ABSTRACT
Gene therapy of cancer represents a promising but challenging area of therapeutic research. The discovery of radiation-inducible genes led to the concept and development of radiation-targeted gene therapy. In this approach, promoters of radiation-inducible genes are used to drive transcription of transgenes in the response to radiation. Constructs in which the radiation-inducible promoter elements activate a transgene encoding a cytotoxic protein are delivered to tumors by adenoviral vectors. The tumoricidal effects are then localized temporally and spatially by X-rays. We review the conceptual development of TNFerade, an adenoviral vector containing radiation-inducible elements of the early growth response-1 promoter upstream of a cDNA encoding human tumor necrosis factor-alpha. We also summarize the preclinical work and clinical trials utilizing this vector as a treatment for diverse solid tumors.
Subject(s)
Gene Expression Regulation, Neoplastic/radiation effects , Genetic Therapy/methods , Neoplasms/therapy , Adenoviridae/genetics , Adenoviridae/metabolism , Clinical Trials as Topic , Early Growth Response Protein 1/genetics , Early Growth Response Protein 1/metabolism , Genetic Vectors/genetics , Genetic Vectors/radiation effects , Humans , Models, Biological , Promoter Regions, Genetic , Radiation, Ionizing , Recombinant Fusion Proteins/genetics , Recombinant Fusion Proteins/metabolism , Time Factors , Tumor Necrosis Factor-alpha/radiation effects , Tumor Necrosis Factor-alpha/therapeutic useABSTRACT
We examined the impact of neuropsychological (NP) impairment on activities of daily living (ADLs) and quality of life in human immunodeficiency virus type-1 (HIV-1)-infected persons of low socioeconomic status (SES). Thirty-nine patients were stratified into one of three groups: cognitively normal (n = 13), mild cognitive impairment (n = 15), and moderate/severe impairment (n = 11). Quality of life was assessed with the Sickness Impact Profile and ADLs were evaluated via structured interview performed in the patient's residence. While there were no significant differences across groups on disease stage, drug use, depression, or estimated premorbid IQ, cognitively impaired patients were more likely to be unemployed and fail social planning and medication management tasks. Our study confirms a previously reported association between NP impairment and unemployment among HIV-1-infected patients. The data also extend this relationship to a low-SES sample with a high base rate of unemployment, and to instrumental activities of daily living other than work.