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Latent Fluorophores for Biomolecular Imaging
Author(s) -
Raines Ronald T.
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.117.3
Subject(s) - rnase p , ribonuclease , rna , pancreatic ribonuclease , cytotoxic t cell , rnase h , enzyme , in vitro , cytotoxicity , biology , biochemistry , bovine pancreatic ribonuclease , in vivo , chemistry , microbiology and biotechnology , gene , genetics
Ribonucleases can be cytotoxic because cleaving RNA renders indecipherable its encoded information. We have shown that, with the subtlest of manipulation, an otherwise innocuous ribonuclease can be transformed into a useful cytotoxin. Bovine pancreatic ribonuclease (RNase A) is the most often studied enzyme. We reasoned that this nontoxic enzyme could become cytotoxic if it were able to evade the endogenous ribonuclease inhibitor protein that protects cellular RNA against invading ribonucleases. By changing a single amino acid residue, we made RNase A toxic to human cells, thereby verifying our hypothesis. We have extended this approach to RNase 1, which is the human homologue of RNase A. Most importantly, we have shown that the cytotoxicity of these enzymes is manifested preferentially against cancer cells, both in vitro and in vivo . A variant of RNase 1 is scheduled to enter a Phase I clinical trial as a cancer chemotherapeutic in early 2008. We are now using a variety of tools, especially new small‐molecule probes known as “latent fluorophores” to delineate the mechanism by which our cytotoxic ribonucleases kill human cancer cells. This work is supported by Grant CA73808 (NIH).