Abstract |
Lack of effective therapy of primary brain tumors has promoted the development of novel experimental approaches utilizing oncolytic viruses combined with gene therapy. Towards this end, we have assessed a conditionally replication-competent, gamma(1)34.5-deleted herpes simplex virus type 1 (HSV-1) expressing cytosine deaminase (CD) for treatment of malignant brain tumors. Our results are summarized as follows: (i) a recombinant HSV (M012) was constructed in which both copies of the gamma(1)34.5 gene were replaced with the bacterial CD gene, under the control of the cellular promoter Egr-1; (ii) M012-infected cells in vitro efficiently convert 5-fluorocytosine (5-FC) to 5-fluorouracil, thereby enhancing cytotoxicity of neighboring, uninfected cells; (iii) both direct and bystander cytotoxicity of murine neuroblastoma and human glioma cell lines after infection with M012 were demonstrated; (iv) direct intracerebral inoculation of A/J mice demonstrated lack of neurotoxicity at doses similar to G207, a gamma(1)34.5-deleted HSV with demonstrated safety in human patient trials and (v) intratumoral injection of M012 into Neuro-2a flank tumors in combination with 5-FC administration significantly reduced tumor growth versus tumors treated with R3659 combined with 5-FC, or treated with M012 alone. Thus, M012 is a promising new oncolytic HSV vector with an enhanced prodrug-mediated, antineoplastic effect that is safe for intracranial administration.
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Authors | M B Guffey, J N Parker, W S Luckett Jr, G Y Gillespie, S Meleth, R J Whitley, J M Markert |
Journal | Cancer gene therapy
(Cancer Gene Ther)
Vol. 14
Issue 1
Pg. 45-56
(Jan 2007)
ISSN: 0929-1903 [Print] England |
PMID | 16990846
(Publication Type: Journal Article, Research Support, N.I.H., Extramural)
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Chemical References |
- Cytosine Deaminase
- Fluorouracil
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Topics |
- Animals
- Bacteria
(enzymology)
- Brain Neoplasms
(drug therapy, therapy)
- Chlorocebus aethiops
- Cytosine Deaminase
(genetics)
- Female
- Fluorouracil
(therapeutic use)
- Genetic Engineering
- Humans
- Mice
- Simplexvirus
(genetics)
- Vero Cells
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