Gonadotropin-releasing hormone analogue conjugates with strong selective antitumor activity

I. Pályi, B. Vincze, Sándor Lovas, I. Mezo, J. Pató, A. Kálnay, G. Turi, D. Gaál, R. Mihalik, I. Péter, I. Teplán, R. F. Murphy

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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-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.

Original languageEnglish
Pages (from-to)2361-2366
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume96
Issue number5
DOIs
StatePublished - Mar 2 1999

Fingerprint

Gonadotropin-Releasing Hormone
Peptides
G2 Phase
Gly-Phe-Leu-Gly
Cell Cycle
cdc25 Phosphatases
LHRH Receptors
Peptide Receptors
Poisons
MCF-7 Cells
G1 Phase
DNA Fragmentation
Blister
Endometrial Neoplasms
Vacuoles
Heterografts
Cell Communication
Cell Division
Proteolysis
Prostate

All Science Journal Classification (ASJC) codes

  • Genetics
  • General

Cite this

Gonadotropin-releasing hormone analogue conjugates with strong selective antitumor activity. / Pályi, I.; Vincze, B.; Lovas, Sándor; Mezo, I.; Pató, J.; Kálnay, A.; Turi, G.; Gaál, D.; Mihalik, R.; Péter, I.; Teplán, I.; Murphy, R. F.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 96, No. 5, 02.03.1999, p. 2361-2366.

Research output: Contribution to journalArticle

Pályi, I, Vincze, B, Lovas, S, Mezo, I, Pató, J, Kálnay, A, Turi, G, Gaál, D, Mihalik, R, Péter, I, Teplán, I & Murphy, RF 1999, 'Gonadotropin-releasing hormone analogue conjugates with strong selective antitumor activity', Proceedings of the National Academy of Sciences of the United States of America, vol. 96, no. 5, pp. 2361-2366. https://doi.org/10.1073/pnas.96.5.2361
Pályi, I. ; Vincze, B. ; Lovas, Sándor ; Mezo, I. ; Pató, J. ; Kálnay, A. ; Turi, G. ; Gaál, D. ; Mihalik, R. ; Péter, I. ; Teplán, I. ; Murphy, R. F. / Gonadotropin-releasing hormone analogue conjugates with strong selective antitumor activity. In: Proceedings of the National Academy of Sciences of the United States of America. 1999 ; Vol. 96, No. 5. pp. 2361-2366.
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AU - Vincze, B.

AU - Lovas, Sándor

AU - Mezo, I.

AU - Pató, J.

AU - Kálnay, A.

AU - Turi, G.

AU - Gaál, D.

AU - Mihalik, R.

AU - Péter, I.

AU - Teplán, I.

AU - Murphy, R. F.

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