Poly[N-(2-hydroxypropyl)methacrylamide] conjugates of bovine pancreatic ribonuclease (RNase A) inhibit growth of human melanoma in nude mice
Language English Country England, Great Britain Media print
Document type Journal Article, Research Support, Non-U.S. Gov't
- MeSH
- Endoribonucleases administration & dosage chemistry therapeutic use MeSH
- Injections, Intraperitoneal MeSH
- Injections, Intravenous MeSH
- Protein Conformation MeSH
- Polymethacrylic Acids administration & dosage chemistry MeSH
- Humans MeSH
- Lymphocytes metabolism MeSH
- Melanoma, Experimental drug therapy pathology MeSH
- Molecular Structure MeSH
- Mice, Nude MeSH
- Mice MeSH
- Tumor Cells, Cultured metabolism MeSH
- Drug Carriers MeSH
- Ribonuclease, Pancreatic administration & dosage chemistry therapeutic use MeSH
- Antineoplastic Agents administration & dosage chemistry therapeutic use MeSH
- Iodine Radioisotopes MeSH
- Cattle MeSH
- Binding Sites physiology MeSH
- Dose-Response Relationship, Drug MeSH
- Xenograft Model Antitumor Assays MeSH
- Drug Administration Routes MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Mice MeSH
- Cattle MeSH
- Female MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Duxon MeSH Browser
- Endoribonucleases MeSH
- Polymethacrylic Acids MeSH
- Drug Carriers MeSH
- Ribonuclease, Pancreatic MeSH
- Antineoplastic Agents MeSH
- Iodine Radioisotopes MeSH
- ribonuclease SPL MeSH Browser
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.
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