title: Tumor growth inhibition by interferon-alpha using PEGylated protein or adenovirus gene transfer with constitutive or regulated expression.
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.
authors.affiliation: Canji, Inc., San Diego, California 92121, USA. bill.demers@canji.com
authors.forename: G William
authors.initials: GW
authors.lastname: Demers
authors.forename: Duane E
authors.initials: DE
authors.lastname: Johnson
authors.forename: Todd
authors.initials: T
authors.lastname: Machemer
authors.forename: L David
authors.initials: LD
authors.lastname: Looper
authors.forename: Amy
authors.initials: A
authors.lastname: Batinica
authors.forename: Josefina C
authors.initials: JC
authors.lastname: Beltran
authors.forename: Barry J
authors.initials: BJ
authors.lastname: Sugarman
authors.forename: John A
authors.initials: JA
authors.lastname: Howe
mesh_terms: D000256:Adenoviridae / Q000378:metabolism*; D000818:Animals; D004318:Doxycycline / Q000378:metabolism; D015967:Gene Expression Regulation, Viral / Q000502:physiology*; D005822:Genetic Vectors / Q000008:administration & dosage / Q000378:metabolism; D016898:Interferon-alpha / Q000008:administration & dosage / Q000097:blood / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D009374:Neoplasms, Experimental / Q000628:therapy; D011092:Polyethylene Glycols / Q000378:metabolism*
chemical_list: D016898:Interferon-alpha; D011092:Polyethylene Glycols; D004318:Doxycycline