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Drugs in R&D 2007Ranpirnase [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... (Review)
Review
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.
Topics: Animals; Antineoplastic Agents; Antiviral Agents; Humans; Neoplasms; Ribonucleases; Virus Diseases
PubMed: 17324010
DOI: 10.2165/00126839-200708020-00007 -
Future Oncology (London, England) Jun 2008Ranpirnase, originally isolated from oocytes of the northern leopard frog (Rana pipiens), is a member of the pancreatic RNase A superfamily of ribonucleases. Ranpirnase... (Review)
Review
Ranpirnase, originally isolated from oocytes of the northern leopard frog (Rana pipiens), is a member of the pancreatic RNase A superfamily of ribonucleases. Ranpirnase exerts antiproliferative and cytotoxic effects in vitro and in vivo and has been shown to act synergistically with different cancer therapeutic agents. The cytotoxic and cytostatic effects of ranpirnase are the consequence of tRNA degradation that results in the disruption of protein translation and the induction of programmed cell death (apoptosis). Ranpirnase has been shown to target malignant cells both in human cancer cell lines and in animal models, and has demonstrated efficacy in the treatment of several human cancers in clinical studies. Most clinical studies have been conducted in patients with malignant mesothelioma, and a confirmatory Phase IIIb trial is currently underway for the treatment of this disease. Owing to its selective destruction of malignant cells and favorable toxicology profile, ranpirnase is a promising antitumor agent with ideal attributes that are generally lacking in conventional cytotoxic drugs.
Topics: Animals; Antineoplastic Agents; Clinical Trials as Topic; Humans; Mesothelioma; Neoplasms; Rana pipiens; Ribonucleases
PubMed: 18518759
DOI: 10.2217/14796694.4.3.341 -
Pathogens (Basel, Switzerland) Dec 2022Adenovirus ocular infections are common ocular viral infections seen worldwide, for which there is no approved antiviral therapy available. Ranpirnase is a novel...
Adenovirus ocular infections are common ocular viral infections seen worldwide, for which there is no approved antiviral therapy available. Ranpirnase is a novel ribonuclease which preferentially degrades tRNA resulting in an inhibition of protein synthesis. The study goal was to determine the anti-adenoviral activity of topical formulations of ranpirnase (OKG-0301) on adenoviral replication in the Ad5/NZW rabbit ocular replication model. NZW rabbits were inoculated in both eyes with human adenovirus type 5 (HAdV5) after corneal scarification. A day later, topical therapy was initiated in both eyes with 0.03% OKG-0301, 0.003% OKG-0301, saline or 0.5% cidofovir. Eyes were cultured to determine HAdV5 eye titers over 2 weeks. OKG-0301 (0.03% and 0.003%) and 0.5% cidofovir decreased viral titers compared to saline. Furthermore, both OKG-0301 formulations and 0.5% cidofovir shortened the duration of the HAdV5 infection compared to saline. Both 0.03% OKG-0301 and 0.003% OKG-0301 demonstrated increased antiviral activity compared to saline in the Ad5/NZW rabbit ocular replication model. The antiviral activity of the OKG-0301 groups was similar to that of the positive antiviral control, 0.5% cidofovir. Ranpirnase (OKG-0301) may be a potential candidate for a topical antiviral for adenoviral eye infections. Further clinical development is warranted.
PubMed: 36558819
DOI: 10.3390/pathogens11121485 -
BioDrugs : Clinical Immunotherapeutics,... 2008Ranpirnase, 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... (Review)
Review
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.
Topics: Animals; Antineoplastic Agents; Humans; Neoplasms; Protein Engineering; Protein Synthesis Inhibitors; Rana pipiens; Ribonucleases
PubMed: 18215091
DOI: 10.2165/00063030-200822010-00006 -
Viruses Feb 2020Currently, no rabies virus-specific antiviral drugs are available. Ranpirnase has strong antitumor and antiviral properties associated with its ribonuclease activity....
Currently, no rabies virus-specific antiviral drugs are available. Ranpirnase has strong antitumor and antiviral properties associated with its ribonuclease activity. TMR-001, a proprietary bulk drug substance solution of ranpirnase, was evaluated against rabies virus in three cell types: mouse neuroblastoma, BSR (baby hamster kidney cells), and bat primary fibroblast cells. When TMR-001 was added to cell monolayers 24 h preinfection, rabies virus release was inhibited for all cell types at three time points postinfection. TMR-001 treatment simultaneous with infection and 24 h postinfection effectively inhibited rabies virus release in the supernatant and cell-to-cell spread with 50% inhibitory concentrations of 0.2-2 nM and 20-600 nM, respectively. TMR-001 was administered at 0.1 mg/kg via intraperitoneal, intramuscular, or intravenous routes to Syrian hamsters beginning 24 h before a lethal rabies virus challenge and continuing once per day for up to 10 days. TMR-001 at this dose, formulation, and route of delivery did not prevent rabies virus transit from the periphery to the central nervous system in this model ( = 32). Further aspects of local controlled delivery of other active formulations or dose concentrations of TMR-001 or ribonuclease analogues should be investigated for this class of drugs as a rabies antiviral therapeutic.
Topics: Animals; Antiviral Agents; Cell Line; Cells, Cultured; Chiroptera; Cricetinae; Female; Fibroblasts; Mesocricetus; Mice; Rabies; Rabies virus; Ribonucleases; Virus Release; Virus Replication
PubMed: 32033253
DOI: 10.3390/v12020177 -
Antiviral Therapy 2017Human papillomaviruses (HPV), the causative agents of anogenital warts, are the most prevalent sexually transmitted infectious agents, and wart treatment poses a...
BACKGROUND
Human papillomaviruses (HPV), the causative agents of anogenital warts, are the most prevalent sexually transmitted infectious agents, and wart treatment poses a persistent challenge. We assessed the safety and efficacy of treating HPV with ranpirnase, an endoribonuclease from the northern leopard frog that has been used extensively in Phase III oncology trials.
METHODS
As initial verification of ranpirnase antiviral activity, we assessed its ability to eliminate papillomaviruses in cultured cells. To further assess its feasibility for treating anogenital warts in humans, we performed a Phase I study. Forty-two male volunteers with genital/perianal warts were treated topically with three different formulations of 1 mg/ml ranpirnase. Patients were monitored for 8 weeks or until healing. Four patients with HIV were treated in accordance with the compassionate programme but were not evaluated.
RESULTS
In cultured cells, ranpirnase showed specific activity against HPV-11 with low toxicity (selectivity index >88). The broad applicability of ranpirnase for treating papillomaviruses was verified using the cottontail rabbit papillomavirus. In the clinical study, eight participants were lost-to-follow-up or discontinued due to protocol violation or non-compliance. Among 30 evaluable participants, topical ranpirnase was moderately well-tolerated, with discontinuation by 5 (16.7%) due to adverse reactions. Clinical healing was achieved by 25 participants (83.3%) and 50% improvement by the 5 discontinued participants (16.7%). The median time to clinical healing was 30 days.
CONCLUSIONS
This study provides the first in vitro and clinical evidence of the antiviral efficacy of ranpirnase against HPV and supports assessment of ranpirnase in expanded clinical studies.
Topics: Administration, Topical; Adult; Animals; Cell Line; Cells, Cultured; Combined Modality Therapy; Condylomata Acuminata; Dose-Response Relationship, Drug; Humans; Kappapapillomavirus; Male; Mice; Middle Aged; Papillomaviridae; Papillomavirus Infections; Rabbits; Ribonucleases; Treatment Outcome; Young Adult
PubMed: 28121292
DOI: 10.3851/IMP3133 -
Expert Opinion on Biological Therapy Jun 2008Ranpirnase, a cytotoxic amphibian ribonuclease, is effective against cancer cells, inducing apoptosis independently of p53 protein. Onconase (the smallest member of the... (Review)
Review
Ranpirnase (Onconase), a cytotoxic amphibian ribonuclease, manipulates tumour physiological parameters as a selective killer and a potential enhancer for chemotherapy and radiation in cancer therapy.
BACKGROUND
Ranpirnase, a cytotoxic amphibian ribonuclease, is effective against cancer cells, inducing apoptosis independently of p53 protein. Onconase (the smallest member of the RNase A superfamily) has moved into clinical testing in the US and Europe.
OBJECTIVE
The main focuses of this review are to examine the manipulation of tumour physiological parameters by ranpirnase and discuss its molecular, pharmacological and physiological roles in preclinical and clinical trials in terms of benefits and toxicity.
METHODS
Relevant literature, including the author's unpublished presentations at recent conferences, was examined.
RESULTS/CONCLUSION
In animal studies, improvements in tumour physiology (i.e., increased blood flow, inhibited oxygen consumption, increased oxygenation and decreased tumour hypertension) and selectively enhanced radiation responses (i.e., increased radiation sensitivity and inhibited repair of sublethal and potentially lethal damage) were observed after ranpirnase treatment in preclinical tumour models. Ranpirnase is a promising candidate as an enhancer for radiation- and chemotherapy. Ongoing clinical trials promise to further improve the treatment of mesothelioma and lung cancer.
Topics: Animals; Antineoplastic Agents; Apoptosis; Clinical Trials as Topic; Drug Screening Assays, Antitumor; Drug Synergism; Extracellular Fluid; Humans; Mice; Mice, Nude; Mice, SCID; Neoplasm Proteins; Neoplasms; Oxygen Consumption; Phosphoinositide-3 Kinase Inhibitors; RNA Stability; RNA, Neoplasm; Radiation-Sensitizing Agents; Rana pipiens; Ribonucleases; Signal Transduction
PubMed: 18476793
DOI: 10.1517/14712598.8.6.813 -
Expert Opinion on Biological Therapy Apr 2006Ranpirnase (Onconase) is a novel cytotoxic ribonuclease. In clinical development as a single agent in patients with malignant mesothelioma (MM), at 480 microg/m2... (Review)
Review
Ranpirnase (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.
Topics: Animals; Antineoplastic Agents; Drugs, Investigational; Humans; Mesothelioma; Ribonucleases
PubMed: 16548765
DOI: 10.1517/14712598.6.4.391 -
Antiviral Research Aug 2016The recent epidemic of Ebola has intensified the need for the development of novel antiviral therapeutics that prolong and improve survival against deadly viral...
The recent epidemic of Ebola has intensified the need for the development of novel antiviral therapeutics that prolong and improve survival against deadly viral diseases. We sought to determine whether ranpirnase, an endoribonuclease from Rana pipiens with a demonstrated human safety profile in phase III oncology trials, can reduce titers of Ebola virus (EBOV) in infected cells, protect mice against mouse-adapted EBOV challenge, and reduce virus levels in infected mice. Our results demonstrate that 0.50 μg/ml ranpirnase is potently effective at reducing EBOV Zaire Kikwit infection in cultured Vero E6 cells (Selectivity Index 47.8-70.2). In a prophylactic study, a single intravenous dose of 0.1 mg/kg ranpirnase protected 70% of mice from progressive infection. Additionally, in a post-exposure prophylactic study, 100% of female mice survived infection after intraperitoneal administration of 0.1 mg/kg ranpirnase for ten days beginning 1 h post challenge. Most of the male counterparts were sacrificed due to weight loss by Study Day 8 or 9; however, the Clinical Activity/Behavior scores of these mice remained low and no significant microscopic pathologies could be detected in the kidneys, livers or spleens. Furthermore, live virus could not be detected in the sera of ranpirnase-treated mice by Study Day 8 or in the kidneys, livers or spleens by Study Day 12, and viral RNA levels declined exponentially by Study Day 12. Because ranpirnase is exceptionally stable and has a long track record of safe intravenous administration to humans, this drug provides a promising new candidate for clinical consideration in the treatment of Ebola virus disease alone or in combination with other therapeutics.
Topics: Animals; Antiviral Agents; Cell Line; Chlorocebus aethiops; Disease Models, Animal; Dose-Response Relationship, Drug; Ebolavirus; Female; Hemorrhagic Fever, Ebola; Humans; Mice; RNA, Viral; Ribonucleases; Vero Cells; Viral Load; Virus Replication
PubMed: 27350309
DOI: 10.1016/j.antiviral.2016.06.009 -
Genes & Cancer May 2011The ribonuclease ranpirnase (Onconase) has been used empirically to treat malignant mesothelioma (MM) patients, and some of them had prolonged survivals. The aim of this...
The ribonuclease ranpirnase (Onconase) has been used empirically to treat malignant mesothelioma (MM) patients, and some of them had prolonged survivals. The aim of this study was to investigate the mechanisms of the therapeutic function of ranpirnase in MM cells. The effects of ranpirnase were studied in vivo and in vitro on 2 MM cell lines (epithelioid REN and sarcomatoid PPM-Mill). We found that ranpirnase was able to inhibit NF-κB nuclear translocation, evaluated by cell fractionation and immunoblotting as well as by immunofluorescence. Also, MMP9 secretion by MM cells was decreased by ranpirnase treatment, as assessed by the reduction of metalloproteinase activity, evaluated by zymography on culture-conditioned media. Ranpirnase induced apoptosis of MM cells in vitro and in vivo, causing a powerful inhibition of MM tumor growth in SCID xenografts, determined by In Vivo Imaging System (IVIS) of tumor cells engineered by lentiviral transduction of the luciferase gene. Finally, mice treated with ranpirnase showed a significantly prolonged survival. Our data provide a mechanistic rationale to explain the beneficial antitumor activity observed in some patients treated with ranpirnase and demonstrate that ranpirnase interferes with the NF-κB pathway, thus influencing MM tumor cell invasiveness and survival. It is hoped that this information will also facilitate the identification of those patients who are more likely to benefit from this drug and will also open a new frontier for the use of this drug in tumor types other than MM.
PubMed: 21901170
DOI: 10.1177/1947601911412375