Combined radiation and enzyme/prodrug treatment for head and neck cancer in an orthotopic animal model.
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.
Hamstra
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DA
The Departments of Pharmacology and Radiation Oncology, The University of Michigan Medical Center, Ann Arbor, Michigan 48105, USA.
Rice
D J
DJ
Pu
A
A
Oyedijo
D
D
Ross
B D
BD
Rehemtulla
A
A
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
D000964:Antimetabolites, Antineoplastic; D011355:Prodrugs; D005437:Flucytosine; D009700:Nucleoside Deaminases; D043525:Cytosine Deaminase