Editorial [Hot Topic: The Therapeutic Potential of Ribonucleases (Guest Editor: Urich Arnold) ]

As the annual number of newly diagnosed cases of cancer is about 10 million worldwide, combat of cancer is one of the most outstanding challenges of recent medicine. The considerable undesired side effects of chemotherapy and/or radiotherapy caused by their little selectivity call for a specific targeting of the affected tissue. Exploiting the target specificity of antibodies, which selectively bind to tumor-associated antigens presented on the cell surface, reduces the systemic toxicity of the coupled compounds. All organisms contain numerous ribonucleolytic enzymes for RNA digestion, processing, and regulation etc., which provide a wide palette of potential cytotoxins. Several of these display a preference for transformed cells per se, others can be converted into tumor specific drugs by modification or fusion to respective targeting moieties. Hence, intensive research is carried out on the use of these enzymes as therapeutics. This issue of Current Pharmaceutical Biotechnology consists of a comprehensive compilation of reviews on the therapeutic potential of RNases, mainly from the RNase A (bovine pancreatic RNase) superfamily. The cytotoxicity of RNases was discovered back in the 1950s but cytotoxic effects were observed only when milligrams of enzyme were injected into solid tumors, while smaller doses of RNase A had no effect. In parallel, RNase A evolved as one of the most intensively studied model proteins in virtually all fields of biochemical research. Still, cytotoxicity has remained one of the most attractive characteristics of RNases because these enzymes could be used, alone or conjugated to ligands or antibodies, as therapeutic agents for cancer treatment. The subject is timely, as an important series of new discoveries and developments in this area has emerged over the past years. With Onconase® (Alfacell Corp., Somerset, NJ, U.S.A.), an RNase from the Northern Leopard frog Rana pipiens, an RNase has reached phase III clinical trials for treatment of non-small cell lung cancer and confirmatory phase IIIb for treatment of malignant mesothelioma. Furthermore, a recently generated fully human fusion protein composed of an anti-ErbB2 single-chain antibody fragment and the human pancreatic RNase (ERB-hRNase immunoRNase) has portended the development of RNase-based drugs from human-sourced building blocks. Thus, the promising medicinal applicability of RNases emphasizes the lasting topicality of these rather old enzymes. With techniques to follow molecules on the cellular and subcellular level, the understanding of the mechanisms and the interplay by which RNases exert cytotoxicity begins to become lucid. On their way from administration to the final intracellular target, the proteins face numerous obstacles and there are tremendous differences in how efficient the particular RNase can cope with the respective prerequisites. The reviews of this issue cover the different stages and underline the sophisticated requirements an RNase-based drug must meet. ACKNOWLEDGEMENTS The editor gratefully acknowledges the contributions of all authors of the reviews for this special issue of Current Pharmaceutical Biotechnology. In the following, the corresponding authors are listed in alphabetical order: Wojciech Ardelt, Ester Boix, Giuseppe D'Alessio, Junichiro Futami, Jurgen Krauss, Massimo Libonati, Alvaro Martinezdel- Pozo, Ronald T. Raines, Marc Ribo, Helene F. Rosenberg, and Susanna M. Rybak