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Tumor growth inhibition by interferon-alpha using PEGylated protein or adenovirus gene transfer with constitutive or regulated expression.
- Source :
-
Molecular therapy : the journal of the American Society of Gene Therapy [Mol Ther] 2002 Jul; Vol. 6 (1), pp. 50-6. - Publication Year :
- 2002
-
Abstract
- Inducible synthesis and secretion of therapeutic proteins following gene transfer could be a viable strategy to deliver biopharmaceuticals that currently require parenteral administration. Evaluating the protein pharmacokinetics and biological responses generated by different delivery modalities will provide a better understanding of the advantages and disadvantages of each strategy. The interferon-alpha (IFN-alpha) family of proteins, used clinically for infectious and malignant diseases, has a short half-life, and IFN-alpha therapy requires frequent administration of the drug by injection. Subcutaneous xenograft tumors were inhibited by weekly administration of polyethylene glycol modified (PEGylated) IFN-alpha protein or by a single administration of an adenovirus constitutively expressing IFN-alpha (IACB). Both treatment modalities inhibited tumor growth in a dose-dependent manner, suggesting that increasing exposure to IFN-alpha could result in effective tumor control. A single adenovirus that encodes the components necessary for tetracycline induction (IADR) expressed IFN-alpha in a ligand-dependent manner. Adding doxycycline to the drinking water of mice treated intravenously with the inducible adenovirus IADR inhibited tumor growth by 85% compared with mice that were not given doxycycline. The correlation between serum IFN-alpha concentration and the degree of tumor growth inhibition did not depend on the delivery technology used. It is likely that it will be feasible to control expression of IFN-alpha by oral administration of small molecule drugs after gene delivery to induce therapeutic concentrations of proteins.
- Subjects :
- Animals
Doxycycline metabolism
Genetic Vectors administration & dosage
Genetic Vectors metabolism
Interferon-alpha administration & dosage
Interferon-alpha blood
Interferon-alpha genetics
Interferon-alpha pharmacology
Mice
Neoplasms, Experimental therapy
Adenoviridae metabolism
Gene Expression Regulation, Viral physiology
Interferon-alpha metabolism
Polyethylene Glycols metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1525-0016
- Volume :
- 6
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Molecular therapy : the journal of the American Society of Gene Therapy
- Publication Type :
- Academic Journal
- Accession number :
- 12095303
- Full Text :
- https://doi.org/10.1006/mthe.2002.0629