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 language | English |
|---|---|
| Pages (from-to) | 2361-2366 |
| Number of pages | 6 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Volume | 96 |
| Issue number | 5 |
| DOIs | |
| State | Published - Mar 2 1999 |
Fingerprint
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 journal › Article
}
TY - JOUR
T1 - Gonadotropin-releasing hormone analogue conjugates with strong selective antitumor activity
AU - Pályi, I.
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.
PY - 1999/3/2
Y1 - 1999/3/2
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=13044272900&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=13044272900&partnerID=8YFLogxK
U2 - 10.1073/pnas.96.5.2361
DO - 10.1073/pnas.96.5.2361
M3 - Article
VL - 96
SP - 2361
EP - 2366
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 5
ER -