The potentiation of radiation response in human colon carcinoma cells in vitro and murine lymphoma in vivo by AG337 (Thymitaq), a novel thymidylate synthase inhibitor.

ABSTRACT

PURPOSE: To determine whether the administration of Thymitaq (AG337), a selective inhibitor of thymidylate synthase (TS), enhances radiation-induced cytotoxicity in vitro and increases tumor control rate in vivo. METHODS AND MATERIALS In vitro studies were carried out with HT-29 human colon carcinoma cells. In vivo studies were carried out using L5178Y(TK-) murine lymphoma implanted in DBA/2 mice. RESULTS: Pretreatment of HT-29 cells to nontoxic concentration of AG337 (<10 microM) for a short period of time (< 24 h) significantly enhanced the radiation induced cell lethality. The radiosensitizing enhancement ratio was 1.7. In contrast, there was no increased cell killing when the drug was exposed immediately after irradiation. In studies using L5178Y(TK-) tumors, the drug alone (50 mg/kg, i.p. x 5) had a minimal tumor growth delay, while a single dose of radiation (17 Gy) resulted in < 10% tumor control at day 30. When radiation and drug (17 Gy + AG337, 50 mg/kg, i.p. x 5) were combined, the tumor control rate reached 90% at Day 30. Using the local tumor control assay (TCD50), the radiation dose modification factor after a single dose of radiation was 2.6. CONCLUSION: The concentration of drug shown to be of radiosensitizing value in the in vivo studies is achievable in humans. The results of the present study further supports the potential utility of AG337 in the treatment of human tumors by radiotherapy.