| Polyamine depletion and cell cycle manipulation in combination with HSV thymidine kinase/ganciclovir cancer gene therapy. | |
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MedLine Citation:
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PMID: 16685452 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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We have shown earlier that polyamine biosynthesis inhibition is accompanied by cell cycle alterations that can be utilized to enhance the efficacy of herpes simplex virus thymidine kinase - ganciclovir (HSV-TK/GCV) cancer gene therapy. In the present study, we asked 1) can the activated polyamine catabolism instead of biosynthesis inhibition be utilized to enhance the efficacy of HSV-TK/GCV gene therapy, and 2) can other known cell cycle inhibitors be used to make tumor cells more sensitive to this form of gene therapy? We show, using rat (9L) and human (U251-MG) glioma cell populations with 15% of HSV-TK-positive cells that DENSPM-induced activation of polyamine catabolism caused a profound polyamine deprivation in U251-MG cells, but there were no associated cell cycle effects in these cells. Consequently, we did not see any enhancement of the HSV-TK/GCV system. Aphidicolin, hydroxyurea, mimosine and resveratrol, but not lovastatin induced an apparent cell cycle arrest, followed by an intense but transient increase of the S phase cells after removal of the drug. This effect was shown to potentiate the HSV-TK/GCV cytotoxicity to some extent, especially in 9L cells and when the GCV treatment was started 0-24 h before the drug treatment. However, the enhancement was weaker than observed earlier with DFMO-induced cell cycle arrest and a considerable degree of the effect appeared to result from the growth-inhibitory actions of the drugs. In summary, we demonstrate that polyamine deprivation via DENSPM action is not associated with cell cycle effects and is not sufficient to cause enhancement of the HSV-TK/GCV system. Also, drugs with a rapid effect to the cell cycle are weak boosters of the HSVTK/GCV gene therapy, thus being less useful than DFMO for enhancement of this gene therapy form in animal studies and clinical trials. |
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Authors:
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Tiina Wahlfors; Anne Karppinen; Juhani Jänne; Leena Alhonen; Jarmo Wahlfors |
Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: International journal of oncology Volume: 28 ISSN: 1019-6439 ISO Abbreviation: Int. J. Oncol. Publication Date: 2006 Jun |
Date Detail:
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Created Date: 2006-05-10 Completed Date: 2006-08-16 Revised Date: 2006-11-15 |
Medline Journal Info:
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Nlm Unique ID: 9306042 Medline TA: Int J Oncol Country: Greece |
Other Details:
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Languages: eng Pagination: 1515-22 Citation Subset: IM |
Affiliation:
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A.I. Virtanen Institute for Molecular Sciences, Department of Biotechnology and Molecular Medicine, University of Kuopio, FI-70211 Kuopio, Finland. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Antineoplastic Agents / therapeutic use Cell Cycle / drug effects* Cell Line, Tumor Combined Modality Therapy Ganciclovir / therapeutic use* Gene Therapy* Glioma / drug therapy, pathology* Humans Polyamines / metabolism* Rats Simplexvirus / enzymology* Thymidine Kinase / genetics* |
| Chemical | |
Reg. No./Substance:
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0/Antineoplastic Agents; 0/Polyamines; 82410-32-0/Ganciclovir; EC 2.7.1.21/Thymidine Kinase |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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