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), necessary for conversion to 5-fluorouracil (5-FU) in rumours transduced with the gene cytosine deaminase (CD), to achieve clinically significant radiosensitization 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 increase 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 maintained 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 concentrations of 25-100 mu g/ml (average 60 mu g/ml) for 6 weeks in standard antifungal treatment. Sufficient 5-FU should be available if conversion efficiency 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 they do not contradict the conclusions.

Conclusions: Increases in tumour control of 20 to 40% can be expected, which should be detectable in a 2-arm randomized trial of 260 (for 20%) or 60 (for 40%) patients.