ranpirnase

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BioDrugs. 2008;22(1):53-8.Links

Ribonucleases as novel chemotherapeutics : the ranpirnase example.

Lee JE, Raines RT.
Department of Biochemistry, University of Wisconsin-Madison, Madison, Wisconsin 53706-1544, USA.
Ranpirnase, a cytotoxic ribonuclease from the frog Rana pipiens, is the archetype of a novel class of cancer chemotherapeutic agents based on homologs and variants of bovine pancreatic ribonuclease (RNase A). Ranpirnase in combination with doxorubicin is in clinical trials for the treatment of unresectable malignant mesothelioma and other cancers. The putative mechanism for ranpirnase-mediated cytotoxicity involves binding to anionic components of the extracellular membrane, cytosolic internalization, and degradation of transfer RNA leading to apoptosis. The maintenance of ribonucleolytic activity in the presence of the cytosolic ribonuclease inhibitor protein is a key aspect of the cytotoxic activity of ranpirnase. The basis for its specific toxicity for cancer cells is not known. This review describes the development of ranpirnase as a cancer chemotherapeutic agent.

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http://www.alfacell.com/tech_platform/background.htm ONCONASE® (ranpirnase), Alfacell's flagship product, is a novel amphibian ribonuclease unique among the superfamily of pancreatic ribonuclease. ONCONASE® has demonstrated on a molecular level to re-regulate the unregulated growth and proliferation of cancer cells, as well as inhibit virus replication (e.g., HIV) in infected cells. Unlike most cancer drugs that attack all cells regardless of their phenotype (malignant vs. normal) and produce a variety of severe toxicities, ONCONASE® is not an indiscriminate cytotoxic agent. ONCONASE® affects primarily malignant exponentially growing cells, and its activity is mediated through elegant molecular mechanisms. One of the most characteristic features of cancer cells is their genetic instability and ability to develop various forms of resistance to treatment - especially to single anti-cancer agents that target the same or similar molecular targets. Tumor cells possess several redundant growth signal transduction pathways interconnected at several levels. Thus, tumor cells can quickly develop multiple "bypass" or alternative pathways of effective pro-growth and anti-apoptosis signaling that defeat the long-term therapeutic efficacy of most anti-cancer drugs. However, using combinations of agents with different mechanisms of action can minimize the development of drug resistance. By affecting multiple intracellular sites, ONCONASE® influences several functions in the tumor cell simultaneously. As such, ONCONASE® has been shown to overcome multiple drug resistance and to enhance the cytotoxicity of a variety of anti-cancer agents.

Synergies with Other Cancer Agents

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http://www.quintbio.com/evadTech.asp
What is the Evade™ Ribonuclease Technology?

Ribonucleases (RNases) are enzymes that degrade ribonucleic acid (RNA). Ribonucleases can be internalized and end up in the cytosol of the cell. Their action is blocked by another protein, ribonuclease inhibitor (RI). The EVade™ RNase technology provides the means to produce enzymatically active variants that have diminished binding to ribonuclease inhibitor.

The EVade™ Ribonucleases degrade ribonucleic acids (RNA), resulting in inhibition of protein synthesis and cell death.

A ribonuclease from frogs has completed a Phase III clinical trials for malignant mesothelioma. While the ribonuclease is effective, renal toxicity results in limiting the dose allowed in clincial trials. Mammalian ribonucleases do not show accumulation in the kidneys.

Advantages of the EVade™ Ribonucleases

• EVade™ RNases kill cancer cells by a novel mechanism - destruction of RNA.
• EVade™ RNases are of mammalian origin and are unlikely to be antigenic.
• The therapeutic index of the EVade™ RNases is unlikely to be curtailed by efflux pumps.
• EVade™ RNases work in combination with small molecule chemotherapeutics, such as vincristine.
• Catalysis is necessary for toxicity. EVade™ RNases are approximately 103-fold better catalysts of RNA degradation than are the amphibian ribonucleases.
• Mammalian RNases are not retained in the kidney.

Quintessence Biosciences is looking for partners with an interest in novel cancer therapies and their potential for combination and targeted therapy.