Preclinical evaluation of locoregional delivery of radiolabeled iododeoxyuridine and thymidylate synthase inhibitor in a hepatoma model.

Abstract

UNLABELLED:

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 [125I]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.

• Authors: K H Chi, H E Wang, F D Chen, Y Chao, R S Liu, S L Chou, Y S Wang, S H Yen
• Journal: Journal of nuclear medicine : official publication, Society of Nuclear Medicine (J Nucl Med) Vol. 42 Issue 2 Pg. 345-51 (Feb 2001) ISSN: 0161-5505 [Print] United States
• PMID: 11216535 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• DNA, Neoplasm
• Iodine Radioisotopes
• Quinazolines
• Thymidylate Synthase
• nolatrexed
• Idoxuridine

Topics

• Animals
• DNA, Neoplasm (metabolism)
• Dose-Response Relationship, Drug
• Drug Evaluation
• Drug Synergism
• Drug Therapy, Combination
• Female
• Humans
• Idoxuridine (administration & dosage, pharmacokinetics, therapeutic use)
• Iodine Radioisotopes (therapeutic use)
• Liver Neoplasms, Experimental (metabolism, radiotherapy)
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C3H
• Neoplasm Transplantation
• Quinazolines (administration & dosage, therapeutic use)
• Rats
• Rats, Sprague-Dawley
• Thymidylate Synthase (antagonists & inhibitors)
• Tumor Cells, Cultured