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HSV-TK/GCV gene therapy approaches for treating brain tumors is limited by the efficacy of gene transfer


Al Musella's Comments: (This is his personal views and are not necessarily the views of the Musella Foundation!)



Website: http://www.asco.org/ac/1,1003,_12-002489-00_18-002003-00_19-00103098-00_29-00A,00.asp?cat=CNS+Tumors&parent=Central+Nervous+System+Tumors&returnpid=2325&SubCat_ID=4

Posted on: 06/14/2003

39th ASCO Annual Meeting • Chicago, IL • May 31-June 3, 2003 (Abstract No. 406)

HSV-TK/GCV gene therapy approaches for treating brain tumors is limited by the efficacy of gene transfer

P. Hadaczek, H. Mirek, M. S. Berger, K. Bankiewicz

University of California San Francisco, San Francisco, CA

These studies evaluated the efficacy of using a suicide gene therapy approach for treating brain tumors. In vitro (using a U87MG cell line) and in vivo (using a xenograft, tumor-bearing rodent model) studies addressed the stability of the thymidine kinase (TK) gene expression over time.

A survival study was also performed to evaluate TK gene expression following convection-enhanced delivery (CED) in inducing robust eradication of U87MG cell-derived brain tumors with consequent ganciclovir (GCV) treatment. Expression of TK in vitro with AAV2-TK decreased rapidly over time. Approximately 24 hours following infection, in vitro observations showed that 100% of the cells were positive for TK, however at 15 and 30 days, TK expression was reduced to approximately 5% and 1%, respectively. Similarly, in vivo experiments in rats implanted with intracranial tumors containing TK transduced U87MG cells confirmed a loss of TK expression within the tumor over time.

This phenomenon was most likely due to a lack of vector genomic integration and the expulsion of episomal forms of the transgene during the rapid division of tumor cells.

Co-infusion of heparin during CED produced a robust transduction of TK gene in U87MG IC tumors and resulted in some therapeutic effects (25.5 vs. 21.4 days, P<0.05) following GCV treatment.

These results strongly indicate that a complete TK gene transfer in the U87MG tumor is required for a suicide gene approach to work.

These results also eliminate the possibility of completely eradicating the growth of tumors using a HSV-TK/GCV system since unaffected tumor masses eventually overgrow normal tissues.

Thus, the usefulness of viral-based vectors for gene therapy in brain tumors remains questionable since unstable and transitional expression of the episomal forms of TK in rapidly dividing tumor cells seems to be a limiting factor for such application.

© Copyright 2003 American Society of Clinical Oncology All rights reserved worldwide

Source: http://www.asco.org/ac/1,1003,_12-002489-00_18-002003-00_19-00103098-00_29-00A,00.asp?cat=CNS+Tumors&parent= Central+Nervous+System+Tumors&returnpid=2325&SubCat_ID=4



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