cytotoxicity of polyspermine-ribonuclease A and polyspermine-dimeric ribonuclease A

0090417 - ÚŽFG 2008 RIV US eng J - Journal Article
Poučková, P. - Morbio, M. - Vottariello, F. - Laurents, D. V. - Matoušek, Josef - Souček, J. - Gotte, G. - Donadelli, M. - Costanzo, C. - Libonati, M.
cytotoxicity of polyspermine-ribonuclease A and polyspermine-dimeric ribonuclease A.
[Cytotoxicita polyspermine-ribonukleázy A a polyspermine-dimericke ribonukleázy A.]
Bioconjugate Chemistry. Roč. 18, - (2007), s. 1946-1955. ISSN 1043-1802. E-ISSN 1520-4812
R&D Projects: GA ČR GA523/04/0755; GA ČR GA521/06/1149
Institutional research plan: CEZ:AV0Z50450515
Keywords : ribonuclease A
Subject RIV: EB - Genetics ; Molecular Biology
Impact factor: 4.384, year: 2007

Polyspermine-ribonuclease A (PS-RNase A) and polyspermine-dimeric ribonuclease A (PS-dimeric RNase A) were prepared by cross-linking ribonuclease A or its covalently linked dimer to polyspermine (PS) using dimethyl suberimidate. The two RNase A derivatives were tested for a possible antitumor action. The in vitro and in vivo cytotoxic activity of PS-RNase A, although strong, is not higher than that known for free polyspermine. PS-dimeric RNase A, which was characterized by mass spectroscopy, titration of free amine groups, and enzymatic assays, proved instead to be a definitely more efficient antitumor agent, both in vitro and in vivo. This result could tentatively be explained in view of the importance of positive charges for ribonuclease activity, considering the higher basicity of PS-dimeric RNase A compared to that of PS-(monomeric)RNase A. It must be also taken into account that the dimeric RNase A moiety of PS-dimeric RNase A could evade the cytoplasmic ribonuclease inhibitor, which instead could trap the monomeric RNase A moiety of the other derivative. The two RNase A derivatives degrade poly(A).poly(U) under conditions where native RNase A is inactive. The results of this work demonstrate once again the importance of positive charges for the functions of mammalian pancreatic type ribonucleases in general, in particular for RNase A derivatives, and the potential therapeutic use of the ribonuclease A derivatives.

Polyspermine-ribonukleáza A a polyspermine - dimerická ribonukleáza A byly připraveny metodou cross-linking ribonukleázy A nebo jejím kovalentně navázaným dimerem k polysperminu pomocí dimethyl suberemidátu. Cytotoxická aktivita vyjádřena protinádorovým efektem in vitro i in vivo byla u prvního derivátu ribonukleázy A silná, ale u dimerické ribonukleázy A byla protinádorově silnější, což je vyvoláno vyšší bosicitou tohoto komplexu.Výsledky této práce demonstrují důležitost savčích ribonukleáz A, vláště pankreatické A RNázy pro potenciální terapeutické využití.
Permanent Link: http://hdl.handle.net/11104/0151311