Rana pipiens oocytes contain two homologues of
pancreatic ribonuclease A that are
cytostatic and cytotoxic to human
cancer cells. Extensively studied
Onconase is in advanced Phase IIIb clinical trials against
malignant mesothelioma, while Amphinase is a novel
enzyme in pre-clinical development.
Onconase is the smallest (104
amino acid residues) member of the
ribonuclease A superfamily while Amphinase (114 residues) is the largest among amphibian
ribonucleases. Both
enzymes share the characteristic frog
ribonucleases C-terminal
disulfide bond but another signature of this group, the N-terminal
pyroglutamate, an integral part of
Onconase active site is not conserved in Amphinase. Although
Onconase and Amphinase are weak catalysts their enzymatic activities are required for
cytostatic and cytotoxic activity. While it was postulated that
tRNA is the primary substrate of
Onconase in vivo there is also extensive indirect evidence that suggests other
RNA species, in particular micro RNAs, may actually be the critical target of these
ribonucleases. The
cytostatic effects of
Onconase and Amphinase are manifested as cell arrest in the G(1) cell cycle phase. Apoptosis then follows involving activation of
endonucleases(s),
caspases,
serine proteases and
transglutaminase.
Onconase was shown to be strongly synergistic when combined with numerous other antitumor modalities.
Onconase and Amphinase are highly cationic molecules and their preferential toxicity towards
cancer cells (having distinctly higher negative charge compared to normal cells) may depend on increased binding efficiency to the cell surface by electrostatic interactions.