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Nora Liebers, Tim Holland-Letz, Mona Welschof, Anders Høgset, Dirk Jäger, Michaela A E Arndt, Jürgen Krauss
Introduction: Photochemical Internalization is a novel drug delivery technology for cancer treatment based on the principle of Photodynamic Treatment. Using a photosensitizer that locates in endocytic vesicles membranes of tumor cells, Photochemical internalization enables cytosolic release of endocytosed antitumor agents in a site-specific manner. The purpose of the present in-vitro study was to explore whether Photochemical Internalization is able to enhance the efficacy of Ranpirnase, a cytotoxic amphibian ribonuclease, for eradication of squamous cell carcinoma of the head and neck...
November 2017: Journal of Experimental Therapeutics & Oncology
Luis Squiquera, Debra J Taxman, Sarah A Brendle, Roberto Torres, Jamie Sulley, Thomas Hodge, Neil Christensen, David Sidransky
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...
2017: Antiviral Therapy
Ruby C Y Lin, Michaela B Kirschner, Yuen Yee Cheng, Nico van Zandwijk, Glen Reid
Malignant pleural mesothelioma (MPM) is a tumor originating in the mesothelium, the membrane lining the thoracic cavities, and is induced by exposure to asbestos. Australia suffers one of the world's highest rates of MPM and the incidence is yet to peak. The prognosis for patients with MPM is poor and median survival following diagnosis is 4-18 months. Currently, no or few effective therapies exist for MPM. Trials of targeted agents such as antiangiogenic agents (VEGF, EGFR) or ribonuclease inhibitors (ranpirnase) largely failed to show efficacy in MPM Tsao et al...
September 2016: Genomics Data
Thomas Hodge, Ken Draper, Trevor Brasel, Alexander Freiberg, Luis Squiquera, David Sidransky, Jamie Sulley, Debra J Taxman
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...
August 2016: Antiviral Research
Ganggang Yang, Chengkai Ma, Quanyi Zhang, Shihui Shi, Ze Wang, Zhongyuan Lü, Xuyang Wang, Xiaoya Xu, Qingqing Cui, Jihong Zhang, Ruigang Zhang, Cunshuan Xu
Ranpirnase (onconase, ONC) is a new drug, with weak RNase activity and strong cytotoxicity to various tumor cells in vitro and in vivo. This study is to obtain recombination onconase (rONC) with high bioactivity. Based on the codon preference of Pichia pastoris, we designed and synthesized the gene according to cDNA sequences of ONC and the α mating factor's prepeptide. We screened positive clones after transforming the recombination plasmids into P. pastoris X-33, GSS115 and SMD1168. We screened the best combination of seven different vectors and host strains...
November 2015: Sheng Wu Gong Cheng Xue Bao, Chinese Journal of Biotechnology
Tobias Weber, Athanasios Mavratzas, Stefan Kiesgen, Stephanie Haase, Benedikt Bötticher, Evelyn Exner, Walter Mier, Ludger Grosse-Hovest, Dirk Jäger, Michaela A E Arndt, Jürgen Krauss
Antibody-drug conjugates (ADCs) have evolved as a new class of potent cancer therapeutics. We here report on the development of ADCs with specificity for the B-cell lineage specific (surface) antigen CD22 being expressed in the majority of hematological malignancies. As targeting moiety a previously generated humanized anti-CD22 single-chain variable fragment (scFv) derivative from the monoclonal antibody RFB4 was reengineered into a humanized IgG1 antibody format (huRFB4). Onconase (ranpirnase), a clinically active pancreatic-type ribonuclease, was employed as cytotoxic payload moiety...
2015: Journal of Immunology Research
Claudia Fiorini, Marco Cordani, Giovanni Gotte, Delia Picone, Massimo Donadelli
Onconase® (ONC) is a member of the RNase super-family that is secreted in oocytes and early embryos of Rana pipiens. Over the last years, research interest about this small and basic frog RNase, also called ranpirnase, constantly increased because of its high cytotoxicity and anticancer properties. Onconase is currently used in clinical trials for cancer therapy; however, the precise mechanisms determining cytotoxicity in cancer cells have not yet been fully investigated. In the present manuscript, we evaluate the antitumoral property of onconase in pancreatic adenocarcinoma cells and in non-tumorigenic cells as a control...
March 2015: Biochimica et Biophysica Acta
Stefan Kiesgen, Michaela A E Arndt, Christoph Körber, Ulrich Arnold, Tobias Weber, Niels Halama, Armin Keller, Benedikt Bötticher, Anne Schlegelmilch, Nora Liebers, Martin Cremer, Christel Herold-Mende, Gerhard Dyckhoff, Philippe A Federspil, Alexandra D Jensen, Dirk Jäger, Roland E Kontermann, Walter Mier, Jürgen Krauss
Cytotoxic ribonucleases such as the leopard frog derivative Ranpirnase (Onconase(®)) have emerged as a valuable new class of cancer therapeutics. Clinical trials employing single agent Ranpirnase in cancer patients have demonstrated significant clinical activity and surprisingly low immunogenicity. However, dose-limiting toxicity due to unspecific uptake of the RNase into non-cancerous cells is reached at relatively low concentrations of > 1 mg/m(2). We have in the present study generated a dimeric anti-EGFR Ranpirnase-diabody fusion protein capable to deliver two Ranpirnase moieties per molecule to EGFR-positive tumour cells...
February 1, 2015: Cancer Letters
Stefan Kiesgen, Nora Liebers, Martin Cremer, Ulrich Arnold, Tobias Weber, Armin Keller, Christel Herold-Mende, Gerhard Dyckhoff, Dirk Jäger, Roland E Kontermann, Michaela A E Arndt, Jürgen Krauss
Due to its frequent overexpression in a variety of solid tumors the epidermal growth factor receptor (EGFR) is a well-established target for therapeutic interventions in epithelial cancers. In order to target EGFR in head and neck cancer, we have generated a ribonuclease (RNase) fusion protein comprising a humanized anti-EGFR antibody single-chain Fv fragment (scFv) and Ranpirnase, an RNase from Rana pipiens. Fusion of Ranpirnase to the N-terminus of the scFv via a flexible glycine-serine linker (G4S)3 resulted in very poor cytotoxicity of the fusion protein...
October 2014: Protein Engineering, Design & Selection: PEDS
Piotr Smolewski, Magdalena Witkowska, Malgorzata Zwolinska, Barbara Cebula-Obrzut, Agata Majchrzak, Aleksandra Jeske, Zbigniew Darzynkiewicz, Wojciech Ardelt, Barbara Ardelt, Tadeusz Robak
Although major advancements in antitumor treatment have been observed, several B cell-derived malignancies still remain incurable. A promising approach that involves targeting RNA either by the use of specific antisense oligonucleotides or cytostatic/cytotoxic ribonucleases (RNases) is being promoted. Two amphibian RNases, onconase (ONC; ranpirnase) and, more recently, r-amphinase (r-Amph), have already been tested, but thus far, mostly on solid tumors. In this study, for the first time we provide comprehensive data on ex vivo and in vivo cytotoxic activity of ONC or r-Amph against cancer cells from different B cell lymphoid malignancies, together with their detailed mode of antitumor action...
July 2014: International Journal of Oncology
Xiao-Min Wang, Zhan-Yun Guo
Ranpirnase (Onconase) is a frogspawn-derived disulfide-rich peptide with ribonuclease activity that may be used for tumor treatment. In the present study, we established an efficient approach for preparing mature ranpirnase which may be used for research and therapeutic purposes. The designed ranpirnase precursors carried a 6xHis-tag and were recombinantly expressed in Escherichia coli. After S-sulfonation, the precursors were purified by immobilized metal-ion affinity chromatography. Following removal of the tag by aminopeptidase cleavage, cyclization and in vitro oxidative refolding, the mature ranpirnase was obtained with considerable yield, and the yield of mature ranpirnase was ~50-60 mg per liter cultures...
September 2013: Biomedical Reports
Donglin Liu, Thomas M Cardillo, Yang Wang, Edmund A Rossi, David M Goldenberg, Chien-Hsing Chang
BACKGROUND: Ranpirnase (Rap) is an amphibian ribonuclease with reported antitumor activity, minimal toxicity, and negligible immunogenicity in clinical studies, but the unfavorable pharmacokinetics and suboptimal efficacy hampered its further clinical development. To improve the potential of Rap-based therapeutics, we have used the DOCK-AND-LOCK™ (DNL™) method to construct a class of novel IgG-Rap immunoRNases. In the present study, a pair of these constructs, (Rap)2-E1-(Rap)2 and (Rap)2-E1*-(Rap)2, comprising four copies of Rap linked to the CH3 and CK termini of hRS7 (humanized anti-Trop-2), respectively, were evaluated as potential therapeutics for triple-negative breast cancer (TNBC)...
March 10, 2014: Molecular Cancer
Agata Majchrzak, Magdalena Witkowska, Aleksandra Mędra, Małgorzata Zwolińska, Jakub Bogusz, Barbara Cebula-Obrzut, Zbigniew Darzynkiewicz, Tadeusz Robak, Piotr Smolewski
Ranpirnase (onconase; ONC) is an endoribonuclease obtained from the frog Rana pipiens. This enzyme exhibits anticancer properties mediated by degradation of cellular RNA and induction of apoptosis. In this study we assessed cytotoxicity of ONC in combination with currently used anticancer drugs on a human diffuse large B-cell lymphoma (DLBCL)-derived cell line (Toledo). Cytotoxic activity was measured by the exclusion of propidium iodide assay while apoptosis was assessed using the annexin-V binding method...
December 2, 2013: Postȩpy Higieny i Medycyny Doświadczalnej
Henrike Westekemper, Michael Freistuehler, Norbert Bornfeld, Klaus-Peter Steuhl, Max Scheulen, Ralf A Hilger
OBJECTIVE: In conjunctival melanoma, local chemotherapy has been based so far on clinical evidence and limited to the therapy of melanoma in situ. Our aim was to define substances that may have the potential to add to therapeutic options in extended local growth and metastatic disease. Two conjunctival cell lines (CRMM-1 and CRMM-2) have been established from recurrent conjunctival melanoma. In this study, we examined the chemosensitivity of these cell lines to different cytotoxic substances...
January 2013: Graefe's Archive for Clinical and Experimental Ophthalmology
Masaki Nasu, Michele Carbone, Giovanni Gaudino, Bevan H Ly, Pietro Bertino, David Shimizu, Paul Morris, Harvey I Pass, Haining Yang
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...
May 2011: Genes & Cancer
C M Goparaju, J D Blasberg, S Volinia, J Palatini, S Ivanov, J S Donington, C Croce, M Carbone, H Yang, H I Pass
Treatment of malignant pleural mesothelioma (MPM) with Ranpirnase (Onconase) results in disruption of protein translation and cell apoptosis. We hypothesize that Onconase exerts an effect via downregulation of nuclear factor kappa B (NFKβ) by specific microRNAs (miRNAs) and that interference of this pathway could have implications for MPM resistance to chemotherapy. Three immortalized MPM cell lines (H2959, H2373 and H2591) were exposed to Onconase at 0-20 μg/ml. Cell counts were measured at 48 and 72 h...
June 16, 2011: Oncogene
Chien-Hsing Chang, Pankaj Gupta, Rosana Michel, Meiyu Loo, Yang Wang, Thomas M Cardillo, David M Goldenberg
Ranpirnase (Rap), an amphibian RNase, has been extensively studied both preclinically and clinically as an antitumor agent. Rap can be administered repeatedly to patients without any untoward immune response, with reversible renal toxicity reported to be dose limiting. To enhance its potency and targeted tumor therapy, we describe the generation of a novel IgG-based immunotoxin, designated 2L-Rap(Q)-hRS7, comprising Rap(Q), a mutant Rap with the putative N-glycosylation site removed, and hRS7, an internalizing, humanized antibody against Trop-2, a cell surface glycoprotein overexpressed in variety of epithelial cancers...
August 2010: Molecular Cancer Therapeutics
Małgorzata Zwolińska, Piotr Smolewski
Onconase (ranpirnase) is a homologous protein obtained from Rana pipiens frog eggs. The activity of onconase, and particularly its antitumor effect, is strictly connected with ribonuclease(RN-ase) activity. Onconase induces cell death through the decomposition of inner cellular RNA,inhibition of protein synthesis, and inhibition of cell growth and proliferation and it also specifically triggers tumor cell apoptosis. A very important mechanisms of its cytotoxicity is also its antioxidant activity. The results of preclinical trials demonstrated a high activity of onconase against tumor cells, also those resistant to cytostatics...
February 19, 2010: Postȩpy Higieny i Medycyny Doświadczalnej
Camillo Porta, Chiara Paglino, Luciano Mutti
Ribonucleases are a superfamily of enzymes which operate at the crossroads of transcription and translation, catalyzing the degradation of RNA; they can be cytotoxic because the cleavage of RNA renders indecipherable its information. Ranpirnase is a novel ribonuclease which preferentially degrades tRNA, thus leading to inhibition of protein synthesis and, ultimately, to cytostasis and cytotoxicity. Ranpirnase has demonstrated antitumor activity both in vitro and in vivo in several tumor models. The maximum tolerated dose emerging from phase I studies was 960 g/m(2), with renal toxicity as the main dose-limiting toxicity...
December 2008: Biologics: Targets & Therapy
Rebecca F Turcotte, Ronald T Raines
Ribonucleases are evoking medical interest because of their intrinsic cytotoxic activity. Most notably, ranpirnase, which is an amphibian ribonuclease, is in advanced clinical trials as a chemotherapeutic agent for the treatment of cancer. Here, we describe a strategy to create a novel antiviral agent based on bovine pancreatic ribonuclease (RNase A), a mammalian homologue of ranpirnase. Specifically, we have linked the N- and C-termini of RNase A with an amino acid sequence that is recognized and cleaved by human immunodeficiency virus (HIV) protease...
November 2008: AIDS Research and Human Retroviruses
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