The Range of High LET Effects from 125 I Decays

Charlton, D.E.

doi:10.2307/3576804

Cited by 103 publications

(50 citation statements)

References 8 publications

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“…From the viewpoint of their cell-killing potential, the advantage of Auger electron-emitting radionuclides is their extremely short range and localized dose deposition. New strategies are being developed for delivery of Auger electron-emitting radionuclides to the nucleus, such as carbon nanotubes (33), gold nanoparticles (34), antibody-based peptides (35), and cell-penetrating peptides (36). Intranuclear delivery of Auger electron-emitting constructs results in relative biological effectiveness similar to that of a emitters but with a reduced crossfire effect compared with a emitters, making them more suitable for single-cell irradiation (9).…”

Section: Discussionmentioning

confidence: 99%

Monte Carlo Evaluation of Auger Electron–Emitting Theranostic Radionuclides

et al. 2015

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Several radionuclides used in medical imaging emit Auger electrons, which, depending on the targeting strategy, either may be exploited for therapeutic purposes or may contribute to an unintentional mean absorbed dose burden. In this study, the virtues of 12 Auger electron-emitting radionuclides were evaluated in terms of cellular S values in concentric and eccentric cell-nucleus arrangements and by comparing their dose-point kernels. Methods: The Monte Carlo code PENELOPE was used to transport the full particulate spectrum of 67 Pt, and 201 Tl by means of event-by-event simulations. Cellular S values were calculated for varying cell and nucleus radii, and the effects of cell eccentricity on S values were evaluated. Dosepoint kernels were determined up to 30 μm. Energy deposition at DNA scales was also compared with an α emitter, 223 Ra. Results: PENELOPE-determined S values were generally within 10% of MIRD values when the source and target regions strongly overlapped, that is, S(nucleus←nucleus) configurations, but greater differences were noted for S(nucleus←cytoplasm) and S(nucleus←cell surface) configurations. Cell eccentricity had the greatest effect when the nucleus was small, compared with the cell size, and when the radiation sources were on the cell surface. Dose-point kernels taken together with the energy spectra of the radionuclides can account for some of the differences in energy deposition patterns between the radionuclides. The energy deposition of most Auger electron emitters at DNA scales of 2 nm or less exceeded that of a monoenergetic 5.77-MeV α particle, but not for 223 Ra. Conclusion: A single-cell dosimetric approach is required to evaluate the efficacy of individual radionuclides for theranostic purposes, taking cell geometry into account, with internalizing and noninternalizing targeting strategies. The therapeutic rationale for molecularly targeted radiotherapy is the selective delivery of a radionuclide to tumor cells via a targeting moiety, thereby enhancing the therapeutic index of the agent. Several Auger electron-emitting radionuclides have been proposed for molecularly targeted radiotherapy of small metastases and disseminated cancer cells, with some promising clinical results (1-3). These radionuclides are well suited to serving as molecularly targeted radiotherapy agents because of the extremely short range in matter (nanometers to a few micrometers) of the low-energy, intermediate-linear-energy-transfer (LET) Auger and Coster-Kronig electrons they emit (4). These electrons account for high energy deposition in the immediate vicinity of the decay site, and because of their short range, irradiation of normal neighboring cells is limited, thus reducing nonspecific radiotoxicity. In addition, radiation emitted during the nuclear decay can be exploited for imaging purposes either with SPECT (in the case of g rays in the energy range of 70-360 keV or Bremsstrahlung imaging for pure b 2 emitters) or PET (in the case of annihilation photons), thus making Auger electron-emitting ra...

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Section: Discussionmentioning

confidence: 99%

Monte Carlo Evaluation of Auger Electron–Emitting Theranostic Radionuclides

et al. 2015

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“…Although it is less efficient in the production of DNA double-strand breaks [0.74 compared with 1.00 per cell per decay for 1251 (Makrigiorgos et al, 1992) The conventional opinion is that the critical cellular target for ionizing radiation damage is nuclear DNA. Therefore, ultra-shortrange radionuclides, such as Auger electron emitters, should be toxic only if delivered to the nucleus of the target cell (Charlton, 1986). This has been confirmed by in vitro studies -using extracellular Na'251, cytoplasmic [1251]iododihydrorhodamine and nuclear '25IUdR -which demonstrated that significant toxicity was associated only with the nuclear located 1251 (Kassis et al, 1987 (1998) 77(12), [2061][2062][2063][2064][2065][2066][2067][2068] .…”

Section: Discussionmentioning

confidence: 99%

Toxicity to neuroblastoma cells and spheroids of benzylguanidine conjugated to radionuclides with short-range emissions

Cunningham

Mairs²,

Wheldon³

et al. 1998

Br J Cancer

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Summary Radiolabelled meta-iodobenzylguanidine (MIBG) is selectively taken up by tumours of neuroendocrine origin, where its cellular localization is believed to be cytoplasmic. The radiopharmaceutical [1311]MIBG is now widely used in the treatment of neuroblastoma, but other radioconjugates of benzylguanidine have been little studied. We have investigated the cytotoxic efficacy of beta, alpha and Auger electronemitting radioconjugates in treating neuroblastoma cells grown in monolayer or spheroid culture. Using a no-carrier-added synthesis route, we produced 1231-, 1251-, 1311-and 211At-labelled benzylguanidines and compared their in vitro toxicity to the neuroblastoma cell line SK-N-BE(2c) grown in monolayer and spheroid culture. The Auger electron-emitting conjugates ([1231]MIBG and [1251]MIBG) and the alpha-emitting conjugate ([211At]MABG) were highly toxic to monolayers and small spheroids, whereas the beta-emitting conjugate [1311]MIBG was relatively ineffective. The Auger emitters were more effective than expected if the cellular localization of MIBG is cytoplasmic. As dosimetrically predicted however, [211At]MABG was found to be extremely potent in terms of both concentration of radioactivity and number of atoms ml-' administered. In contrast, the Auger electron emitters were ineffective in the treatment of larger spheroids, while the beta emitter showed greater efficacy. These findings suggest that short-range emitters would be well suited to the treatment of circulating tumour cells or small clumps, whereas beta emitters would be superior in the treatment of subclinical metastases or macroscopic tumours. These experimental results provide support for a clinical strategy of combinations ('cocktails') of radioconjugates in targeted radiotherapy.Keywords: meta-iodobenzylguanidine; neuroblastoma; tageted radiotherapy; astatine Meta-iodobenzylguanidine (MIBG) is a structural analogue of the neuroadrenergic blocking drugs bretylium and guanethidine. It is selectively accumulated by an active mechanism in cells of neural crest origin. Radiolabelled MIBG allows the scintigraphic imaging of neural crest tumours (Weiland et al, 1980) and ['311]MIBG is used in the treatment of neuroblastoma and phaeochromocytoma (Hartmann et al, 1987;Mastrangelo, 1987;Schwabe et al, 1987;Voute et al, 1988). Clinical experience since 1984 has demonstrated its potential, with an objective response rate of 35% in patients with progressive heavily pretreated disease (Hoefnagel, 1994). Clinical studies are now evaluating the role of ['311]MIBG at an earlier stage in therapy, either as a first line treatment or in combination with other treatment modalities (DeKraker et al, 1995;Gaze et al, 1995;Mastrangelo et al, 1995).Although many patients show beneficial responses to ['311]MIBG treatment, a significant number subsequently relapse from previously undetected tumour sites (Sisson et al, 1989). This suggests that microtumours below the limit of clinical detectability have survived ['311]MIBG therapy. A possible explanation for the rela...

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“…Although the high-LET-type radiotoxicity of DNA-incorporated Auger emitters has been well established (4,10,25,26), direct experimental comparisons with the densely ionizing high-LET radiations such as α particles have become available only recently through the in vivo and in vitro work of Rao et al (9) and Howell et al (11). For spermatogonial cell killing (9), RBE values of 7.9 ± 2.4 and 6.7 ± 1.4 were obtained for 125 IUdR and 210 Pocitrate, respectively, indicating that the dense shower of Auger electrons from DNAbound 125 I decays is as lethal as 5.3-MeV α particles emitted by 210 Po.…”

Section: High-let Response: Auger Emitters Vs α Emittersmentioning

confidence: 99%

Induction of Sperm Head Abnormalities by Incorporated Radionuclides: Dependence on Subcellular Distribution, Type of Radiation, Dose Rate, and Presence of Radioprotectors

Rao

Narra²,

Howell³

et al. 1991

Radiation Research

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In contrast to the biological effects caused by exposure to external beams of radiation, the effects of tissue-incorporated radionuclides are highly dependent on the type of radiation emitted and on their distribution at the macroscopic, microscopic, and subcellular levels, which are in turn determined by the chemical nature of the radionuclides administered. Induction of abnormalities of sperm heads in mice is investigated in this work after the injection of a variety of radiochemicals including α emitters. When the initial slopes of the dose-response curves are used to compare the relative biological effectiveness (RBE) of different radiocompounds, the α particles emitted in the decay of 210 Po are more effective than Auger electrons emitted by 125 I incorporated in the DNA of the spermatogonial cells, and both emissions are more effective than X rays. It is also shown that the Auger emitters ( 125 I, 111 In) distributed in the cell nucleus are more efficient in producing abnormalities than the same radionuclides localized in the cytoplasm. These findings are consistent with our earlier observations, where spermatogonial cell survival is assayed as a function of the testicular absorbed dose. Further, chronic irradiation of testis with γ rays from intratesticularly administered 7 Be is about three times more effective in causing abnormalities than a single acute exposure to 120-kVp X rays. The resulting RBE values correlate well with our data on sperm head survival with the same radiocompounds. Finally, the radioprotector cysteamine, when administered in small, nontoxic amounts, significantly reduces the incidence of sperm abnormalities from α-particle radiation as well as emissions from 125 I incorporated into DNA, the dose reduction factors being 10 and 14, respectively.

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The Range of High LET Effects from 125 I Decays

Cited by 103 publications

References 8 publications

Monte Carlo Evaluation of Auger Electron–Emitting Theranostic Radionuclides

Monte Carlo Evaluation of Auger Electron–Emitting Theranostic Radionuclides

Toxicity to neuroblastoma cells and spheroids of benzylguanidine conjugated to radionuclides with short-range emissions

Induction of Sperm Head Abnormalities by Incorporated Radionuclides: Dependence on Subcellular Distribution, Type of Radiation, Dose Rate, and Presence of Radioprotectors

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