Friday, October 19, 2007

Protease pretreatment increases the efficacy of adenovirus-mediated gene

MED 01-06 21174940 NDN- 222-0229-6489-7

Kuriyama, N.; Kuriyama, H.; Julin, C. M.; Lamborn, K. R.; Israel, M. A.

JOURNAL NAME- Cancer Res
VOL. 61
2001 Mar 1
PP. 1805-9
DOCUMENT TYPE- Journal Article
JOURNAL CODE- CNF; 2984705R
JOURNAL SUBSET- MEDJSIM
ISSN- 0008-5472
CORPORATE AUTHOR- Brain Tumor Research Center, Department of Neurological
Surgery, University of California, San Francisco 94143-0520, USA.
PUBLICATION COUNTRY- United States
LANGUAGE- English

Effective virus-mediated gene therapy for cancer will be facilitated by
procedures that enhance the low level of gene transfer mediated by
replication-deficient, recombinant viral vectors. We found recently that
protease pretreatment of solid tumors is a useful strategy for enhancing
virus-mediated gene transduction in vivo. In this study, we examined the
potential of protease pretreatment to improve the efficacy of a gene therapy
strategy for prodrug activation that depends on infection with a recombinant
adenovirus encoding herpes simplex virus thymidine kinase (Ad-HSV-tk).
Trypsin or a dissolved mixture of collagenase/dispase was inoculated into
xenografts derived from the human glioblastoma multiforme-derived cell
lines, U87 or U251. Ad-HSV-tk was administered 24 h after protease
pretreatment, and animals were then treated for 10 days with ganciclovir
(GCV). We found that protease pretreatment increased the efficacy of
adenovirus mediated HSV-tk/GCV gene therapy in these experimental tumor
models. Mice receiving Ad-HSV-tk/GCV after protease pretreatment
demonstrated a significantly greater regression of tumors compared with
those treated with Ad-HSV-tk/GCV alone. No adverse effects of protease
pretreatment were observed. No signs of metastasis were seen either by
histological inspection of lymph nodes or by a PCR-based analysis of
selected mouse tissues to detect human tumor cells. Our findings indicate
that protease pretreatment may be a useful strategy to enhance the efficacy
of virus-mediated cancer gene therapy.

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