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 [I-12 5/I-131]5-iodo-2'-deoxyuridine ([I-125/I-131]IdUTd) into DNA by the additio n of Thymitaq, a thymidylate synthase inhibitor, as a strategy of molecular radiotherapy for hepatoma treatment. Methods: The synergistic effect of co mbination [I-125]/dUrd and Thymitaq in clonogenic survival and DNA incorpor ation was shown on the human hepatoma cell line Hep3B. Radiobiodistribution of intrahepatic arterially injected [I-125]IdUrd and Thymitaq was studied in a rat N1S1 hepatoma model. In vivo therapeutic effects of locoregional d elivery of both drugs were evaluated in mouse subcutaneous hepatoma and asc itic hepatoma models, Results: In a clonogenic assay, Thymitaq showed a syn ergistic effect with [I-125]IdUrd but not cold IdUrd. Thymitaq had a dose-d ependent modulation effect on DNA-[I-125]IdUrd incorporation. The biodistri bution study indicated a slower clearance rate of [I-125]IdUdR in the hepat oma as well as an initially higher uptake of [I-125]IdUrd into DNA when the [I-125]IdUrd was combined with Thymitaq. In vive studies showed a superior therapeutic effect of combination Thymitaq and [I-125]IdUrd in both subcut aneous and ascites tumor models, but the combination of [I-131]IdUrd and [I -125]IdUrd may be more effective than Auger electron emitters alone for the treatment of subcutaneous tumor. Conclusion: The strategy of locoregional delivery of [I-125/I-131]IdUrd to a tumor site through an intrahepatic arte rial, intratumoral, or intraperitoneal route in combination with Thy mitaq is promising and may also have a favorable therapeutic index in vive.