Onconase (ONC) and bovine seminal ribonuclease (BS-RNase) are homologs of bovine pancreatic ribonuclease (RNase A). Unlike RNase A, ONC and BS-RNase can evade the cytosolic ribonuclease inhibitor protein and are potent cytotoxins. Here, the endogenous cytotoxic activities of ONC and BS-RNase are compared in a wide variety of assays. Injections of ONC into one or both testes of mice and rats evokes a stronger aspermatogenic activity than does the injection of BS-RNase. Epididymides exposed to ONC lose mass and all sperm. Testicular tissue is gradually colonized by immunite and fibrocytic cells. Yet, Leydig cells are always present and functional in the ligamented parts of testicles injected with ONC or BS-RNase. ONC is likewise more toxic to mouse embryos than is BS-RNase, both in vitro and in vivo. The antiproliferative effect of ONC on human tumor cell line ML-2 and lymphocytes in a mixed lymphocyte culture is also more pronounced than is that of BS-RNase. The number of granulocyte-macrophage colony-forming units is repressed almost completely by ONC, whereas a five-fold higher dose of BS-RNase does not cause substantial inhibition. In mice, ONC is less immunogenic than BS-RNase but more immunogenic than RNase A. Together, these data indicate that ONC is a pluripotent cytotoxin, and serves as the benchmark with which to gauge the cytotoxicity of other ribonucleases.

• MeSH
• antitumorózní látky chemie   toxicita   MeSH
• buněčné dělení účinky léků   MeSH
• embryonální a fetální vývoj účinky léků   MeSH
• endoribonukleasy chemie   toxicita   MeSH
• epididymis účinky léků   MeSH
• kmenové buňky účinky léků   MeSH
• krysa rodu Rattus MeSH
• léky antitumorózní - screeningové testy MeSH
• lidé MeSH
• lymfocyty účinky léků   MeSH
• molekulární modely MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• ribonukleasy chemie   toxicita   MeSH
• semenotvorné kanálky účinky léků   MeSH
• skot MeSH
• spermatogeneze účinky léků   MeSH
• spermatogonie účinky léků   MeSH
• test smíšené lymfocytární kultury MeSH
• testis účinky léků   MeSH
• tvorba protilátek účinky léků   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• skot MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, U.S. Gov't, P.H.S. MeSH
• srovnávací studie MeSH
• Názvy látek
• antitumorózní látky MeSH
• endoribonukleasy MeSH
• ranpirnase MeSH Prohlížeč
• ribonuclease SPL MeSH Prohlížeč
• ribonukleasy MeSH

Bovine seminal ribonuclease (BS-RNase) exerts a potent cytotoxic activity when administered intratumorally (i.t.) to the nude mice bearing human tumors. The ineffective treatment with intravenous (i.v.) or intraperitoneal (i.p.) administration led us to the synthesis of polymeric conjugates with BS-RNase to prevent it from degradation in the blood vessel. Hydrophilic poly[N-(2-hydroxypropyl)methacrylamide] (PHPMA) was used for BS-RNase modification and a PHPMA-BS-RNase conjugates were prepared. Classic conjugate (P-BS) with BS-RNase bound to the polymer by its oligopeptide site chains was prepared by aminolytic reaction of the polymer precursor bearing reactive ester groups situated in the side chains of polymer, while star-like conjugate (S-BS) was synthesized by the reaction of PHPMA containing end-chain reactive group with BS-RNase in aqueous buffer solution at pH 8. In contrast to the total ineffectiveness of free BS-RNase administered i.v. at a daily dose 10 mg/kg, application of P-BS and S-BS conjugates at doses 2 mg/kg and 0.5 mg/kg caused significant inhibition of the growth of human melanoma in nude mice. On the base of these results the effect of i.v. administered S-BS on the metastatic process and the survival of C57Bl/6 inbred mice inoculated with B16 melanoma cells was investigated. Sixty per cent of mice treated with S-BS (0.5 mg/kg/day) survived 100 days without metastatic foci when the experiment terminated. The average survival time of the treated groups was 75.5 days compared to 32.7 days in the control group. BS-RNase conjugated to water soluble polymers appears to be the first BS RNase preparation which exerts anticancer and antimetastatic activity following its intravenous administration.

• MeSH
• antitumorózní látky aplikace a dávkování   terapeutické užití   toxicita   MeSH
• endoribonukleasy aplikace a dávkování   terapeutické užití   toxicita   MeSH
• injekce intraperitoneální MeSH
• injekce intravenózní MeSH
• kyseliny polymethakrylové MeSH
• lidé MeSH
• melanom experimentální farmakoterapie   patologie   sekundární   MeSH
• melanom farmakoterapie   patologie   sekundární   MeSH
• metastázy nádorů prevence a kontrola   MeSH
• myši inbrední C57BL MeSH
• myši nahé MeSH
• myši MeSH
• nosiče léků MeSH
• skot MeSH
• vztah mezi dávkou a účinkem léčiva 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
• ribonuclease SPL MeSH Prohlížeč