Effect of hyaluronidase and PEG chain conjugation on the biologic and antitumor activity of RNase A

• Published in: Journal of controlled release 2004-02, Vol.94 (2), p.401-410
• Main Authors: MATOUSEK, Josef, POUCKOVA, Pavla, HLOUSKOVA, Daniela, ZADINOVA, Marie, SOUCEK, Josef, SKVOR, Jiri
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - metabolism; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Antitumor; Aspermatogenesis; Biological and medical sciences; Cattle; Cell Line, Tumor; Drug Screening Assays, Antitumor - methods; Drug Synergism; Embryotoxicity; Female; General pharmacology; Humans; Hyaluronidase; Hyaluronoglucosaminidase - metabolism; Hyaluronoglucosaminidase - pharmacology; Hyaluronoglucosaminidase - therapeutic use; Male; Medical sciences; Melanoma; Mice; Mice, Inbred C57BL; Mice, Nude; PEG; Pharmaceutical technology. Pharmaceutical industry; Pharmacology. Drug treatments; Polyethylene Glycols - metabolism; Polyethylene Glycols - pharmacology; Polyethylene Glycols - therapeutic use; Ribonuclease A; Ribonuclease, Pancreatic - metabolism; Ribonuclease, Pancreatic - pharmacology; Ribonuclease, Pancreatic - therapeutic use; Sheep; Xenograft Model Antitumor Assays - methods
• ISSN: 0168-3659; 1873-4995
• DOI: 10.1016/j.jconrel.2003.10.025

Subcutaneous application of bovine RNase A conjugated to HYase (bovine hyaluronidase), polyethylene glycol (PEG) and HYase+PEG resulted in a marked reduction of the width of the spermatogenic layers of the mouse testes. The number of sperms in caput epididymidis was significantly decreased in mice injected with conjugated RNase A. There was not any significant embryotoxic effect of free RNase A even conjugated with HYse, PEG and HYse+PEG. The immunogenicity, expressed in production of antibodies against free RNase A or conjugates with PEG, was very low. However, the immunogenic action of this enzyme conjugated only to HYase was much higher and produced the same immunogenicity as HYase itself. The immunogenic effect of RNase A+HYase conjugate decreased when PEG was joined to this conjugate. The inhibitory effect of RNase A conjugated to HYase, PEG and HYase+PEG on human ML-2 cells studied in vitro, was practically ineffective. On the other side, when RNase A conjugated to HYase or PEG was administered intraperitoneally into the mice bearing human melanoma, the antitumor effect was pronounced.