The hydrophilic poly[N-(2-hydroxypropyl)methacrylamide] (PHPMA) was used for RNase A or BS-RNase modification to prevent their degradation in bloodstream or fast elimination. Two PHPMA chains (classic and star-like) were synthesized and their conjugates with both enzymes were tested on the CD-1 nude mice bearing various human tumors. These RNase conjugates injected intravenously or intraperitoneally into the mice bearing melanoma, neuroblastoma or ovarian tumor caused significant reduction of transplanted tumors following ten daily doses of 2.5 and/or 1 mg/kg, respectively, while free RNase A or BS-RNase injected in doses of 10 mg/kg exerted only negligible antitumor activity. Histological examination confirmed potent cytotoxic effect of RNase A conjugates in ovarian tumor. Despite the antitumor activity observed in vivo, the in vitro cytotoxic activity of RNase A conjugates was not pronounced and did not differ from that caused by the free RNase A. The in vitro experiments with 125I-labeled preparations demonstrated that polymer conjugates were internalized by tumor cells very poorly in contrast to the dose-dependent internalization of the wild enzyme preparation. Surprisingly, mice injected with EL-4 leukemic cells, which were preincubated for 4 h with BS-RNase conjugates, exerted significantly prolonged survival compared with the control non-treated mice. It may be supposed that both BS-RNase and RNase A conjugates with PHPMA act after administration in vivo by a mechanism different from that or those occurring under in vitro conditions because in vivo they exert an antitumor action, whereas in vitro, they are ineffective. The experiments proved that RNase A, when conjugated to PHPMA, produced identical aspermatogenic and antitumor effects as BS-RNase conjugated to this polymer and that this preparation may be regarded as a potential anticancer drug.

• MeSH
• antitumorózní látky * aplikace a dávkování   imunologie   MeSH
• buněčné dělení účinky léků   MeSH
• ELISA MeSH
• injekce intraperitoneální MeSH
• injekce intravenózní MeSH
• lidé MeSH
• methakryláty MeSH
• myši nahé MeSH
• myši MeSH
• nádorové buňky kultivované MeSH
• nádory vaječníků farmakoterapie   MeSH
• neuroblastom farmakoterapie   MeSH
• pankreas enzymologie   MeSH
• pankreatická ribonukleasa aplikace a dávkování   imunologie   farmakologie   MeSH
• polymery MeSH
• ribonukleasy aplikace a dávkování   imunologie   farmakologie   MeSH
• skot MeSH
• sperma enzymologie   MeSH
• spermatogeneze účinky léků   MeSH
• těhotenství MeSH
• teratogeny farmakologie   MeSH
• transplantace nádorů MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• skot MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antitumorózní látky * MeSH
• hydroxypropyl methacrylate MeSH Prohlížeč
• methakryláty MeSH
• pankreatická ribonukleasa MeSH
• polymery MeSH
• ribonukleasy MeSH
• teratogeny MeSH

Recently hydrophilic poly[N-(2-hydroxypropyl)methacrylamide] (PHPMA) was used for BS-RNase modification to prevent its degradation in bloodstream or fast elimination. Polymer-conjugated BS-RNase preparations proved to be cytotoxic after intravenous or intraperitoneal application, whereas native BS-RNase was ineffective. Here RNase A unimer was conjugated with two HPMA polymers (classic and star) and their antitumor effects both in vitro and in vivo were compared with those of BS-RNase polymers. Surprisingly, the antitumor effect of RNase A conjugates was also pronounced. The RNase A conjugates (classic and star) injected intravenously to mice bearing melanoma tumor caused a significant reduction in tumor volume following ten doses of 5 and 1 mg/kg, respectively. Despite the antitumor activity observed in vivo, the in vitro tested cytotoxic activity of RNase A did not differ from that caused by native RNase A while native BS-RNase (50 microg/ml) totally inhibited DNA synthesis in treated cells. The experiments with 125I-labeled preparations demonstrated concentration-dependent internalization of native BS-RNase by tumor cells within an hour, whereas the polymer conjugate (S-BS) was not internalized. On the contrary, the in vivo experiments showed that whereas 40% of S-BS conjugate persisted in bloodstream for 24h after administration, 98% of the native BS-RNase was already eliminated. Improved antitumor activities of PHPMA-modified RNases in vivo might be ascribed to their prolonged retention in bloodstream, better proteolytic stability and resistance to the action of the ribonuclease inhibitor.

• MeSH
• antitumorózní látky aplikace a dávkování   chemie   terapeutické užití   MeSH
• endoribonukleasy aplikace a dávkování   chemie   terapeutické užití   MeSH
• injekce intraperitoneální MeSH
• injekce intravenózní MeSH
• konformace proteinů MeSH
• kyseliny polymethakrylové aplikace a dávkování   chemie   MeSH
• lidé MeSH
• lymfocyty metabolismus   MeSH
• melanom experimentální farmakoterapie   patologie   MeSH
• molekulární struktura MeSH
• myši nahé MeSH
• myši MeSH
• nádorové buňky kultivované metabolismus   MeSH
• nosiče léků MeSH
• pankreatická ribonukleasa aplikace a dávkování   chemie   terapeutické užití   MeSH
• radioizotopy jodu MeSH
• skot MeSH
• vazebná místa fyziologie   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• xenogenní modely - testy antitumorózní aktivity MeSH
• způsoby aplikace léků MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• skot MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antitumorózní látky MeSH
• Duxon MeSH Prohlížeč
• endoribonukleasy MeSH
• kyseliny polymethakrylové MeSH
• nosiče léků MeSH
• pankreatická ribonukleasa MeSH
• radioizotopy jodu MeSH
• ribonuclease SPL MeSH Prohlížeč