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Ribonucleases and their antitumor activity
1Institute of Animal Physiology and Genetics, Academy of Sciences of the Czech Republic, 277-21, Libechov, Czech Republic. matousek@iapg.cas.cz
Abstract:
The antitumor effect of ribonucleases was studied with animal ribonucleolytic enzymes, bovine pancreatic RNase A, bovine seminal RNase (BS-RNase), onconase and angiogenin. While bovine pancreatic RNase A exerts a minor antitumor effect, BS-RNase and onconase exert significant effects. Angiogenin, as RNase, works in an opposite way, it initiates vascularization of tumors and subsequent tumor growth. Ribonunclease inhibitors are not able to inhibit the antitumor effectiveness of BS-RNase or onconase. However, they do so in the case of pancreatic RNases. Conjugation of BS-RNase with antibodies against tumor antigens (preparation of immunotoxins) like the conjugation of the enzyme with polymers enhances the antitumor activity of the ribonuclease. After conjugation with polymers, the half-life of BS-RNase in blood is extended and its immunogenicity reduced. Recombinant RNases have the same functional activity as the native enzymes. The synthetic genes have also been modified, some of them with gene sequences typical for the BS-RNase parts. Recent experimental efforts are directed to the preparation of 'humanized antitumor ribonuclease' that would be structurally similar to human enzyme with minimal immunogenicity and side effects. The angiogenesis of tumors is attempted to be minimized by specific antibodies or anti-angiogenic substances.
Insights
Bovine seminal RNase (BS-RNase) and onconase show significant antitumor effects, unlike pancreatic RNase A. Enhancing BS-RNase through conjugation or creating humanized versions may improve cancer treatment by boosting efficacy and reducing side effects.
Area of Science:
- Biochemistry
- Oncology
- Enzymology
Background:
- Ribonucleases (RNases) are enzymes that degrade RNA.
- Certain RNases exhibit antitumor properties, while others, like angiogenin, can promote tumor growth via angiogenesis.
- Understanding RNase mechanisms is crucial for developing novel cancer therapies.
Purpose of the Study:
- To evaluate the antitumor potential of various animal ribonucleases.
- To investigate factors influencing RNase efficacy, including conjugation and genetic modification.
- To explore strategies for minimizing immunogenicity and side effects of antitumor RNases.
Main Methods:
- Comparative analysis of bovine pancreatic RNase A, bovine seminal RNase (BS-RNase), onconase, and angiogenin.
- Assessment of RNase inhibitor effects on antitumor activity.
- Preparation and evaluation of BS-RNase immunotoxins and polymer conjugates.
- Investigation of recombinant RNase activity and synthetic gene modifications.
- Exploration of 'humanized' RNase development and anti-angiogenesis strategies.
Main Results:
- BS-RNase and onconase demonstrated significant antitumor effects, whereas bovine pancreatic RNase A had a minor effect.
- Angiogenin promoted tumor vascularization and growth.
- RNase inhibitors did not affect BS-RNase or onconase efficacy but inhibited pancreatic RNases.
- Conjugation of BS-RNase with antibodies or polymers enhanced its antitumor activity, extended half-life, and reduced immunogenicity.
- Recombinant RNases retained functional activity; synthetic genes were modified for improved properties.
Conclusions:
- BS-RNase and onconase are promising candidates for antitumor therapies.
- Enzyme modification, such as conjugation and humanization, can significantly enhance therapeutic potential and safety.
- Targeting angiogenesis is a complementary strategy for cancer treatment.