Poly[N-(2-hydroxypropyl)methacrylamide] conjugates of bovine pancreatic ribonuclease (RNase A) inhibit growth of human melanoma in nude mice.
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.
Soucek
J
J
Institute of Hematology and Blood Transfusion, Prague 2, Czech Republic.
Poucková
P
P
Strohalm
J
J
Plocová
D
D
Hlousková
D
D
Zadinová
M
M
Ulbrich
K
K
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use*; D001665:Binding Sites / Q000502:physiology; D002417:Cattle; D004305:Dose-Response Relationship, Drug; D004333:Drug Administration Routes; D004337:Drug Carriers; D004722:Endoribonucleases / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D007457:Iodine Radioisotopes; D008214:Lymphocytes / Q000378:metabolism; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D015394:Molecular Structure; D011109:Polymethacrylic Acids / Q000008:administration & dosage* / Q000737:chemistry; D011487:Protein Conformation; D012259:Ribonuclease, Pancreatic / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D004337:Drug Carriers; D007457:Iodine Radioisotopes; D011109:Polymethacrylic Acids; C011533:Duxon; D004722:Endoribonucleases; C032523:ribonuclease SPL; D012259:Ribonuclease, Pancreatic