123I-ITdU-mediated nanoirradiation of DNA efficiently induces cell kill in HL60 leukemia cells and in doxorubicin-, beta-, or gamma-radiation-resistant cell lines.

Abstract

UNLABELLED:

Resistance to radiotherapy or chemotherapy is a common cause of treatment failure in high-risk leukemias. We evaluated whether selective nanoirradiation of DNA with Auger electrons emitted by 5-(123)I-iodo-4'-thio-2'-deoxyuridine ((123)I-ITdU) can induce cell kill and break resistance to doxorubicin, beta-, and gamma-irradiation in leukemia cells.

METHODS:

4'-thio-2'-deoxyuridine was radiolabeled with (123/131)I and purified by high-performance liquid chromatography. Cellular uptake, metabolic stability, DNA incorporation of (123)I-ITdU, and the effect of the thymidylate synthase (TS) inhibitor 5-fluoro-2'-deoxyuridine (FdUrd) were determined in HL60 leukemia cells. DNA damage was assessed with the comet assay and quantified by the olive tail moment. Apoptosis induction and irradiation-induced apoptosis inhibition by benzoylcarbonyl-Val-Ala-Asp-fluoromethyl ketone (z-VAD.fmk) were analyzed in leukemia cells using flow cytometry analysis.

RESULTS:

The radiochemical purity of ITdU was 95%. Specific activities were 900 GBq/micromol for (123)I-ITdU and 200 GBq/micromol for (131)I-ITdU. An in vitro cell metabolism study of (123)I-ITdU with wild-type HL60 cells demonstrated an uptake of 1.5% of the initial activity/10(6) cells of (123)I-ITdU. Ninety percent of absorbed activity from (123)I-ITdU in HL60 cells was specifically incorporated into DNA. (123)I-ITdU caused extensive DNA damage (olive tail moment > 12) and induced more than 90% apoptosis in wild-type HL60 cells. The broad-spectrum inhibitor of caspases zVAD-fmk reduced (123)I-ITdU-induced apoptosis from more than 90% to less than 10%, demonstrating that caspases were central for (123)I-ITdU-induced cell death. Inhibition of TS with FdUrd increased DNA uptake of (123)I-ITdU 18-fold and the efficiency of cell kill about 20-fold. In addition, (123)I-ITdU induced comparable apoptotic cell death (>90%) in sensitive parental leukemia cells and in leukemia cells resistant to beta-irradiation, gamma-irradiation, or doxorubicin at activities of 1.2, 4.1, 12.4, and 41.3 MBq/mL after 72 h. This finding indicates that (123)I-ITdU breaks resistance to beta-irradiation, gamma-irradiation, and doxorubicin in leukemia cells.

CONCLUSION:

(123)I-ITdU-mediated nanoirradiation of DNA efficiently induced apoptosis in sensitive and resistant leukemia cells against doxorubicin, beta-irradiation, and gamma-irradiation and may provide a novel treatment strategy for overcoming resistance to conventional radiotherapy or chemotherapy in leukemia. Cellular uptake and cell kill are highly amplified by inhibiting TS with FdUrd.

• Authors: Sven N Reske, Sandra Deisenhofer, Gerhard Glatting, Boris D Zlatopolskiy, Agnieszka Morgenroth, Andreas T J Vogg, Andreas K Buck, Claudia Friesen
• Journal: Journal of nuclear medicine : official publication, Society of Nuclear Medicine (J Nucl Med) Vol. 48 Issue 6 Pg. 1000-7 (Jun 2007) ISSN: 0161-5505 [Print] United States
• PMID: 17504875 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 5-iodo-4'-thio-2'-deoxyuridine
• Antineoplastic Agents
• Iodine Radioisotopes
• Radiopharmaceuticals
• Doxorubicin
• Deoxyuridine

Topics

• Antineoplastic Agents (pharmacology)
• Apoptosis
• Beta Particles
• Cell Line, Tumor
• DNA Damage
• Deoxyuridine (analogs & derivatives, therapeutic use)
• Doxorubicin (pharmacology)
• Drug Resistance, Neoplasm
• Gamma Rays
• HL-60 Cells
• Humans
• Iodine Radioisotopes
• Nanotechnology
• Radiation Tolerance
• Radiopharmaceuticals (pharmacology)