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Plant thymidine kinase 1: a novel efficient suicide gene for malignant glioma therapy.

Khan, Zahidul; Knecht, Wolfgang; Willer, Mette; Rozpedowska, Elzbieta LU ; Kristoffersen, Peter; Clausen, Anders Ranegaard LU ; Munch-Petersen, Birgitte; Almqvist, Per M; Gojkovic, Zoran and Piskur, Jure LU , et al. (2010) In Neuro-Oncology 12. p.549-558
Abstract
The prognosis for malignant gliomas remains poor, and new treatments are urgently needed. Targeted suicide gene therapy exploits the enzymatic conversion of a prodrug, such as a nucleoside analog, into a cytotoxic compound. Although this therapeutic strategy has been considered a promising regimen for central nervous system (CNS) tumors, several obstacles have been encountered such as inefficient gene transfer to the tumor cells, limited prodrug penetration into the CNS, and inefficient enzymatic activity of the suicide gene. We report here the cloning and successful application of a novel thymidine kinase 1 (TK1) from the tomato plant, with favorable characteristics in vitro and in vivo. This enzyme (toTK1) is highly specific for the... (More)
The prognosis for malignant gliomas remains poor, and new treatments are urgently needed. Targeted suicide gene therapy exploits the enzymatic conversion of a prodrug, such as a nucleoside analog, into a cytotoxic compound. Although this therapeutic strategy has been considered a promising regimen for central nervous system (CNS) tumors, several obstacles have been encountered such as inefficient gene transfer to the tumor cells, limited prodrug penetration into the CNS, and inefficient enzymatic activity of the suicide gene. We report here the cloning and successful application of a novel thymidine kinase 1 (TK1) from the tomato plant, with favorable characteristics in vitro and in vivo. This enzyme (toTK1) is highly specific for the nucleoside analog prodrug zidovudine (azidothymidine, AZT), which is known to penetrate the blood-brain barrier. An important feature of toTK1 is that it efficiently phosphorylates its substrate AZT not only to AZT monophosphate, but also to AZT diphosphate, with excellent kinetics. The efficiency of the toTK1/AZT system was confirmed when toTK1-transduced human glioblastoma (GBM) cells displayed a 500-fold increased sensitivity to AZT compared with wild-type cells. In addition, when neural progenitor cells were used as delivery vectors for toTK1 in intracranial GBM xenografts in nude rats, substantial attenuation of tumor growth was achieved in animals exposed to AZT, and survival of the animals was significantly improved compared with controls. The novel toTK1/AZT suicide gene therapy system in combination with stem cell-mediated gene delivery promises new treatment of malignant gliomas. (Less)
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published
subject
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Neuro-Oncology
volume
12
pages
549 - 558
publisher
Oxford University Press
external identifiers
  • wos:000278817700005
  • scopus:77957068644
ISSN
1523-5866
DOI
10.1093/neuonc/nop067
language
English
LU publication?
yes
id
b07e449e-768d-466f-8154-db1de4dbde95 (old id 1552647)
date added to LUP
2010-03-08 13:02:38
date last changed
2018-05-29 09:56:52
@article{b07e449e-768d-466f-8154-db1de4dbde95,
  abstract     = {The prognosis for malignant gliomas remains poor, and new treatments are urgently needed. Targeted suicide gene therapy exploits the enzymatic conversion of a prodrug, such as a nucleoside analog, into a cytotoxic compound. Although this therapeutic strategy has been considered a promising regimen for central nervous system (CNS) tumors, several obstacles have been encountered such as inefficient gene transfer to the tumor cells, limited prodrug penetration into the CNS, and inefficient enzymatic activity of the suicide gene. We report here the cloning and successful application of a novel thymidine kinase 1 (TK1) from the tomato plant, with favorable characteristics in vitro and in vivo. This enzyme (toTK1) is highly specific for the nucleoside analog prodrug zidovudine (azidothymidine, AZT), which is known to penetrate the blood-brain barrier. An important feature of toTK1 is that it efficiently phosphorylates its substrate AZT not only to AZT monophosphate, but also to AZT diphosphate, with excellent kinetics. The efficiency of the toTK1/AZT system was confirmed when toTK1-transduced human glioblastoma (GBM) cells displayed a 500-fold increased sensitivity to AZT compared with wild-type cells. In addition, when neural progenitor cells were used as delivery vectors for toTK1 in intracranial GBM xenografts in nude rats, substantial attenuation of tumor growth was achieved in animals exposed to AZT, and survival of the animals was significantly improved compared with controls. The novel toTK1/AZT suicide gene therapy system in combination with stem cell-mediated gene delivery promises new treatment of malignant gliomas.},
  author       = {Khan, Zahidul and Knecht, Wolfgang and Willer, Mette and Rozpedowska, Elzbieta and Kristoffersen, Peter and Clausen, Anders Ranegaard and Munch-Petersen, Birgitte and Almqvist, Per M and Gojkovic, Zoran and Piskur, Jure and Ekström, Tomas J},
  issn         = {1523-5866},
  language     = {eng},
  pages        = {549--558},
  publisher    = {Oxford University Press},
  series       = {Neuro-Oncology},
  title        = {Plant thymidine kinase 1: a novel efficient suicide gene for malignant glioma therapy.},
  url          = {http://dx.doi.org/10.1093/neuonc/nop067},
  volume       = {12},
  year         = {2010},
}