The potential of the
thymidylate synthase inhibitor,
Tomudex to interact with ionizing radiation was assessed in vitro and in vivo in comparison with
5-fluorouracil. A concentration of 1 microM
Tomudex decreased the shoulder of the radiation survival curves for normally oxygenated and hypoxic human HT-29 colon
carcinoma cells and human SCC-25 head and neck
squamous carcinoma cells, resulting in enhancement ratios of 10 and 2.8 for normally oxygenated and hypoxic HT-29 cells at 5 Gray, respectively, and enhancement ratios of 19.5 and 2.7 for normally oxygenated and hypoxic SCC-25 cell at 5 Gray, respectively. Two schedules of
Tomudex administered to animals bearing the
Lewis lung carcinoma resulted in additive
tumor growth delay with the fractionated
radiation therapy. In nude mice bearing the HT-29 colon
carcinoma grown as a xenograft, administration of
Tomudex daily for 5 days on a 1 or 2-week schedule resulted in increased
tumor growth delay along with fractionated
radiation therapy on the same schedules. However, administration of
Tomudex intermittently on a 2-week schedule appeared to be more interactive with daily fractionated
radiation therapy on the 2-week schedule. In each assay, the results obtained with
Tomudex were equal to or exceeded those obtained with
5-fluorouracil. These findings indicate that clinical trial of
Tomudex along with fractionated
radiation therapy is warranted.