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J. Biol. Chem., Vol. 278, Issue 26, 23817-23822, June 27, 2003

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Antitumor Activity and Other Biological Actions of Oligomers of Ribonuclease A^*

Josef Matousek , Giovanni Gotte , Pavla Pouckova ¶, Josef Soucek ||, Tomas Slavik , Francesca Vottariello  and Massimo Libonati  **

From the Institute of Animal Physiology and Genetics, Academy of Sciences of the Czech Republic, Libechov 27721, Czech Republic, the Department of Neurological and Vision Sciences, Section of Biological Chemistry, Medical Faculty, the University of Verona, Strada Le Grazie 8, 37134 Verona, Italy, the ^¶Institute of Biophysics, Medical Faculty of Charles University, Prague 12000, Czech Republic, and the ^||Institute of Hematology and Blood Transfusion, the University of Prague, Prague 12820, Czech Republic

Dimers, trimers, and tetramers of bovine ribonuclease A, obtained by lyophilization of the enzyme from 40% acetic acid solutions, were purified and isolated by cation exchange chromatography. The two conformers constituting each aggregated species were assayed for their antitumor, aspermatogenic, or embryotoxic activities in comparison with monomeric RNase A and bovine seminal RNase, which is dimeric in nature. The antitumor action was tested in vitro on ML-2 (human myeloid leukemia) and HL-60 (human myeloid cell line) cells and in vivo on the growth of human non-pigmented melanoma (line UB900518) transplanted subcutaneously in nude mice. RNase A oligomers display a definite antitumor activity that increases as a function of the size of the oligomers. On ML-2 and HL-60 cells, dimers and trimers generally show a lower activity than bovine seminal RNase; the activity of tetramers, instead, is similar to or higher than that of the seminal enzyme. The growth of human melanoma in nude mice is inhibited by RNase A oligomers in the order dimers < trimers < tetramers. The action of the two tetramers is very strong, blocking almost completely the growth of melanoma. RNase A dimers, trimers, and tetramers display aspermatogenic effects similar to those of bovine seminal RNase, but, contrarily, they do not show any embryotoxic activity.

Received for publication, March 17, 2003 , and in revised form, April 11, 2003.

^* This work was supported by the Grant Agency of the Czech Republic through grant 523/01/0114 and the Italian Ministero dell'Università e della Ricerca Scientifica e Tecnologica (MURST), Progetti di Rilevante Importanza Nazionale (PRIN) 2000, 2001, 2002. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^** To whom correspondence should be addressed. Tel.: 39-045-8027166; Fax: 39-045-8027170; E-mail: massimo.libonati{at}univr.it.

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