RT Journal Article
SR Electronic
T1 Preclinical Evaluation of Locoregional Delivery of Radiolabeled Iododeoxyuridine and Thymidylate Synthase Inhibitor in a Hepatoma Model
JF Journal of Nuclear Medicine
JO J Nucl Med
FD Society of Nuclear Medicine
SP 345
OP 351
VO 42
IS 2
A1 Kwan-Hwa Chi
A1 Hsin-Ell Wang
A1 Fu-Du Chen
A1 Yee Chao
A1 Ren-Shyan Liu
A1 Shuan-Lan Chou
A1 Yu-Shan Wang
A1 Sang-Hue Yen
YR 2001
UL http://jnm.snmjournals.org/content/42/2/345.abstract
AB 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.