title: Combined radiation and enzyme/prodrug treatment for head and neck cancer in an orthotopic animal model.
abstract: In an effort to improve the therapeutic outcome for squamous cell cancer of the head and neck, we have used the enzyme cytosine deaminase (CD) and the prodrug 5-fluorocytosine (5-FC) as a means to deliver the chemotherapeutic agent 5-fluorouracil (5-FU) in a tumor-specific manner and have evaluated the use of this treatment in combination with external-beam radiation. Infection of SCCVII cells in culture with a CD-expressing retrovirus and treatment with 5-FC was cytotoxic depending on the time of treatment and dose of 5-FC. An orthotopic model of squamous cell cancer of the head and neck was used in vivo to study the CD/5-FC system both alone and with concurrent radiation due to the radiosensitizing properties that 5-FU generates in situ. Treated mice were imaged using magnetic resonance imaging (MRI), and their survival was evaluated. Neither 5-FU nor radiation either alone or combined provided a survival advantage. In contrast, 5-FC treatment prolonged survival and decreased tumor burden compared to control animals, but the tumors recurred after the treatment ceased. Finally, combined treatment with concurrent administration of 5-FC and radiation resulted in a synergistic decrease in tumor growth and enhanced survival over treatment with 5-FC or radiation alone.
authors.affiliation: The Departments of Pharmacology and Radiation Oncology, The University of Michigan Medical Center, Ann Arbor, Michigan 48105, USA.
authors.forename: D A
authors.initials: DA
authors.lastname: Hamstra
authors.forename: D J
authors.initials: DJ
authors.lastname: Rice
authors.forename: A
authors.initials: A
authors.lastname: Pu
authors.forename: D
authors.initials: D
authors.lastname: Oyedijo
authors.forename: B D
authors.initials: BD
authors.lastname: Ross
authors.forename: A
authors.initials: A
authors.lastname: Rehemtulla
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000532:radiotherapy / Q000628:therapy*; D002455:Cell Division; D003131:Combined Modality Therapy; D043525:Cytosine Deaminase; D004195:Disease Models, Animal; D005437:Flucytosine / Q000627:therapeutic use*; D006258:Head and Neck Neoplasms / Q000188:drug therapy / Q000532:radiotherapy / Q000628:therapy*; D051379:Mice; D009700:Nucleoside Deaminases / Q000627:therapeutic use*; D011355:Prodrugs / Q000627:therapeutic use*; D012190:Retroviridae / Q000235:genetics; D014161:Transduction, Genetic; D014407:Tumor Cells, Cultured
chemical_list: D000964:Antimetabolites, Antineoplastic; D011355:Prodrugs; D005437:Flucytosine; D009700:Nucleoside Deaminases; D043525:Cytosine Deaminase