Therapeutic potential of 5‐[<sup>125</sup>I]iodo‐2′‐deoxyuridine and methotrexate in the treatment of advanced neoplastic meningitis

Kassis, Amin I.; Kirichian, Agop M.; Wang, Ketai; Semnani, Elham Safaie; Adelstein, S. James

doi:10.1080/09553000400017671

Cited by 22 publications

(20 citation statements)

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“…Similar findings occur with [ 123 I]UdR [40]. Therapeutic doses of [ 125 I]UdR injected intrathecally into rats with intrathecal tumours significantly delay the onset of paralysis, and the coadministration of methotrexate, an antimetabolite that enhances IUdR uptake by DNA-synthesising cells, substantially enhances the therapeutic efficacy (Figure 9) as exemplified by a 5 -6-log tumour cell kill and the curing of ∼ 30% of the tumour-bearing rats [41,42].…”

Section: Nonenergetic Particlessupporting

confidence: 68%

“…The extreme degree of cytotoxicity observed with DNAincorporated Auger-electron emitters has been exploited in experimental radionuclide therapy. In most of these in vivo studies, the thymidine analogue 5-iodo-2′-deoxyuridine (IUdR) has been used [39][40][41][42], and the results have shown excellent therapeutic efficacy. For example, the injection of [ 125 I]UdR into mice bearing an intraperitoneal ascites ovarian cancer has led to a 5-log reduction in tumour cell survival [39].…”

Section: Nonenergetic Particlesmentioning

confidence: 99%

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Radiotargeting agents for cancer therapy

Kassis¹

2005

Expert Opinion on Drug Delivery

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Although the general radiobiological principles underlying external beam therapy and radionuclide therapy are the same, there are significant differences in the radiobiological effects observed in mammalian cells. In external beam therapy and brachytherapy, emissions are composed of photons, whereas in radionuclide therapy, the radiations of interest are particulate. This article will explore the special features that characterise the biological effects consequent to the traversal of charged particles through mammalian cells. In addition, it will highlight what has been learned when these radionuclides and targeting radiopharmaceuticals are used to treat cancers.

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Section: Nonenergetic Particlessupporting

confidence: 68%

Section: Nonenergetic Particlesmentioning

confidence: 99%

Radiotargeting agents for cancer therapy

Kassis¹

2005

Expert Opinion on Drug Delivery

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“…Indeed, other studies have demonstrated that the efficacy of Auger electron radiotherapy can be significantly enhanced by MTX. For example, the administration of MTX before the injection of 5-[ 125 I]iodo-29-deoxyuridine ( 125 IUdR) in rats with intrathecal TE-671 human rhabdomyosarcoma enhanced 125 IUdR uptake by tumor cells and augmented the therapeutic efficacy of this Auger electron-emitting radiopharmaceutical (36). Paclitaxel, docetaxel (Taxotere; SanofiAventis), gemcitabine, topotecan, 5-fluorouracil, doxorubicin, tirapazamine, or halogenated pyrimidines have also been combined with targeted a-or b-radioimmunotherapy and have been shown to inhibit the growth of various malignant cell lines in vitro or provide antitumor effects in mouse xenograft models and in human clinical trials more effectively than either treatment alone (15,16).…”

Section: Discussionmentioning

confidence: 99%

Trastuzumab-Resistant Breast Cancer Cells Remain Sensitive to the Auger Electron–Emitting Radiotherapeutic Agent ¹¹¹In-NLS-Trastuzumab and Are Radiosensitized by Methotrexate

Costantini

Bateman²,

McLarty³

et al. 2008

J Nucl Med

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Our goals in this study were to determine whether 111 In-trastuzumab coupled to peptides harboring nuclear localizing sequences (NLSs) could kill trastuzumab-resistant breast cancer cell lines through the emission of Auger electrons and whether the combination of radiosensitization with methotrexate (MTX) would augment the cytotoxicity of this radiopharmaceutical. Methods: Trastuzumab was derivatized with sulfosuccinimidyl-4-(Nmaleimidomethyl)cyclohexane-1-carboxylate for reaction with NLS peptides and then conjugated with diethylenetriaminepentaacetic acid for labeling with 111 In. HER2 expression was determined by Western blot and by radioligand binding assay using 111 In-trastuzumab in a panel of breast cancer cell lines, including SK-BR-3, MDA-MB-231 and its HER2-transfected subclone (231-H2N), and 2 trastuzumab-resistant variants (TrR1 and TrR2). Nuclear importation of 111 In-NLS-trastuzumab and 111 Intrastuzumab in breast cancer cells was measured by subcellular fractionation, and the clonogenic survival of these cells was determined after incubation with 111 In-NLS-trastuzumab, 111 Intrastuzumab, or trastuzumab (combined with or without MTX). Survival curves were analyzed according to the dose-response model, and the radiation-enhancement ratio was calculated from the survival curve parameters. Results: The expression of HER2 was highest in SK-BR-3 cells (12.6 · 10 5 receptors/cell), compared with 231-H2N and TrR1 cells (6.1 · 10 5 and 5.1 · 10 5 receptors/cell, respectively), and lowest in MDA-MB-231 and TrR2 cells (0.4 · 10 5 and 0.6 · 10 5 receptors/cell, respectively). NLS peptides increased the nuclear uptake of 111 In-trastuzumab in MDA-MB-231, 231-H2N, TrR1, and TrR2 cells from 0.1% 6 0.01%, 2.5% 6 0.2%, 2.8% 6 0.7%, and 0.5% 6 0.1% to 0.5% 6 0.1%, 4.6% 6 0.1%, 5.2% 6 0.6%, and 1.5% 6 0.2%, respectively. The cytotoxicity of 111 In-NLS-trastuzumab on breast cancer cells was directly correlated with the HER2 expression densities of the cells. On a molar concentration basis, the effective concentration required to kill 50% of 231-H2N and TrR1 cells for 111 In-NLS-trastuzumab was 9-to 12-fold lower than for 111 Intrastuzumab and 16-to 77-fold lower than for trastuzumab.MDA-MB-231 and TrR2 cells were less sensitive to 111 In-NLStrastuzumab or 111 In-trastuzumab, and both cell lines were completely insensitive to trastuzumab. The radiation-enhancement ratio induced by MTX for 231-H2N and TrR1 cells after exposure to 111 In-NLS-trastuzumab was 1.42 and 1.68, respectively. Conclusion: Targeted Auger electron radioimmunotherapy with 111 In-NLS-trastuzumab can overcome resistance to trastuzumab, and MTX can potently enhance the sensitivity of HER2-overexpressing breast cancer cells to the lethal Auger electrons emitted by this radiopharmaceutical.

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“…Further analysis indicates that 17% of SSBs and 100% of DSBs take place within the plasmid molecule in which an 125 IEH molecule decays, whereas 83% of SSBs are formed in neighboring plasmid DNA molecules. ᭧ 2006 by Radiation Research Society its potential for use in cancer therapy (6)(7)(8). The decay of this Auger-electron emitter produces a cascade of extremely low-energy electrons, ϳ21 on average: of these, ϳ18 electrons have a range Ͻ100 nm and ϳ8 electrons travel Ͻ2 nm (9).…”

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confidence: 99%

Mechanisms Underlying Production of Double-Strand Breaks in Plasmid DNA after Decay of¹²⁵I-Hoechst

et al. 2006

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Previously, the kinetics of strand break production by (125)I-labeled m-iodo-p-ethoxyHoechst 33342 ((125)IEH) in supercoiled (SC) plasmid DNA had demonstrated that approximately 1 DSB is produced per (125)I decay both in the presence and absence of the hydroxyl radical scavenger DMSO. In these experiments, an (125)IEH:DNA molar ratio of 42:1 was used. We now hypothesize that this DSB yield (but not the SSB yield) may be an overestimate due to subsequent decays occurring in any of the 41 (125)IEH molecules still bound to nicked (N) DNA. To test our hypothesis, (125)IEH was incubated with SC pUC19 plasmids ((125)IEH:DNA ratio of approximately 3:1) and the SSB and DSB yields were quantified after the decay of (125)I. As predicted, the number of DSBs produced per (125)I decay is one-half that reported previously ( approximately 0.5 compared to approximately 1, +/- DMSO) whereas the number of SSBs ( approximately 3/(125)I decay) is similar to that obtained previously ( approximately 90% are generated by OH radicals). Direct visualization by atomic force microscopy confirms formation of L and N DNA after (125)IEH decays in SC DNA and supports the strand break yields reported. These findings indicate that although SSB production is independent of the number of (125)IEH bound to DNA, the DSB yield can be augmented erroneously by (125)I decays occurring in N DNA. Further analysis indicates that 17% of SSBs and 100% of DSBs take place within the plasmid molecule in which an (125)IEH molecule decays, whereas 83% of SSBs are formed in neighboring plasmid DNA molecules.

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Therapeutic potential of 5‐[¹²⁵I]iodo‐2′‐deoxyuridine and methotrexate in the treatment of advanced neoplastic meningitis

Abstract: Intrathecal injection of MTX-(125)IdUrd is efficacious in the therapy of advanced intrathecal tumours.

Cited by 22 publications

References 20 publications

Radiotargeting agents for cancer therapy

Radiotargeting agents for cancer therapy

Trastuzumab-Resistant Breast Cancer Cells Remain Sensitive to the Auger Electron–Emitting Radiotherapeutic Agent ¹¹¹In-NLS-Trastuzumab and Are Radiosensitized by Methotrexate

Mechanisms Underlying Production of Double-Strand Breaks in Plasmid DNA after Decay of¹²⁵I-Hoechst

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Therapeutic potential of 5‐[125I]iodo‐2′‐deoxyuridine and methotrexate in the treatment of advanced neoplastic meningitis

Abstract: Intrathecal injection of MTX-(125)IdUrd is efficacious in the therapy of advanced intrathecal tumours.

Cited by 22 publications

References 20 publications

Radiotargeting agents for cancer therapy

Radiotargeting agents for cancer therapy

Trastuzumab-Resistant Breast Cancer Cells Remain Sensitive to the Auger Electron–Emitting Radiotherapeutic Agent 111In-NLS-Trastuzumab and Are Radiosensitized by Methotrexate

Mechanisms Underlying Production of Double-Strand Breaks in Plasmid DNA after Decay of125I-Hoechst

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Product

Resources

About

Therapeutic potential of 5‐[¹²⁵I]iodo‐2′‐deoxyuridine and methotrexate in the treatment of advanced neoplastic meningitis

Trastuzumab-Resistant Breast Cancer Cells Remain Sensitive to the Auger Electron–Emitting Radiotherapeutic Agent ¹¹¹In-NLS-Trastuzumab and Are Radiosensitized by Methotrexate

Mechanisms Underlying Production of Double-Strand Breaks in Plasmid DNA after Decay of¹²⁵I-Hoechst