Gonadotropin-releasing hormone analogue conjugates with strong selective antitumor activity

Citation
I. Palyi et al., Gonadotropin-releasing hormone analogue conjugates with strong selective antitumor activity, P NAS US, 96(5), 1999, pp. 2361-2366
Citations number
50
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Multidisciplinary
Journal title
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
ISSN journal
0027-8424 → ACNP
Volume
96
Issue
5
Year of publication
1999
Pages
2361 - 2366
Database
ISI
SICI code
0027-8424(19990302)96:5<2361:GHACWS>2.0.ZU;2-Y
Abstract
Conjugation of gonadotropin-releasing hormone (GnRH) analogues GnRH-III, MI -1544, and MI-1892 through lysyl side chains and a tetrapeptide spacer, Gly -Phe-Leu-Gly (X) to a copolymer, poly (N-vinylpyrrolidone-co-maleic acid) ( P) caused increased antiproliferative activity toward MCF-7 and MDA-MB-231 breast, PC3 and LNCaP prostate, and Ishikawa endometrial cancer cell lines in culture and against tumor development by xenografts of the breast cancer cells in immunodeficient mice. MCF-7 cells treated with P-X-1544 and P-X-1 892 displayed characteristic signs of apoptosis, including vacuoles in the cytoplasm, rounding up, apoptotic bodies, bleb formation, and DNA fragmenta tion. Conjugates, but not free peptides, inhibited cdc25 phosphatase and ca used accumulation of Ishikawa and PC3 cells in the G(2)/M phase of the cell cycle after 24 h at lower doses and in the G(1) and G(2) phases after 48 h . Since P-X-peptides appear to be internalized, the increased cytotoxicity of the conjugates is attributed to protection of peptides from proteolysis, enhanced interaction of the peptides with the GnRH receptors, and/or inter nalization of P-X-peptide receptor complexes so that P can exert toxic effe cts inside, possibly by inhibiting enzymes involved in the cell cycle. The additional specificity of P-X-peptides compared with free peptides for dire ct antiproliferative effects on the cancer cells but not for interactions i n the pituitary indicates the therapeutic potential of the conjugates.