Cancer Research Annual Meeting 2010 Jordan
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Meeting Abstracts Online
This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Black, M. E.
Right arrow Articles by Sabo, P.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Black, M. E.
Right arrow Articles by Sabo, P.
[Cancer Research 61, 3022-3026, April 1, 2001]
© 2001 American Association for Cancer Research

Experimental Therapeutics

Herpes Simplex Virus-1 Thymidine Kinase Mutants Created by Semi-Random Sequence Mutagenesis Improve Prodrug-mediated Tumor Cell Killing1

Margaret E. Black2, Mark S. Kokoris and Peter Sabo

Department of Pharmaceutical Sciences, Washington State University, Pullman, Washington 99164-6534 [M. E. B.], and Chiroscience R&D, Inc., Bothell, Washington 98021 [M. E. B., M. S. K., P. S.]

ABSTRACT

Cancer suicide gene therapy affords the prospect of using the most optimal genes available because the source of the therapeutic gene is often irrelevant. Currently, there are numerous preclinical and clinical trials to develop tumor ablative therapies that use viral, yeast, or bacterial genes. One such gene, the herpes simplex virus type 1 (HSV-1) thymidine kinase (TK) is widely used as a suicide gene in combination with ganciclovir. In the study reported here, a restricted set of random sequences (semi-random) was introduced into the active site of HSV-1 TK, and the resulting variants were selected on the basis of their ability to confer increased ganciclovir or acyclovir sensitivity to Escherichia coli. Sequence analysis demonstrated that functional mutants contained three to five amino acid substitutions that are unique and novel combinations. On the basis of enzyme assay results, three mutants were identified for further analysis in vitro. These three mutants conferred substantial increased sensitivity to both ganciclovir and acyclovir when compared with IC50s of wild-type TK expressing rat C6 glioma cells. One mutant, SR39, was further evaluated in a xenograft tumor model in nude mice. Expression of SR39 in tumors was shown to prevent tumor growth at prodrug dosages that did not affect wild-type HSV-1 TK-expressing tumors. The use of any of these mutants as a suicide gene should provide a more effective and safer alternative to wild-type TK, because lower, less immunosuppressive doses of ganciclovir will be necessary for tumor ablation, and the use of acyclovir may now be possible.




This article has been cited by other articles:


Home page
 Molecular Cancer TherapeuticsHome page
M. Trepel, C. A. Stoneham, H. Eleftherohorinou, N. D. Mazarakis, R. Pasqualini, W. Arap, and A. Hajitou
A heterotypic bystander effect for tumor cell killing after adeno-associated virus/phage-mediated, vascular-targeted suicide gene transfer
Mol. Cancer Ther., August 1, 2009; 8(8): 2383 - 2391.
[Abstract] [Full Text] [PDF]

Home page
 JNMHome page
M. Johnson, B. D.W. Karanikolas, S. J. Priceman, R. Powell, M. E. Black, H.-M. Wu, J. Czernin, S.-C. Huang, and L. Wu
Titration of Variant HSV1-tk Gene Expression to Determine the Sensitivity of 18F-FHBG PET Imaging in a Prostate Tumor
J. Nucl. Med., May 1, 2009; 50(5): 757 - 764.
[Abstract] [Full Text] [PDF]

Home page
 JNMHome page
Y. Likar, K. Dobrenkov, M. Olszewska, E. Vider, L. Shenker, S. Cai, N. Pillarsetty, H. Hricak, and V. Ponomarev
A New Acycloguanosine-Specific Supermutant of Herpes Simplex Virus Type 1 Thymidine Kinase Suitable for PET Imaging and Suicide Gene Therapy for Potential Use in Patients Treated with Pyrimidine-Based Cytotoxic Drugs
J. Nucl. Med., May 1, 2008; 49(5): 713 - 720.
[Abstract] [Full Text] [PDF]

Home page
 J Antimicrob ChemotherHome page
C. Shi, A. R. Parker, L. Hua, C. N. Morrell, S. C. Lee, V. Bandaru, J. S. Dumler, T. C. Wu, and J. R. Eshleman
Anti-gene padlocks eliminate Escherichia coli based on their genotype
J. Antimicrob. Chemother., February 1, 2008; 61(2): 262 - 272.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
J. Balzarini, S. Liekens, N. Solaroli, K. El Omari, D. K. Stammers, and A. Karlsson
Engineering of a Single Conserved Amino Acid Residue of Herpes Simplex Virus Type 1 Thymidine Kinase Allows a Predominant Shift from Pyrimidine to Purine Nucleoside Phosphorylation
J. Biol. Chem., July 14, 2006; 281(28): 19273 - 19279.
[Abstract] [Full Text] [PDF]

Home page
 JNMHome page
W. E. Sander, M. E. Metzger, K. Morizono, A. Bonifacino, S. R. Penzak, Y.-M. Xie, I. S.Y. Chen, J. Bacon, S. G. Sestrich, L. P. Szajek, et al.
Noninvasive Molecular Imaging to Detect Transgene Expression of Lentiviral Vector in Nonhuman Primates
J. Nucl. Med., July 1, 2006; 47(7): 1212 - 1219.
[Abstract] [Full Text] [PDF]

Home page
 JNMHome page
S. S. Yaghoubi, M. A. Couto, C.-C. Chen, L. Polavaram, G. Cui, L. Sen, and S. S. Gambhir
Preclinical Safety Evaluation of 18F-FHBG: A PET Reporter Probe for Imaging Herpes Simplex Virus Type 1 Thymidine Kinase (HSV1-tk) or Mutant HSV1-sr39tk's Expression
J. Nucl. Med., April 1, 2006; 47(4): 706 - 715.
[Abstract] [Full Text] [PDF]

Home page
 Nucleic Acids ResHome page
J. A. M. Braks, B. Franke-Fayard, H. Kroeze, C. J. Janse, and A. P. Waters
Development and application of a positive-negative selectable marker system for use in reverse genetics in Plasmodium
Nucleic Acids Res., March 14, 2006; 34(5): e39 - e39.
[Abstract] [Full Text] [PDF]

Home page
 Protein Eng Des SelHome page
S. D. Mahan, G. C. Ireton, C. Knoeber, B. L. Stoddard, and M. E. Black
Random mutagenesis and selection of Escherichia coli cytosine deaminase for cancer gene therapy
Protein Eng. Des. Sel., August 1, 2004; 17(8): 625 - 633.
[Abstract] [Full Text] [PDF]

Home page
 MutagenesisHome page
R. Thust, M.T. Tomicic, R. Grabner, C. Friedrichs, P. Wutzler, and B. Kaina
Cytogenetic detection of a trans-species bystander effect: induction of sister chromatid exchanges in murine 3T3 cells by ganciclovir metabolized in HSV thymidine kinase gene-transfected Chinese hamster ovary cells
Mutagenesis, January 1, 2004; 19(1): 27 - 33.
[Abstract] [Full Text] [PDF]

Home page
 Molecular Cancer TherapeuticsHome page
K. J. P. Yoon, E. J. Krull, C. L. Morton, W. G. Bornmann, R. E. Lee, P. M. Potter, and M. K. Danks
Activation of a camptothecin prodrug by specific carboxylesterases as predicted by quantitative structure-activity relationship and molecular docking studies
Mol. Cancer Ther., November 1, 2003; 2(11): 1171 - 1181.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
J. I. Grove, A. L. Lovering, C. Guise, P. R. Race, C. J. Wrighton, S. A. White, E. I. Hyde, and P. F. Searle
Generation of Escherichia Coli Nitroreductase Mutants Conferring Improved Cell Sensitization to the Prodrug CB1954
Cancer Res., September 1, 2003; 63(17): 5532 - 5537.
[Abstract] [Full Text] [PDF]

Home page
 JNMHome page
J. G. Tjuvajev, M. Doubrovin, T. Akhurst, S. Cai, J. Balatoni, M. M. Alauddin, R. Finn, W. Bornmann, H. Thaler, P. S. Conti, et al.
Comparison of Radiolabeled Nucleoside Probes (FIAU, FHBG, and FHPG) for PET Imaging of HSV1-tk Gene Expression
J. Nucl. Med., August 1, 2002; 43(8): 1072 - 1083.
[Abstract] [Full Text] [PDF]


HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Meeting Abstracts Online
Copyright © 2001 by the American Association for Cancer Research.