function after treatment with a targeted cytotoxic analog of luteinizing hormone-releasing hormone. Proc Natl Acad Sci USA 1997;94:1420-1425.
Kovacs M, Schally AV, Csernus B, Busto R, Rekasi Z, Nagy A. Targeted cytotoxic analogue of luteinizing hormone-releasing hormone (LH-RH) only transiently decreases the gene expression of pituitary receptors for LH-RH. J Neuroendocrinology 2002;14:5-13.
Nagy A, Plonowski A, Schally AV. Stability of cytotoxic luteinizing 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 2000;97:829-834.
Bauer W, Briner U, Doepfner W, Haller R, Huguenin R, Marbach P, Petcher TJ, Pless J. SMS 201-995: A very potent and selective octapeptide analogue of somatostatin with prolonged action. Life Sci 1982;31:1133-1140.
Cai R-Z, Szoke B, Lu R, Fu D, Redding TW, Schally AV. Synthesis and biological activity of highly potent octapeptide analogs of somatostatin. Proc Natl Acad Sci USA 1986;83:1896-1900.
Patel YC. Molecular pharmacology of somatostatin receptor subtypes. J Endocrinol Invest 1997;20:348-367.
Lamberts SW, Krenning EP, Reubi JC. The role of somatostatin and its analogs in the diagnosis and treatment of tumors. Endocr Rev 1991;12:450-482.
Schally AV. Oncological applications of somatostatin analogs. Cancer Res 1988;48:6977-6985.
Buscail L, Saint-Laurent N, Chastre E, Vaillant JC, Gespach C, Capella G, Kalthoff H, Lluis F, Vaysse N, Susini C. Loss of sst2 somatostatin receptor gene expression in human pancreatic and colorectal cancer. Cancer Res 1996;56:1823-1827.
Krenning EP, Kwekkeboom DJ, Bakker WH, Breeman WA, Kooij PP, Oei HY, van Hagen M, Postema PT, de Jong M, Reubi JC, Visser TJ, Reijs AEM, Hofland LJ, Koper JW, Lamberts SWJ, Krenning EP. Somatostatin receptor scintigraphy with [111In-DTPA-D-Phe1]- and [123I-Tyr3]-octreotide: the Rotterdam experience with more than 1000 patients. Eur J Nucl Med 1993;20:716-731.
Halmos G, Schally AV, Sun B, Davis R, Bostwick DG, Plonowski A. 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 2000;85:2564-2571.
Koppan M, Nagy A, Schally AV, Arencibia JM, Plonowski A, Halmos G. Targeted cytotoxic analogue of somatostatin AN-238 inhibits the growth of androgen-independent Dunning R-3327-AT-1 prostate cancer in rats at nontoxic doses. Cancer Res 1998;58:4132-4137.
Plonowski A, Schally AV, Nagy A, Sun B, Szepeshazi K. Inhibition of PC-3 human androgen-independent prostate cancer and its metastases by cytotoxic somatostatin analogue AN-238. Cancer Res 1999;59:1947-1953.
Kahan Z, Nagy A, Schally AV, Hebert F, Sun B, Groot K, Halmos G. Inhibition of growth of MX- 1, MCF-7, MIII and MDA-MB-231 human breast cancer xenografts after administration of a targeted cytotoxic analog of somatostatin, AN-238. Int J Cancer 1999;82:592-598.
Halmos G, Sun B, Schally AV, Hebert F, Nagy A. Human ovarian cancers express somatostatin receptors. J Clin Endocrinol Metab. 2000;85:3509-3512.
Plonowski A, Schally AV, Koppan M, Nagy A, Arencibia JM, Csernus B, Halmos G. Inhibition of the UCI-107 human ovarian carcinoma cell line by a targeted cytotoxic analog of somatostatin, AN-238. Cancer 2001;92:1168-1176.
Reubi JC, Kvols L. Somatostatin receptors in human renal cell carcinomas. Cancer Res. 1992;52:6074-6078.
Plonowski A, Schally AV, Nagy A, Kiaris H, Hebert F, Halmos G. Inhibition of metastatic renal cell carcinomas expressing somatostatin receptors by a targeted cytotoxic analog of somatostatin AN-238. Cancer Res 2000;60:2996-3001.
Kiaris H, Schally AV, Nagy A, Sun B, Szepeshazi K, Halmos G. Regression of U-87MG human glioblastomas in nude mice after treatment with a cytotoxic somatostatin analog AN-238. Clin Cancer Res 2000;6:709-717.
Kiaris H, Schally AV, Nagy A, Szepeshazi K, Hebert F, Halmos G. 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 2001;37:620-628.
Szepeshazi K, Schally AV, Halmos G, Sun B, Hebert F, Csernus B, Nagy A. Targeting of cytotoxic somatostatin analog AN-238 to somatostatin receptor subtypes 5 and/or 3 in experimental pancreatic cancer. Clin Cancer Res 2001;7:2854-2861.
Benali N, Cordelier P, Calise D, Pagés P, Rochaix P, Nagy A, Estéve JP, Pour PM, Schally AV, Vaysse N, Susini C, Buscail L. Inhibition of growth and metastatic progression of pancreatic carcinoma in hamster after somatostatin receptor subtype2 (sst2) gene expression and administration of cytotoxic somatostatin analog AN-238. Proc Natl Acad Sci USA 2000;97:9180-9185.
Szepeshazi K, Schally AV, Halmos G, Armatis P, Hebert F, Sun B, Feil A, Kiaris H, Nagy A. Targeted cytotoxic somatostatin analogue AN-238 inhibits somatostatin receptor-positive experimental colon cancers independently of their p53 status. Cancer Res 2002;62:781-788.
Radulovic S, Nagy A, Szoke B, Schally AV. Cytotoxic analog of somatostatin containing methotrexate inhibits growth of MIA-PaCa-2 human pancreatic cancer xenografts in nude mice. Cancer Letters 1992;62:263-271.
Sunday ME, Kaplan LM, Motoyama E, Chin WW, Spindel ER. Gastrin-releasing peptide (mammalian bombesin) gene expression in health and disease. Lab Invest 1988;59:5-24.
Cuttitta F, Carney DN, Mulshine J, Moody TW, Fedorko J, Fischler A, Minna JD. Bombesin-like peptides can function as autocrine growth factors in human small-cell lung cancer. Nature 1985;316:823-826.
Kiaris H, Schally AV, Nagy A, Sun B, Armatis P, Szepeshazi K. 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 1999;81:966-971.
Sun B, Halmos G, Schally AV, Wang X, Martinez M. The presence of receptors for bombesin/gastrin-releasing peptide and mRNA for 3 receptor subtypes in human prostate cancers. The Prostate 2000;42:295-303.
Cai R-Z, Reile H, Armatis P, Schally AV. Potent bombesin antagonists with C-terminal Leu ř(CH2N)-Tac-NH2 or its derivatives. Proc Natl Acad Sci USA 1994;91:12664–12668.
Markwalder R, Reubi JC. Gastrin-releasing peptide receptors in the human prostate: relation to neoplastic transformation. Cancer Res 1999;59:1152-1159.
Shriver SP, Bourdeau HA, Gubish CT, Tirpak DL, Davis AL, Luketich JD, Siegfried JM. Sex-specific expression of gastrin-releasing peptide receptor: relationship to smoking history and risk of lung cancer. J Natl Cancer Inst 2000;92:24-33.
Plonowski A, Nagy A, Schally AV, Sun B, Groot K, Halmos G. In vivo inhibition of PC-3 human androgen-independent prostate cancer by a targeted cytotoxic bombesin analogue AN-215. Int. J Cancer 2000;88:652-657.
Szereday Z, Schally AV, Nagy A, Plonowski A, Bajo AM, Halmos G, Szepeshazi K, Groot K. Effective treatment of experimental U-87MG human glioblastoma in nude mice with a targeted cytotoxic bombesin analogue, AN-215 Br J Cancer 2002;86:1322-1327.