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-2'-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. Radiobiodistribution of intrahepatic arterially injected [¹²⁵]IdUrd and Thymitaq was studied in a rat N1S1 hepatoma model. In vivo therapeutic effects of locoregional delivery of both drugs were evaluated in mouse subcutaneous hepatoma and ascitic hepatoma 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 combination 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 Thymitaq is promising and may also have a favorable therapeutic index in vivo.