Onconase and amphinase, the antitumor ribonucleases from Rana pipiens oocytes.
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.
Ardelt
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W
Alfacell Corporation, 300 Atrium Drive, Somerset, NJ 08873, USA. wardelt@alfacell.com
Shogen
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K
Darzynkiewicz
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Z
D000595:Amino Acid Sequence; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002986:Clinical Trials as Topic; D004795:Enzyme Stability; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D009865:Oocytes / Q000201:enzymology*; D012343:RNA, Transfer / Q000037:antagonists & inhibitors; D011894:Rana pipiens; D012260:Ribonucleases / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D016415:Sequence Alignment
D000970:Antineoplastic Agents; D012343:RNA, Transfer; D012260:Ribonucleases; C522843:amphinase, Rana pipiens; C058703:ranpirnase