Gonadotropin-releasing hormone analogue conjugates with strong selective antitumor activity.

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-1892 displayed characteristic signs of apoptosis, including vacuoles in the cytoplasm, rounding up, apoptotic bodies, bleb formation, and DNA fragmentation. Conjugates, but not free peptides, inhibited cdc25 phosphatase and caused accumulation of Ishikawa and PC3 cells in the G2/M phase of the cell cycle after 24 h at lower doses and in the G1 and G2 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 internalization of P-X-peptide receptor complexes so that P can exert toxic effects inside, possibly by inhibiting enzymes involved in the cell cycle. The additional specificity of P-X-peptides compared with free peptides for direct antiproliferative effects on the cancer cells but not for interactions in the pituitary indicates the therapeutic potential of the conjugates.
AuthorsI Pályi, B Vincze, S Lovas, I Mezö, J Pató, A Kálnay, G Turi, D Gaál, R Mihalik, I Péter, I Teplán, R F Murphy
JournalProceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 96 Issue 5 Pg. 2361-6 (Mar 2 1999) ISSN: 0027-8424 [Print] UNITED STATES
PMID10051647 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
Chemical References
  • Antineoplastic Agents
  • Cell Cycle Proteins
  • Hormone Antagonists
  • MI 1892
  • Maleates
  • Polyvinyls
  • poly-N-vinylpyrrolidione-co-maleic acid
  • Gonadotropin-Releasing Hormone
  • MI 1544
  • Phosphoprotein Phosphatases
  • cdc25 Phosphatases
  • Animals
  • Antineoplastic Agents (therapeutic use)
  • Apoptosis
  • Bone Marrow Transplantation (immunology)
  • Breast Neoplasms (drug therapy, metabolism, pathology)
  • Cell Cycle (drug effects)
  • Cell Cycle Proteins (metabolism)
  • Cell Division
  • DNA Fragmentation
  • Endometrial Neoplasms (drug therapy, metabolism, pathology)
  • Female
  • Gonadotropin-Releasing Hormone (analogs & derivatives, therapeutic use)
  • Hormone Antagonists (therapeutic use)
  • Humans
  • Immunosuppression (methods)
  • Maleates (therapeutic use)
  • Mice
  • Mice, Inbred CBA
  • Phosphoprotein Phosphatases (metabolism)
  • Polyvinyls (therapeutic use)
  • Thymectomy
  • Transplantation, Heterologous
  • Transplantation, Isogeneic
  • Tumor Cells, Cultured
  • Whole-Body Irradiation
  • cdc25 Phosphatases

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