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J Nucl Med. 2008; 49 (Supplement 1):15P
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Oncology-Basic Science: Basic Science

Therapeutic Approaches

Preferential tumor targeting and selective cytotoxicity of 5-[131/125I]-iodo-4'-thio-2'-deoxyuridine

Agnieszka Morgenroth1, Falk Schmidt1, Cornelia Dinger1, Boris Zlatopolskiy1, Gerhard Glatting1 and Sven Reske1

1 Nuclear Medicine Clinic, University of Ulm, Ulm, Germany

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Objectives: Auger-electron emitting radiopharmaceuticals are attractive for targeted nanoirradiation therapy, provided that DNA of malignant cells is selectively addressed. We examined 5-[123/125/131]iodo-4'-thio-2'-deoxyuridine for targeting DNA in tumor cells in a SCID mouse model. Furthermore, the effect of thymidylate synthase inhibitor 5-fluoro-2'-deoxyuridine on specific targeting and induction of apoptotic death of cancer cells was investigated.

Methods: For comparative biodistribution experiments with [131I]ITdU three groups of HL60-xenografed scid mice received pre-treatment with different doses of FdUrd 30 min prior to ITdU injection. Tumor and normal organ tissues were dissected 30 min and 24 h post injection and uptake of [131I]ITdU (%ID/g tissue) by organ and tumor tissue was determined. Cellular distribution of [125I]ITdU and induced apoptotic effect were imaged by microautoradiography and TUNEL assay, respectively.

Results: Pretreatment with 20 µmol/kg FdUrd preferentially increased tumor ITdU uptake by a factor of 4, doubled spleen uptake and reduced intestinal uptake to about 50%, resulting in favorable tumor to normal tissue ratios and thus tumor selectivity. ITdU was exclusively localized within the nucleus and incorporated into DNA (348±115 cpm/µg DNA) of tumor cells, compared to 58±10 and 100±2 in spleen and small intestine. In FdUrd pretreated animals 24 h we observed after injection of ITdU > 90% tumoral apoptosis induction and thus a highly radiotoxic effect in tumor cells but not in cells of major proliferating tissues.

Conclusions: We conclude that pretreatment with an appropriate dose of FdUrd confers targeting and radiotoxic selectivity to ITdU in tumor cells in vivo compared to proliferating cells in major proliferating tissues.

Research Support: KFO 120, German Research Foundation





This Article
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Right arrow Email this article to a friend
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Right arrow Alert me to new issues of the journal
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Google Scholar
Right arrow Articles by Morgenroth, A.
Right arrow Articles by Reske, S.
PubMed
Right arrow Articles by Morgenroth, A.
Right arrow Articles by Reske, S.