Ranpirnase--an antitumour ribonucleaseRanpirnase (Onconase) is a novel cytotoxic ribonuclease. In clinical development as a single agent in patients with malignant mesothelioma (MM), at 480 microg/m2 intravenously weekly, analysis of survival indicated prolonged periods of stable disease in Phase II trials and a potential survival benefit, compared with doxorubicin, in a small unpublished Phase III trial. In all clinical studies it has generally demonstrated a favourable safety profile except for easily controlled allergic reactions and dose modifications for renal impairment. Standard first-line treatment for MM has recently been established with an antifolate and cisplatin. At present, a Phase III trial of doxorubicin with or without ranpirnase is nearing completion in MM patients without prior chemotherapy or one prior chemotherapy regimen. Onconase (ONC) is a ribonuclease isolated from amphibian oocytes that is cytostatic and cytotoxic to numerous tumor lines. ONC shows in vivo anti-tumor activity in mouse tumor model. Cytotoxic ribonucleases (RNases), such as ranpiranase, represent a novel mechanism-based approach to anticancer therapy. These relatively small proteins selectively attack malignant cells, triggering apoptotic response and inhibiting protein synthesis. Ranpirnase, originally isolated from oocytes of Rana pipiens, is a member of a family of endoribonucleases. The anticancer effects of ranpiranase have been documented in both in vitro and in vivo experimental tumor models. The effects of ranpiranase appear to be selective for cancer cells. Based on Phase I study data, the maximum tolerated dose (MTD) was 960 microg/m2, with the dose-limiting toxicity (DLT) characterized by proteinuria with or without azotemia, peripheral edema, and fatigue. Ranpirnase did not induce myelosuppression, mucositis, alopecia, cardiotoxicity, coagulopathy, hepatotoxicity, or adverse metabolic effects. Phase II tumor-specific trials investigated the activity of ranpirnase in malignant mesothelioma, breast cancer, non-small cell lung cancer, and renal cell cancer. A Phase III randomized study in malignant mesothelioma patients compares the combination of ranpirnase plus doxorubicin to doxorubicin monotherapy. Effect of N-terminal and Met23 mutations on the structure and dynamics of onconase.
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use of chemotherapy in patients with advanced malignant pleural mesothelioma:
a clinical practice guideline.
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