Radioimmunotherapy with Alpha-Particle Emitters: Microdosimetry of Cells with a Heterogeneous Antigen Expression and with Various Diameters of Cells and Nuclei

Kvinnsland, Yngve; Stokke, Trond; Aurlien, E.

doi:10.1667/0033-7587(2001)155[0288:rwapem]2.0.co;2

Cited by 47 publications

(41 citation statements)

References 13 publications

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“…This SD was, in some cases, slightly higher than theoretic estimations. However, previous studies observed relatively high biologic variability in the number of antigens present at the surface of tumor cells (26,27), possibly explaining the discrepancy between our theoretic estimations and experimental measurements.…”

Section: Uncertaintiescontrasting

confidence: 81%

Ex Vivo Activity Quantification in Micrometastases at the Cellular Scale Using the α-Camera Technique

et al. 2013

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Targeted a-therapy (TAT) appears to be an ideal therapeutic technique for eliminating malignant circulating, minimal residual, or micrometastatic cells. These types of malignancies are typically infraclinical, complicating the evaluation of potential treatments. This study presents a method of ex vivo activity quantification with an a-camera device, allowing measurement of the activity taken up by tumor cells in biologic structures a few tens of microns. Methods: We examined micrometastases from a murine model of ovarian carcinoma after injection of a radioimmunoconjugate labeled with 211 At for TAT. At different time points, biologic samples were excised and cryosectioned. The activity level and the number of tumor cells were determined by combined information from 2 adjacent sections: one exposed to the a-camera and the other stained with hematoxylin and eosin. The time-activity curves for tumor cell clusters, comprising fewer than 10 cells, were derived for 2 different injected activities (6 and 1 MBq). Results: High uptake and good retention of the radioimmunoconjugate were observed at the surface of tumor cells. Dosimetric calculations based on the measured time-integrated activity indicated that for an injected activity of 1 MBq, isolated tumor cells received at least 12 Gy. In larger micrometastases (#100 mm in diameter), the activity uptake per cell was lower, possibly because of hindered penetration of radiolabeled antibodies; however, the mean absorbed dose delivered to tumor cells was above 30 Gy, due to cross-fire irradiation. Conclusion: Using the a-camera, we developed a method of ex vivo activity quantification at the cellular scale, which was further applied to characterize the behavior of a radiolabeled antibody administered in vivo against ovarian carcinoma. This study demonstrated a reliable measurement of activity. This method of activity quantification, based on experimentally measured data, is expected to improve the relevance of small-scale dosimetry studies and thus to accelerate the optimization of TAT. On the basis of the characteristics of the a-particle, targeted a-therapy (TAT) has been acknowledged as a potentially efficient therapeutic technique (1) for decades. a-particles have a short range in tissue, making the irradiation specific, and a high linear energy transfer, making them highly cytotoxic (2). These properties make them suitable for the treatment of hematologic malignancies or minimal residual or micrometastatic diseases (3,4). The first clinical trials using TAT have been started for the treatment of leukemia (5,6), ovarian carcinoma (7), and residual tumor cells after surgery of malignant brain tumors (8).Micrometastatic diseases are infraclinical and hardy or not localized with in vivo imaging techniques. Thus, targeted radionuclide therapies of tumor cells or micrometastases require complex evaluations. Activity quantification of micrometric lesions by imaging is difficult in patients because of the limited spatial resolution. Only rough estimations of the activity of...

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Section: Uncertaintiescontrasting

confidence: 81%

Ex Vivo Activity Quantification in Micrometastases at the Cellular Scale Using the α-Camera Technique

et al. 2013

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“…The reliability of this approach stems from its use of emitted radiations to ascertain the distribution. Other experimental techniques, such as flow cytometry (24,25), can also be used to derive the distribution. Because of the ubiquitous presence of LN distributions, many investigators studying radiobiologic responses to radiopharmaceuticals and other radiochemicals may find this distribution useful to fold into their dose-response models (8,24,26).…”

Section: Discussionmentioning

confidence: 99%

Lognormal Distribution of Cellular Uptake of Radioactivity: Statistical Analysis of α-Particle Track Autoradiography

Neti¹,

Howell²

2008

J Nucl Med

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Recently, the distribution of radioactivity among a population of cells labeled with 210 Po was shown to be well described by a lognormal (LN) distribution function (J Nucl Med. 2006;47:1049-1058 with the aid of autoradiography. To ascertain the influence of Poisson statistics on the interpretation of the autoradiographic data, the present work reports on a detailed statistical analysis of these earlier data. Methods: The measured distributions of a-particle tracks per cell were subjected to statistical tests with Poisson, LN, and Poisson-lognormal (P-LN) models. Results: The LN distribution function best describes the distribution of radioactivity among cell populations exposed to 0.52 and 3.8 kBq/mL of 210 Po-citrate. When cells were exposed to 67 kBq/mL, the P-LN distribution function gave a better fit; however, the underlying activity distribution remained lognormal. Conclusion: The present analysis generally provides further support for the use of LN distributions to describe the cellular uptake of radioactivity. Care should be exercised when analyzing autoradiographic data on activity distributions to ensure that Poisson processes do not distort the underlying LN distribution.

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“…Targeting of single signaling components often does not result in optimal cytotoxicity. This is partly due to non-uniform distributions of target antigen expression in cell populations, which may limit the ability to target all cells with toxic levels of therapeutic agents [14][15][16]. Therefore, developing therapeutic approaches that concomitantly target multiple signaling components of the EGFR and PI3K pathways might significantly sensitise prostate cancer cells to radiotherapy and improve treatment outcome.…”

mentioning

confidence: 99%

NVP-BEZ235 Enhances Radiosensitivity of Human Prostate Cancer Cells but Acts as a Radioprotector to Normal Prostate Cells

Maleka

Serafin

Hamunyela

et al. 2015

GJCT

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Targeted therapy for prostate cancer may offer potential improvement over current conventional therapiesÃ‚Â because of its specificity. Although conventional treatments are effective, they are not always curative, andhave several limitations. In prostate cancer, activation of the epidermal growth factor receptor (EGFR) and theÃ‚Â phosphatidylinositol-3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathways have been implicatedin tumorigenesis, and resistance to both conventional and targeted anticancer therapies. Single-target therapiesÃ‚Â may fail due to cellular heterogeneity. Concomitant targeting of EGFR and PI3K/mTOR cell signaling componentsÃ‚Â may enhance the efficacy of radiotherapy. In this study, the effect of an EGFR inhibitor (AG-1478) and a dualÃ‚Â inhibitor of PI3K and mTOR (NVP-BEZ235) on the radiation response of a human prostate carcinoma cell lineÃ‚Â (DU145) and a normal prostate cell line (1542N) was investigated, using the colony forming assay. Treatment ofDU145 cells with AG-1478 and NVP-BEZ235, either singly or in combination, resulted in a slight radiosensitisationÃ‚Â of DU145 cells. Neither AG-1478 nor a cocktail of both inhibitors had an effect on the radiation response of theÃ‚Â 1542N cell line. Interestingly, NVP-BEZ235 significantly protected 1542N cells from radiation-induced cell death.Ã‚Â These data suggest that a specific inhibitor of PI3K and mTOR (NVP-BEZ235) could potentially be effective as aÃ‚Â radio-protector.

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Radioimmunotherapy with Alpha-Particle Emitters: Microdosimetry of Cells with a Heterogeneous Antigen Expression and with Various Diameters of Cells and Nuclei

Cited by 47 publications

References 13 publications

Ex Vivo Activity Quantification in Micrometastases at the Cellular Scale Using the α-Camera Technique

Ex Vivo Activity Quantification in Micrometastases at the Cellular Scale Using the α-Camera Technique

Lognormal Distribution of Cellular Uptake of Radioactivity: Statistical Analysis of α-Particle Track Autoradiography

NVP-BEZ235 Enhances Radiosensitivity of Human Prostate Cancer Cells but Acts as a Radioprotector to Normal Prostate Cells

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