Interaction of tomudex with radiation in vitro and in vivo.
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.
Lilly Research Laboratories, Lilly Corporate Center, DC 0540, Indianapolis, IN 46285, USA.
B A
BA
Teicher
G
G
Ara
Y N
YN
Chen
A
A
Recht
C N
CN
Coleman
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D018827:Carcinoma, Lewis Lung / Q000188:drug therapy / Q000532:radiotherapy; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000532:radiotherapy; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D003131:Combined Modality Therapy; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005472:Fluorouracil / Q000494:pharmacology; D019073:HT29 Cells / Q000187:drug effects / Q000528:radiation effects; D006258:Head and Neck Neoplasms / Q000188:drug therapy / Q000532:radiotherapy; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000188:drug therapy* / Q000532:radiotherapy*; D011799:Quinazolines / Q000494:pharmacology*; D011836:Radiation Tolerance / Q000187:drug effects*; D013876:Thiophenes / Q000494:pharmacology*; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D000964:Antimetabolites, Antineoplastic; D004791:Enzyme Inhibitors; D011799:Quinazolines; D013876:Thiophenes; D013940:Thymidylate Synthase; C068874:raltitrexed; D005472:Fluorouracil