The potential therapeutic gain of radiation-associated gene therapy with the suicide gene cytosine deaminase

Purpose: To estimate the concentration of 5-fluorocylosine (5-FC), necessar y for conversion to 5-fluorouracil (5-FU) in rumours transduced with the ge ne cytosine deaminase (CD), to achieve clinically significant radiosensitiz ation to radiotherapy. Materials and methods: Starting with a tumour control probability (TCP) of 37% from radiotherapy of 66 Gy in 2 Gy fractions, estimates were made of in crease in TCP expected from sensitizer enhancement ratios (SER) of 1.1, 1.2 , etc. SER values for 5-FU were obtained from a literature review. Clinical toxicity of 5-FC is also reviewed. Results: 5-FU has been reported to be an effective radiosensitizer if maint ained for several days after each irradiation at concentrations of 0.6-0.9 mu g/ml in surrounding medium. 5-FC is well tolerated by patients at concen trations of 25-100 mu g/ml (average 60 mu g/ml) for 6 weeks in standard ant ifungal treatment. Sufficient 5-FU should be available if conversion effici ency from 5-FC is 1-3%. SER values of 1.1 to 1.2 should be achievable with daily 2 Gy fractions. In vitro and xenograft experiments are reviewed and t hey do not contradict the conclusions. Conclusions: Increases in tumour control of 20 to 40% can be expected, whic h should be detectable in a 2-arm randomized trial of 260 (for 20%) or 60 ( for 40%) patients.