Poly[N-(2-hydroxypropyl)methacrylamide] conjugates of bovine pancreatic ribonuclease (RNase A) inhibit growth of human melanoma in nude mice.

Abstract

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.

• Authors: J Soucek, P Poucková, J Strohalm, D Plocová, D Hlousková, M Zadinová, K Ulbrich
• Journal: Journal of drug targeting (J Drug Target) Vol. 10 Issue 3 Pg. 175-83 (May 2002) ISSN: 1061-186X [Print] England
• PMID: 12075818 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Drug Carriers
• Iodine Radioisotopes
• Polymethacrylic Acids
• Duxon
• Endoribonucleases
• ribonuclease SPL
• Ribonuclease, Pancreatic

Topics

• Animals
• Antineoplastic Agents (administration & dosage, chemistry, therapeutic use)
• Binding Sites (physiology)
• Cattle
• Dose-Response Relationship, Drug
• Drug Administration Routes
• Drug Carriers
• Endoribonucleases (administration & dosage, chemistry, therapeutic use)
• Female
• Humans
• Injections, Intraperitoneal
• Injections, Intravenous
• Iodine Radioisotopes
• Lymphocytes (metabolism)
• Melanoma, Experimental (drug therapy, pathology)
• Mice
• Mice, Nude
• Molecular Structure
• Polymethacrylic Acids (administration & dosage, chemistry)
• Protein Conformation
• Ribonuclease, Pancreatic (administration & dosage, chemistry, therapeutic use)
• Tumor Cells, Cultured (metabolism)
• Xenograft Model Antitumor Assays