Preclinical Evaluation of Locoregional Delivery of Radiolabeled Iododeoxyuridine and Thymidylate Synthase Inhibitor in a Hepatoma Model

We report improved incorporation of the radiolabeled-thymidine analog [125I/131I]5-iodo-29-deoxyuridine ([125I/131I]IdUrd) into DNA by the addition of Thymitaq, a thymidylate synthase inhibitor, as a strategy of molecular radiotherapy for hepatoma treatment. Methods: The synergistic effect of combination [125I]IdUrd and Thymitaq in clonogenic survival and DNA incorporation was shown on the human hepatoma cell line Hep3B. Radiobiodis-tribution of intrahepatic arterially injected [125]IdUrd and Thymi-taq was studied in a rat N1S1 hepatoma model. In vivo thera-peutic effects of locoregional delivery of both drugs were evaluated in mouse subcutaneous hepatoma and ascitic hepa-toma models. Results: In a clonogenic assay, Thymitaq showed a synergistic effect with [125I]IdUrd but not cold IdUrd. Thymitaq had a dose-dependent modulation effect on DNA-[125I]IdUrd incorporation. The biodistribution study indicated a slower clearance rate of [125I]IdUdR in the hepatoma as well as an initially higher uptake of [125I]IdUrd into DNA when the [125I]IdUrd was combined with Thymitaq. In vivo studies showed a superior therapeutic effect of combination Thymitaq and [125I]IdUrd in both subcutaneous and ascites tumor models, but the combi-nation of [131I]IdUrd and [125I]IdUrd may be more effective than Auger electron emitters alone for the treatment of subcutaneous tumor. Conclusion: The strategy of locoregional delivery of [125I/131I]IdUrd to a tumor site through an intrahepatic arterial, intratumoral, or intraperitoneal route in combination with Thy-mitaq is promising and may also have a favorable therapeutic index in vivo. Key Words: hepatoma; radioactive iododeoxyuridine; AG337; molecular radiotherapy; locoregional deliver