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.
- MeSH
- dimerizace MeSH
- financování organizované MeSH
- gelová chromatografie MeSH
- kultivované buňky MeSH
- lidé MeSH
- molekulární struktura MeSH
- pankreatická ribonukleasa MeSH
- proliferace buněk účinky léků MeSH
- reagencia zkříženě vázaná chemie MeSH
- RNA metabolismus MeSH
- spektrometrie hmotnostní - ionizace laserem za účasti matrice MeSH
- spermin chemie MeSH
- Check Tag
- lidé MeSH
Previously we have shown that monomeric RNase A has no significant biological activity, whereas its oligomers (dimer to tetramer) prepared by lyophilizing from 50% acetic acid solutions, show remarkable aspermatogenic and antitumor activities. Furthermore, conjugates prepared by chemical binding of native RNase A to polyethylene glycol (PEG) have shown a significant aspermatogenic and antitumor activities. In this work we show that the chemical conjugation of PEG to the RNase A C-dimer, and to the two RNase A trimers (NC-trimer and C- trimer) decreases the aspermatogenic activity of the oligomers while increasing their inhibitory activity on the growth of the human UB900518 amelanotic melanoma transplanted in athymic nude mice. Moreover, the PEG-conjugated RNaseA oligomers are devoid, like the free oligomers, of any embryotoxic activity.
- MeSH
- antispermatogenní látky farmakologie MeSH
- dimerizace MeSH
- embryo savčí účinky léků MeSH
- lidé MeSH
- melanom experimentální farmakoterapie MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- pankreatická ribonukleasa farmakologie chemie MeSH
- peptidové fragmenty farmakologie chemie MeSH
- polyethylenglykoly farmakologie chemie MeSH
- protinádorové látky farmakologie chemie MeSH
- spermatogeneze účinky léků MeSH
- transplantace nádorů MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- práce podpořená grantem MeSH
- MeSH
- experimenty na zvířatech MeSH
- fotochemoterapie metody využití MeSH
- fotosenzibilizující látky farmakologie klasifikace terapeutické užití MeSH
- inbrední kmeny potkanů MeSH
- indoly terapeutické užití MeSH
- laserová terapie MeSH
- lasery využití MeSH
- lidé MeSH
- modely nemocí na zvířatech MeSH
- myši MeSH
- nádory terapie MeSH
- porfyriny terapeutické užití MeSH
- syndromy imunologické nedostatečnosti MeSH
- transplantace nádorů MeSH
- výsledek terapie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- MeSH
- buněčné dělení účinky léků MeSH
- finanční podpora výzkumu jako téma MeSH
- neuroblastom farmakoterapie MeSH
- pankreas enzymologie MeSH
- protinádorové látky aplikace a dávkování imunologie MeSH
- ribonukleasy aplikace a dávkování farmakologie MeSH
- skot MeSH
- spermie enzymologie MeSH
- transplantace nádorů MeSH
- zvířata MeSH
- Check Tag
- skot MeSH
- zvířata MeSH
- MeSH
- myši MeSH
- protinádorové látky MeSH
- ribonukleasy terapeutické užití MeSH
- skot MeSH
- sperma enzymologie MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- skot MeSH
- zvířata MeSH
