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AN-207

Description of AN-207: AN-207, a new targeted cytotoxic analog of LH-RH. AN-207 consists of the agonist [D-Lys(6)]LH-RH linked to 2-pyrrolino-doxorubicin, an intensely potent derivative of doxorubicin. LHRH receptors expressed in a high percentage of human NHL specimens can be used for effective targeted therapy with the cytotoxic LHRH analogue AN-207. Targeted chemotherapy with AN-207 could be considered for treatment of advanced prostate cancer.

AN-207 is a potent derivative of 2-pyrrolinodoxorubicin conjugated to [D-Lys6] luteinizing hormone-releasing hormone (LH-RH), which was demonstrated to be less toxic than the nonconjugated chemotherapeutic radical and significantly more active in slowing neoplastic cellular growth. In this study we investigate the molecular mechanisms underlying the cytotoxic action of AN-207. We stably transfected COS cells with a LH-RH receptor (LH-RH-Rc) mammalian expression vector and examined the effect of AN-207 on known markers of cellular apoptosis. Apoptotic induction by AN-207, as measured by Bax and Bcl-2 protein levels, was increased in stable cells that express LH-RH-Rc compared with parental cells. DNA fragmentation also was increased by AN-207 treatment when compared with AN-201. Clinically used LH-RH antagonists partially inhibited apoptotic Bax expression and DNA fragmentation induced by AN-207, and blocked AN-207 induced down-regulation of Bcl-2 steady-state protein levels. In cell proliferation studies, after 72 h AN-207 exhibited greater cytotoxicity than AN-201 at equivalent concentrations, in COS cells expressing LH-RH-Rc but not in parental COS cells. In addition, survival of LH-RH-Rc positive cells treated with AN-207 was partially restored by LH-RH antagonist. This study demonstrates the receptor-specific cytotoxic effect of 2-pyrrolinodoxorubicin conjugated to [D-Lys6] LH-RH, exerted through induction of apoptosis and modulation of Bax, Bcl-2, and DNA fragmentation (source: Proc Natl Acad Sci U S A. 1999 Jan 19;96(2):669-73.).

 1: Keller G, Schally AV, Gaiser T, Nagy A, Baker B, Halmos G, Engel JB. Receptors for luteinizing hormone releasing hormone (LHRH) expressed in human non-Hodgkin's lymphomas can be targeted for therapy with the cytotoxic LHRH analogue AN-207. Eur J Cancer. 2005 Sep;41(14):2196-202. PubMed PMID: 16182122.

2: Stangelberger A, Schally AV, Nagy A, Szepeshazi K, Kanashiro CA, Halmos G. Inhibition of human experimental prostate cancers by a targeted cytotoxic luteinizing hormone-releasing hormone analog AN-207. Prostate. 2006 Feb 1;66(2):200-10. PubMed PMID: 16173040.

3: Engel JB, Keller G, Schally AV, Nagy A, Chism DD, Halmos G. Effective treatment of experimental human endometrial cancers with targeted cytotoxic luteinizing hormone-releasing hormone analogues AN-152 and AN-207. Fertil Steril. 2005 Apr;83 Suppl 1:1125-33. PubMed PMID: 15831285.

4: Arencibia JM, Bajo AM, Schally AV, Krupa M, Chatzistamou I, Nagy A. Effective treatment of experimental ES-2 human ovarian cancers with a cytotoxic analog of luteinizing hormone-releasing hormone AN-207. Anticancer Drugs. 2002 Oct;13(9):949-56. PubMed PMID: 12394258.

5: 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 Lett. 2002 Feb 8;176(1):57-63. PubMed PMID: 11790454.

6: Arencibia JM, Schally AV, Halmos G, Nagy A, Kiaris H. In vitro targeting of a cytotoxic analog of luteinizing hormone-releasing hormone AN-207 to ES-2 human ovarian cancer cells as demonstrated by microsatellite analyses. Anticancer Drugs. 2001 Jan;12(1):71-8. PubMed PMID: 11272290.

7: Chatzistamou L, Schally AV, Nagy A, Armatis P, Szepeshazi K, Halmos G. Effective treatment of metastatic MDA-MB-435 human estrogen-independent breast carcinomas with a targeted cytotoxic analogue of luteinizing hormone-releasing hormone AN-207. Clin Cancer Res. 2000 Oct;6(10):4158-65. PubMed PMID: 11051271.

8: Kahán 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 Jun 15;85(12):2608-15. PubMed PMID: 10375109.

9: 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 Obstet Gynecol. 1999 May;180(5):1095-103. PubMed PMID: 10329861.

10: Koppán 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 Feb 1;38(2):151-8. PubMed PMID: 9973101.

11: Danila DC, Schally AV, Nagy A, Alexander JM. Selective induction of apoptosis by the cytotoxic analog AN-207 in cells expressing recombinant receptor for luteinizing hormone-releasing hormone. Proc Natl Acad Sci U S A. 1999 Jan 19;96(2):669-73. PubMed PMID: 9892691; PubMed Central PMCID: PMC15194.

12: Jungwirth A, Schally A, 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 Oncol. 1997 May;10(5):877-84. PubMed PMID: 21533457.