Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on sleep in brain health

LIVE: Thursday 2nd May 2024, 18:00-19:30 (CEST)

Quality sleep is essential for health. But what happens to our brains when sleep patterns are disturbed? Join our experts to explore the interplay between sleep disruption and neurological diseases, and the questions that you need to be asking your patients to help you prevent the harmful effects of sleep deprivation.
ADVANCED SEARCH
Log in
Top
Journal of Translational Medicine
Published in: Journal of Translational Medicine 1/2011

Open Access 01-12-2011 | Research

Bacterial glucuronidase as general marker for oncolytic virotherapy or other biological therapies

Authors: Michael Hess, Jochen Stritzker, Barbara Härtl, Julia B Sturm, Ivaylo Gentschev, Aladar A Szalay

Published in: Journal of Translational Medicine | Issue 1/2011

Login to get access

Abstract

Background

Oncolytic viral tumor therapy is an emerging field in the fight against cancer with rising numbers of clinical trials and the first clinically approved product (Adenovirus for the treatment of Head and Neck Cancer in China) in this field. Yet, until recently no general (bio)marker or reporter gene was described that could be used to evaluate successful tumor colonization and/or transgene expression in other biological therapies.

Methods

Here, a bacterial glucuronidase (GusA) encoded by biological therapeutics (e.g. oncolytic viruses) was used as reporter system.

Results

Using fluorogenic probes that were specifically activated by glucuronidase we could show 1) preferential activation in tumors, 2) renal excretion of the activated fluorescent compounds and 3) reproducible detection of GusA in the serum of oncolytic vaccinia virus treated, tumor bearing mice in several tumor models. Time course studies revealed that reliable differentiation between tumor bearing and healthy mice can be done as early as 9 days post injection of the virus. Regarding the sensitivity of the newly developed assay system, we could show that a single infected tumor cell could be reliably detected in this assay.

Conclusion

GusA therefore has the potential to be used as a general marker in the preclinical and clinical evaluation of (novel) biological therapies as well as being useful for the detection of rare cells such as circulating tumor cells.
Appendix
Available only for authorised users
Literature
1.
Kirn DH, Thorne SH: Targeted and armed oncolytic poxviruses: a novel multi-mechanistic therapeutic class for cancer. Nat Rev Cancer. 2009, 9: 64-71. 10.1038/nrc2545.CrossRefPubMed
2.
Garcia-Aragoncillo E, Hernandez-Alcoceba R: Design of virotherapy for effective tumor treatment. Curr Opin Mol Ther. 2010, 12: 403-411.PubMed
3.
Moss B: Genetically engineered poxviruses for recombinant gene expression, vaccination, and safety. Proc Natl Acad Sci USA. 1996, 93: 11341-11348. 10.1073/pnas.93.21.11341.PubMedCentralCrossRefPubMed
4.
Zhang Q, Yu YA, Wang E, Chen N, Danner RL, Munson PJ, Marincola FM, Szalay AA: Eradication of solid human breast tumors in nude mice with an intravenously injected light-emitting oncolytic vaccinia virus. Cancer Res. 2007, 67: 10038-10046. 10.1158/0008-5472.CAN-07-0146.CrossRefPubMed
5.
Yu YA, Shabahang S, Timiryasova TM, Zhang Q, Beltz R, Gentschev I, Goebel W, Szalay AA: Visualization of tumors and metastases in live animals with bacteria and vaccinia virus encoding light-emitting proteins. Nat Biotechnol. 2004, 22: 313-320. 10.1038/nbt937.CrossRefPubMed
6.
Puhlmann M, Brown CK, Gnant M, Huang J, Libutti SK, Alexander HR, Bartlett DL: Vaccinia as a vector for tumor-directed gene therapy: biodistribution of a thymidine kinase-deleted mutant. Cancer Gene Ther. 2000, 7: 66-73. 10.1038/sj.cgt.7700075.CrossRefPubMed
7.
Gentschev I, Stritzker J, Hofmann E, Weibel S, Yu YA, Chen N, Zhang Q, Bullerdiek J, Nolte I, Szalay AA: Use of an oncolytic vaccinia virus for the treatment of canine breast cancer in nude mice: preclinical development of a therapeutic agent. Cancer Gene Ther. 2009, 16: 320-328. 10.1038/cgt.2008.87.CrossRefPubMed
8.
Heo J, Breitbach CJ, Moon A, Kim CW, Patt R, Kim MK, Lee YK, Oh SY, Woo HY, Parato K: Sequential Therapy With JX-594, A Targeted Oncolytic Poxvirus, Followed by Sorafenib in Hepatocellular Carcinoma: Preclinical and Clinical Demonstration of Combination Efficacy. Mol Ther. 2011, 19: 1170-1179. 10.1038/mt.2011.39.PubMedCentralCrossRefPubMed
9.
Liu TC, Hwang T, Park BH, Bell J, Kirn DH: The targeted oncolytic poxvirus JX-594 demonstrates antitumoral, antivascular, and anti-HBV activities in patients with hepatocellular carcinoma. Mol Ther. 2008, 16: 1637-1642. 10.1038/mt.2008.143.CrossRefPubMed
10.
Park BH, Hwang T, Liu TC, Sze DY, Kim JS, Kwon HC, Oh SY, Han SY, Yoon JH, Hong SH: Use of a targeted oncolytic poxvirus, JX-594, in patients with refractory primary or metastatic liver cancer: a phase I trial. Lancet Oncol. 2008, 9: 533-542. 10.1016/S1470-2045(08)70107-4.CrossRefPubMed
11.
Pedersen J, Karapanagiotou L, Alam S, Puglisi M, Britton L, Sassi S, Mansfield D, Yap T, De-Bono J, Harrington K: Preliminary results of a Phase 1 study of intravenous administration of GL-ONC1 Vaccinia virus in patients with advanced solid cancer with real time imaging. 2010, 6th NCRI Cancer Conference; BT Convention Center, Liverpool, UK
12.
Bennett JJ, Tjuvajev J, Johnson P, Doubrovin M, Akhurst T, Malholtra S, Hackman T, Balatoni J, Finn R, Larson SM: Positron emission tomography imaging for herpes virus infection: Implications for oncolytic viral treatments of cancer. Nat Med. 2001, 7: 859-863. 10.1038/89991.CrossRefPubMed
13.
Chen N, Zhang Q, Yu YA, Stritzker J, Brader P, Schirbel A, Samnick S, Serganova I, Blasberg R, Fong Y, Szalay AA: A novel recombinant vaccinia virus expressing the human norepinephrine transporter retains oncolytic potential and facilitates deep-tissue imaging. Mol Med. 2009, 15: 144-151.PubMedCentralCrossRefPubMed
14.
Dingli D, Peng KW, Harvey ME, Greipp PR, O'Connor MK, Cattaneo R, Morris JC, Russell SJ: Image-guided radiovirotherapy for multiple myeloma using a recombinant measles virus expressing the thyroidal sodium iodide symporter. Blood. 2004, 103: 1641-1646. 10.1182/blood-2003-07-2233.CrossRefPubMed
15.
Haddad D, Chen NG, Zhang Q, Chen CH, Yu YA, Gonzalez L, Carpenter SG, Carson J, Au J, Mittra A: Insertion of the human sodium iodide symporter to facilitate deep tissue imaging does not alter oncolytic or replication capability of a novel vaccinia virus. J Transl Med. 2011, 9: 36-10.1186/1479-5876-9-36.PubMedCentralCrossRefPubMed
16.
Fang W, Vikerpuur M, Sandholm M: A fluorometric beta-glucuronidase assay for analysis of bacterial growth in milk. Vet Microbiol. 1995, 46: 361-367. 10.1016/0378-1135(95)00044-B.CrossRefPubMed
17.
Jefferson RA, Burgess SM, Hirsh D: beta-Glucuronidase from Escherichia coli as a gene-fusion marker. Proc Natl Acad Sci USA. 1986, 83: 8447-8451. 10.1073/pnas.83.22.8447.PubMedCentralCrossRefPubMed
18.
Jefferson RA, Kavanagh TA, Bevan MW: GUS fusions: beta-glucuronidase as a sensitive and versatile gene fusion marker in higher plants. EMBO J. 1987, 6: 3901-3907.PubMedCentralPubMed
19.
Stahl P, Fishman W: Beta-D-glucuronidase. Methods in enzymatic analysis. Edited by: JB, MG. 1984, Weinheim, Germany: Verlag Chemie, 246-256.
20.
Wang SM, Chern JW, Yeh MY, Ng JC, Tung E, Roffler SR: Specific activation of glucuronide prodrugs by antibody-targeted enzyme conjugates for cancer therapy. Cancer Res. 1992, 52: 4484-4491.PubMed
21.
Cheng CM, Lu YL, Chuang KH, Hung WC, Shiea J, Su YC, Kao CH, Chen BM, Roffler S, Cheng TL: Tumor-targeting prodrug-activating bacteria for cancer therapy. Cancer Gene Ther. 2008, 15: 393-401. 10.1038/cgt.2008.10.CrossRefPubMed
22.
de Graaf M, Pinedo HM, Oosterhoff D, van der Meulen-Muileman IH, Gerritsen WR, Haisma HJ, Boven E: Pronounced antitumor efficacy by extracellular activation of a doxorubicin-glucuronide prodrug after adenoviral vector-mediated expression of a human antibody-enzyme fusion protein. Hum Gene Ther. 2004, 15: 229-238. 10.1089/104303404322886084.CrossRefPubMed
23.
Huang PT, Chen KC, Prijovich ZM, Cheng TL, Leu YL, Roffler SR: Enhancement of CPT-11 antitumor activity by adenovirus-mediated expression of beta-glucuronidase in tumors. Cancer Gene Ther. 2011, 18: 381-389. 10.1038/cgt.2011.3.CrossRefPubMed
24.
Tzou SC, Roffler S, Chuang KH, Yeh HP, Kao CH, Su YC, Cheng CM, Tseng WL, Shiea J, Harm IH: Micro-PET imaging of beta-glucuronidase activity by the hydrophobic conversion of a glucuronide probe. Radiology. 2009, 252: 754-762. 10.1148/radiol.2523082055.CrossRefPubMed
25.
Antunes IF, Haisma HJ, Elsinga PH, Dierckx RA, de Vries EF: Synthesis and evaluation of [18F]-FEAnGA as a PET Tracer for beta-glucuronidase activity. Bioconjug Chem. 2010, 21: 911-920. 10.1021/bc9004602.CrossRefPubMed
26.
Su YC, Chuang KH, Wang YM, Cheng CM, Lin SR, Wang JY, Hwang JJ, Chen BM, Chen KC, Roffler S, Cheng TL: Gene expression imaging by enzymatic catalysis of a fluorescent probe via membrane-anchored beta-glucuronidase. Gene Ther. 2007, 14: 565-574. 10.1038/sj.gt.3302896.CrossRefPubMed
27.
Sterenczak KA, Willenbrock S, Barann M, Klemke M, Soller JT, Eberle N, Nolte I, Bullerdiek J, Murua Escobar H: Cloning, characterisation, and comparative quantitative expression analyses of receptor for advanced glycation end products (RAGE) transcript forms. Gene. 2009, 434: 35-42. 10.1016/j.gene.2008.10.027.CrossRefPubMed
28.
Stritzker J, Weibel S, Hill PJ, Oelschlaeger TA, Goebel W, Szalay AA: Tumor-specific colonization, tissue distribution, and gene induction by probiotic Escherichia coli Nissle 1917 in live mice. Int J Med Microbiol. 2007, 297: 151-162. 10.1016/j.ijmm.2007.01.008.CrossRefPubMed
29.
Seubert CM, Stritzker J, Hess M, Donat U, Sturm JB, Chen N, von Hof JM, Krewer B, Tietze LF, Gentschev I, Szalay AA: Enhanced tumor therapy using vaccinia virus strain GLV-1h68 in combination with a beta-galactosidase-activatable prodrug seco-analog of duocarmycin SA. Cancer Gene Ther. 2011, 18: 42-52. 10.1038/cgt.2010.49.PubMedCentralCrossRefPubMed
30.
Chen KC, Wu CH, Chang CY, Lu WC, Tseng Q, Prijovich ZM, Schechinger W, Liaw YC, Leu YL, Roffler SR: Directed evolution of a lysosomal enzyme with enhanced activity at neutral pH by mammalian cell-surface display. Chem Biol. 2008, 15: 1277-1286. 10.1016/j.chembiol.2008.10.008.CrossRefPubMed
31.
Sharma SK, Bagshawe KD, Melton RG, Sherwood RF: Human immune response to monoclonal antibody-enzyme conjugates in ADEPT pilot clinical trial. Cell Biophys. 1992, 21: 109-120.CrossRefPubMed
32.
Chen KC, Wu SY, Leu YL, Prijovich ZM, Chen BM, Wang HE, Cheng TL, Roffler SR: A humanized immunoenzyme with enhanced activity for glucuronide prodrug activation in the tumor microenvironment. Bioconjug Chem. 2011, 22: 938-948. 10.1021/bc1005784.CrossRefPubMed
33.
Heine D, Muller R, Brusselbach S: Cell surface display of a lysosomal enzyme for extracellular gene-directed enzyme prodrug therapy. Gene Ther. 2001, 8: 1005-1010. 10.1038/sj.gt.3301474.CrossRefPubMed
34.
Weyel D, Sedlacek HH, Muller R, Brusselbach S: Secreted human beta-glucuronidase: a novel tool for gene-directed enzyme prodrug therapy. Gene Ther. 2000, 7: 224-231. 10.1038/sj.gt.3301072.CrossRefPubMed
Metadata
Title
Bacterial glucuronidase as general marker for oncolytic virotherapy or other biological therapies
Authors
Michael Hess
Jochen Stritzker
Barbara Härtl
Julia B Sturm
Ivaylo Gentschev
Aladar A Szalay
Publication date
01-12-2011
Publisher
BioMed Central
Published in
Journal of Translational Medicine / Issue 1/2011
Electronic ISSN: 1479-5876
DOI
https://doi.org/10.1186/1479-5876-9-172

Other articles of this Issue 1/2011

Journal of Translational Medicine 1/2011 Go to the issue

Research

15 kDa Granulysin versus GM-CSF for monocytes differentiation: analogies and differences at the transcriptome level

Editorial

Create a translational medicine knowledge repository - Research downsizing, mergers and increased outsourcing have reduced the depth of in-house translational medicine expertise and institutional memory at many pharmaceutical and biotech companies: how will they avoid relearning old lessons?

Research

Cancer/Testis antigens as potential predictors of biochemical recurrence of prostate cancer following radical prostatectomy

Research

Human umbilical cord blood-derived mononuclear cell transplantation: case series of 30 subjects with Hereditary Ataxia

Review

An immunologic portrait of cancer

Research

Interferon signaling patterns in peripheral blood lymphocytes may predict clinical outcome after high-dose interferon therapy in melanoma patients

ACC 2024 Congress Coverage

Cardiology Video

Highlights from the ACC 2024 Congress

Watch now

Watch official videos from the ACC congress summarizing key highlights from the last year in heart failure, cardiomyopathies, valvular disease, pulmonary vascular disease, and pediatric cardiology.

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits