Highly efficient DNA incorporation of intratumourally injected [<sup>125</sup>I]iododeoxyuridine under thymidine synthesis blocking in human glioblastoma xenografts

Buchegger, Franz; Adamer, Florence; Schaffland, Andreas O.; Kosinski, Marek; Grannavel, Carine; Dupertuis, Y.M.; Tribolet, Nicolas de; Mach, Jean‐Pierre; Delaloye, Angelika Bischof

doi:10.1002/ijc.20112

Cited by 18 publications

(17 citation statements)

References 12 publications

(15 reference statements)

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“…Accordingly, we found a rapid and extensive dehalogenation of 123 I-ITdU mediated by HL60. As described for IdUrd (30), the TS inhibitor FdUrd could completely block TS-mediated dehalogenation of 123 I-ITdU in a nontoxic concentration and increase substrate flux through the thymidine salvage pathway as indicated by the 18-fold increased DNA uptake of 123 I-ITdU, resulting in roughly 20-fold apoptosis induction. Because TS is overexpressed in many leukemic An increased radiotoxicity of cells retained in S-phase after FdUrd pretreatment was observed by Perillo-Adamer et al (34) in glioblastoma cell lines.…”

Section: Discussionmentioning

confidence: 75%

123I-ITdU-Mediated Nanoirradiation of DNA Efficiently Induces Cell Kill in HL60 Leukemia Cells and in Doxorubicin-, -, or -Radiation-Resistant Cell Lines

Reske

Deisenhofer²,

Glatting³

et al. 2007

Journal of Nuclear Medicine

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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-49-thio-29-deoxyuridine ( 123 I-ITdU) can induce cell kill and break resistance to doxorubicin, b-, and g-irradiation in leukemia cells. Methods: 49-thio-29-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-29-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 benzoylcarbonylVal-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/mmol for 123 I-ITdU and 200 GBq/mmol 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 IITdU-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 b-irradiation, g-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 b-irradiation, g-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, b-irradiation, and g-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.

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Section: Discussionmentioning

confidence: 75%

123I-ITdU-Mediated Nanoirradiation of DNA Efficiently Induces Cell Kill in HL60 Leukemia Cells and in Doxorubicin-, -, or -Radiation-Resistant Cell Lines

Reske

Deisenhofer²,

Glatting³

et al. 2007

Journal of Nuclear Medicine

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“…Binding assays were performed with HT-29 cells at confluence as already described [20,22]. For saturation studies, cells were incubated in triplicate with increasing concentrations (0.3-30 nmol/L) of purified 99m Tc-NT-XIX for 1 h at 37°C.…”

Section: Binding Assaysmentioning

confidence: 99%

“…Modification of Arg 8 -Arg 9 and Tyr 11 -Ile 12 led to increased plasma stability, high affinity for NTR1 and also good in vivo tumour uptake [17][18][19]. With one analogue (NT-XI), visualisation of the tumour of a patient with ductal pancreatic adenocarcinoma was possible, which demonstrates the potential utility of NT analogues for imaging of these tumours [20].…”

Section: Introductionmentioning

confidence: 99%

A stable neurotensin-based radiopharmaceutical for targeted imaging and therapy of neurotensin receptor-positive tumours

García-Garayoa

Bläuenstein

Blanc

et al. 2008

Eur J Nucl Med Mol Imaging

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Purpose Neurotensin (NT) and its high affinity receptor (NTR1) are involved in several neoplastic processes. Thus, NT-based radiopharmaceuticals are potential tracers for targeted diagnosis and therapy of NTR-positive tumours. A new analogue based on NT(8-13), NT-XIX, with the three enzymatic cleavage sites stabilised, was synthesised and tested. Methods The synthesis was performed by Boc strategy. Labelling with 99m Tc/ 188Re was performed using the tricarbonyl technique. Metabolic stability was tested in vitro and in vivo. NT-XIX was further characterised in vitro in HT-29 cells and in vivo in nude mice with HT-29 xenografts. Results NT-XIX showed much longer half-lives than nonstabilised analogues. Binding to NTR1 was highly specific, although the affinity was lower than that of natural NT. Bound activity rapidly internalised into HT-29 cells and 50% remained trapped after 24 h. In the time-course biodistribution, the highest uptake was found in the tumour at all p.i. times. In vivo uptake was specific, and accumulation of activity in the kidneys was low. Radioactivity clearance from healthy organs was faster than that from the tumour, resulting in improved tumour-to-tissue ratios and good SPECT/CT imaging. Treatment with 188 Re-NT-XIX (30 MBq, in three or four fractions) decreased tumour growth by 50% after 3 weeks. Conclusion The high in vivo stability and the favourable in vivo behaviour makes NT-XIX an excellent candidate for the imaging and therapy of NTR1-positive tumours.

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“…It was reported (20,21) that pretreatment with nontoxic concentrations of the thymidylate synthase inhibitor such as 5-fluoro-29-deoxyuridine increased cellular uptake of 29-deoxynucleosides such as ITdU and IdU in tumor cells. In contrast, uptake of 131 I-IV-14 in HL60 and Mia-PaCa-2 cells (Fig.…”

Section: Cellular Uptake Studiesmentioning

confidence: 99%

Synthesis and Biologic Study of IV-14, a New Ribonucleoside Radiotracer for Tumor Visualization

Zlatopolskiy¹,

Morgenroth²,

Kunkel³

et al. 2009

J Nucl Med

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Highly efficient DNA incorporation of intratumourally injected [¹²⁵I]iododeoxyuridine under thymidine synthesis blocking in human glioblastoma xenografts

Abstract: Intratumoural (i.t.) injection of radio-iododeoxyuridine

Cited by 18 publications

References 12 publications

123I-ITdU-Mediated Nanoirradiation of DNA Efficiently Induces Cell Kill in HL60 Leukemia Cells and in Doxorubicin-, -, or -Radiation-Resistant Cell Lines

123I-ITdU-Mediated Nanoirradiation of DNA Efficiently Induces Cell Kill in HL60 Leukemia Cells and in Doxorubicin-, -, or -Radiation-Resistant Cell Lines

A stable neurotensin-based radiopharmaceutical for targeted imaging and therapy of neurotensin receptor-positive tumours

Synthesis and Biologic Study of IV-14, a New Ribonucleoside Radiotracer for Tumor Visualization

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Highly efficient DNA incorporation of intratumourally injected [125I]iododeoxyuridine under thymidine synthesis blocking in human glioblastoma xenografts

Abstract: Intratumoural (i.t.) injection of radio-iododeoxyuridine

Cited by 18 publications

References 12 publications

123I-ITdU-Mediated Nanoirradiation of DNA Efficiently Induces Cell Kill in HL60 Leukemia Cells and in Doxorubicin-, -, or -Radiation-Resistant Cell Lines

123I-ITdU-Mediated Nanoirradiation of DNA Efficiently Induces Cell Kill in HL60 Leukemia Cells and in Doxorubicin-, -, or -Radiation-Resistant Cell Lines

A stable neurotensin-based radiopharmaceutical for targeted imaging and therapy of neurotensin receptor-positive tumours

Synthesis and Biologic Study of IV-14, a New Ribonucleoside Radiotracer for Tumor Visualization

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Highly efficient DNA incorporation of intratumourally injected [¹²⁵I]iododeoxyuridine under thymidine synthesis blocking in human glioblastoma xenografts