A new pyrimidine-specific reporter gene: A mutated human deoxycytidine kinase suitable for PET during treatment with acycloguanosine-based cytotoxic drugs Journal Article
| Authors: | Likar, Y.; Zurita, J.; Dobrenkov, K.; Shenker, L.; Cai, S.; Neschadim, A.; Medin, J. A.; Sadelain, M.; Hricak, H.; Ponomarev, V. |
| Article Title: | A new pyrimidine-specific reporter gene: A mutated human deoxycytidine kinase suitable for PET during treatment with acycloguanosine-based cytotoxic drugs |
| Abstract: | In this article, we describe a series of new human-derived reporter genes based on human deoxycytidine kinase (dCK) suitable for clinical PET. Methods: Native dCK and its mutant reporter genes were tested in vitro and in vivo for their phosphorylation of pyrimidine- and acycloguanosine-based radiotracers including 2′-deoxy-2′-fluoroarabinofuranosylcytosine, 2′-fluoro-2′-deoxyarabinofuranosyl-5-ethyluracil (FEAU), penciclovir, and 9-[4-fluoro-3-(hydroxymethyl)butyl]guanine (FHBG) and clinically applied antiviral and anticancer drugs. Results: Cells transduced with dCK mutant reporter genes showed high in vitro and in vivo uptake of pyrimidine-based radiopharmaceuticals (18F-FEAU) comparable to that of herpes simplex virus type-1 thymidine kinase (HSV1-tk)-transduced cells. These mutants did not phosphorylate acycloguanosine-based radio-tracers ( 18F-FHBG) or antiviral drugs (ganciclovir). Furthermore, the mutants displayed suicidal activation of clinically used pyrimidine-based prodrugs (cytarabine, gemcitabine). Conclusion: The mutants of human dCK can be used as pyrimidine-specific PET reporter genes for imaging with 18F-FEAU during treatment with acycloguanosine-based antiviral drugs. Additionally, the prosuicidal activity of these reporters with pyrimidine-based analogs will allow for the safe elimination of transduced cells. Copyright © 2010 by the Society of Nuclear Medicine, Inc. |
| Keywords: | controlled study; unclassified drug; human cell; genetics; mutation; cytotoxic agent; nonhuman; antineoplastic agents; gemcitabine; cytarabine; positron emission tomography; antineoplastic agent; animal cell; mouse; animal; metabolism; animals; mice; animal tissue; computer assisted tomography; animal experiment; animal model; tomography, x-ray computed; aciclovir; in vivo study; in vitro study; enzyme activity; molecular imaging; cell line, tumor; phosphorylation; genetic transduction; transduction, genetic; chemistry; enzyme phosphorylation; diagnostic agent; drug accumulation; drug uptake; substrate specificity; tumor cell line; positron-emission tomography; radiopharmaceutical agent; 2' fluoro 5 ethylarabinosyluracil; 2'-fluoro-5-ethylarabinosyluracil; drug derivative; uracil arabinoside; arabinofuranosyluracil; reporter gene; genes, reporter; radioactive tracers; antivirus agent; tracer; enzyme specificity; pet; lymphocyte; lymphocytes; drug sensitivity; herpes simplex virus 1; ganciclovir; cell strain 3t3; nih 3t3 cells; mutant; feau; fhbg; 9 [4 fluoro 3 (hydroxymethyl)butyl]guanine f 18; pyrimidine; acyclovir; prodrug; 5 ethyl 2' fluorouracil arabinoside; 5 ethyl 2' fluorouracil arabinoside f 18; tritium; prodrugs; fluorine radioisotopes; suicide gene; dck; carbon 14; deoxycytidine kinase; penciclovir; fluorine |
| Journal Title: | Journal of Nuclear Medicine |
| Volume: | 51 |
| Issue: | 9 |
| ISSN: | 0161-5505 |
| Publisher: | Society of Nuclear Medicine |
| Date Published: | 2010-09-01 |
| Start Page: | 1395 |
| End Page: | 1403 |
| Language: | English |
| DOI: | 10.2967/jnumed.109.074344 |
| PUBMED: | 20810757 |
| PROVIDER: | scopus |
| PMCID: | PMC4405132 |
| DOI/URL: | |
| Notes: | --- - "Export Date: 20 April 2011" - "CODEN: JNMEA" - "Source: Scopus" |
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