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Curated Journal Articles on Mesothelioma

Ranpirnase: amphibian ribonuclease A, P-30 protein-alfacell.

Drugs in R&D. 2007;8(2):120-4. [Link]

Abstract

Ranpirnase [Onconase] is an amphibian oocyte/early embryo ribonuclease (RNase) of 105 amino acids in length that is capable of controlling tumour growth by degrading RNA within cancer cells, resulting in inhibition of protein synthesis and arresting mitosis in G(1 )phase. It represents the first successful isolation, purification and characterisation of the oocytic/early embryonic factor that is capable of controlling cell growth activities of the early embryonic tissues.

Alfacell Corporation is currently conducting clinical trials of ranpirnase in patients with unresectable malignant mesothelioma and non-small-cell lung cancer. The company may initiate phase II clinical trials in breast cancer and oesophageal cancer in 2006. Alfacell expanded a research agreement with the National Cancer Institute in September 2002, allowing the NCI to examine the effects of ranpirnase as a radiation enhancer. However, investigation in this use of ranpirnase now appears to be discontinued.

Alfacell is conducting a confirmatory phase IIIb registration trial of ranpirnase plus doxorubicin versus doxorubicin alone in more than 360 patients with unresectable malignant mesothelioma, and will assess survival as the primary endpoint. The targeted treatment group in this trial represents 90% of malignant mesothelioma patients at the time of diagnosis. The trial is being conducted in the US, Canada, Poland, Italy, Germany, Australia, New Zealand, Russia, Romania, Mexico and Brazil. In April 2006, a
total of 210 events (patient deaths) was reached, representing two-thirds of the required events for the study. Results from the protocol-specified first interim analysis based on one-third of the required events have been reported and the company has the option to conduct a second interim analysis of the data at any point after 210 events. A final analysis will be undertaken at 316 events.

Alfacell completed a phase III trial of single-agent ranpirnase in patients with unresectable malignant mesothelioma in April 1999. The efficacy of ranpirnase was compared with that of doxorubicin (head-to-head). The primary objectives were overall survival, progression-free survival and quality of life. In preclinical studies, ranpirnase demonstrated significant activity against neuroblastoma, rhabdomyosarcoma and chemotherapy-resistant variants of these cancer cells. Development for these indications has been discontinued.

Preclinical investigations conducted by Alfacell showed synergistic antitumour effects between ranpirnase and proteasome inhibitors. However, development is this area has been discontinued.

Alfacell announced in May 2003 that it would be providing ranpirnase to the federal severe acute respiratory syndrome (SARS) testing programme for evaluation against the human coronavirus implicated in the disease. No further development has been reported.

Alfacell has received nine US and four European patents for ranpirnase. Patents issued in the US range from the 1996-issued patent (No. 5 559 212) covering the amino acid sequence of ranpirnase, to the patent (No. 6 175 003 B1) issued in January 2001 protecting the gene sequences of the compound plus another genetically engineered variant, effectively protecting the company’s proprietary technology. In August 2002, Alfacell received a US patent (No. 6 423 515 B1) entitled ‘Methods of Making Nucleic Acids Encoding Ribonucleases’. This patent is effective until 2020.

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