Abstract
Background. Many gene therapy strategies would benefit from efficient, regional organ delivery
of therapeutic genes. Methods. Regional perfusions of lung, liver, or bladder were performed to determine if rapid
and efficient gene transfer can be accomplished in vivo, and to determine if in vivo
gene transfer can be limited to the organ of interest. In addition, herpes simplex
virus tumor necrosis factor (HSVtnf), carrying the human tumor necrosis factorα gene
was used as a treatment for methylcholanthrene sarcoma in a syngeneic lung metastases
model in Fisher rats. Results. A 20-minute perfusion using HSV carrying β-galactosidase (HSVlac) produced significant
expression of this marker gene isolated to the target organs, without organ-specific
tissue injury or inflammation. Regional perfusion of organs with HSV carrying the
cytokine gene tumor necrosis factor α also resulted in high-level local organ production
of this cytokine (2851 ± 53 pg/g tissue in perfused lung versus 0 for the contralateral
lung). For the current vector construct, expression of the gene of interest peaked
between 2 and 4 days and was undetectable by 2 weeks after perfusion. In animals undergoing
perfusion as treatment for pulmonary sarcoma, there was no difference between tumor
counts in lungs perfused with HSVlac (17 ± 6) or HSVtnf (22 ± 8), but either treatment
resulted in lower tumor counts than controls (111 ± 24 nodules per lung, P <.02). Conclusions. Regional organ perfusion using herpes viral vectors is an effective and well-tolerated
in vivo method of transiently delivering potentially toxic gene products to target
organs in directing gene therapy. Regional lung perfusion with HSV amplicons reduces
tumor burden in a rat model of pulmonary metastases, though HSVtnf cannot be demonstrated
to augment the cytopathic effect of the HSV amplicon alone in the current model. (Surgery
2001;129:324-34.)
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Article info
Publication history
Accepted:
September 3,
2000
Footnotes
☆Supported in part by grants F32CA68802 (A. D. B.), RO1CA76416 (Y. F.), RO1CA72632 (Y. F.), and RO1CA61524 (Y. F.) from the National Institutes of Health and MBC-99366 (Y. F.) From the American Cancer Society.
☆☆Reprint requests: Yuman Fong, MD, Department of Surgery, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021.
★Surgery 2001;129:324-34.
Identification
Copyright
© 2001 Mosby, Inc. Published by Elsevier Inc. All rights reserved.
