The potential therapeutic gain of radiation-associated gene therapy with the suicide gene cytosine deaminase.
OBJECTIVE
To estimate the concentration of 5-fluorocytosine (5-FC), necessary for conversion to 5-fluorouracil (5-FU) in tumours transduced with the gene cytosine deaminase (CD), to achieve clinically significant radiosensitization to radiotherapy.


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 microg/ml in surrounding medium. 5-FC is well tolerated by patients at concentrations of 25-100 microg/ml (average 60 microg/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.
Lambin
P
P
University Hospital Gasthuisberg, Department of Radiation Oncology, Leuven, Belgium. Philippe.Lambin@uz.kuleuven.ac.be
Nuyts
S
S
Landuyt
W
W
Theys
J
J
De Bruijn
E
E
Anné
J
J
Van Mellaert
L
L
Fowler
J
J
D000818:Animals; D000963:Antimetabolites / Q000008:administration & dosage* / Q000378:metabolism; D043525:Cytosine Deaminase; D004305:Dose-Response Relationship, Drug; D005437:Flucytosine / Q000008:administration & dosage* / Q000378:metabolism; D005472:Fluorouracil / Q000008:administration & dosage* / Q000378:metabolism; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D051379:Mice; D008954:Models, Biological; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000378:metabolism / Q000628:therapy*; D009700:Nucleoside Deaminases / Q000235:genetics* / Q000378:metabolism; D011838:Radiation-Sensitizing Agents / Q000008:administration & dosage* / Q000378:metabolism; D014407:Tumor Cells, Cultured
D000963:Antimetabolites; D011838:Radiation-Sensitizing Agents; D005437:Flucytosine; D009700:Nucleoside Deaminases; D043525:Cytosine Deaminase; D005472:Fluorouracil