Nucleic Acids Research, 2003, Vol. 31, No. 3 1024-1032
© 2003 Oxford University Press
Ribonuclease inhibitor as an intracellular sentry
1 Department of Biochemistry and 2 Department of Chemistry, University of Wisconsin–Madison, Madison, WI 53706, USA
*To whom correspondence should be addressed at Department of Biochemistry, University of Wisconsin–Madison, 433 Babcock Drive, Madison, WI 53706-1544, USA. Tel: +1 608 262 8588; Fax: +1 608 262 3453; Email: raines{at}biochem.wisc.edu
Present address:
Marcia C. Haigis, Department of Biology, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA
Onconase® (ONC) is a homolog of RNase A that is in clinical trials as a cancer chemotherapeutic agent. The toxicity of ONC and RNase A variants relies on their ability to evade the cytosolic ribonuclease inhibitor protein (RI) and degrade cellular RNA. We find that these ribonucleases are more toxic for more rapidly growing cells. The enhanced cytotoxicity does not arise from variation in the endogenous level of RI, which is virtually constant. Overproduction of RI diminishes the potency of toxic RNase A variants, but has no effect on the cytotoxicity of ONC. Thus, RI constrains the cytotoxicity of RNase A. These data provide new insights for the development of an optimal ribonuclease-based cancer chemotherapy.
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