Radiotargeting agents for cancer therapy

Kassis, Amin I.

doi:10.1517/17425247.2.6.981

Cited by 19 publications

(16 citation statements)

References 33 publications

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“…We previously showed that, in vitro, noninternalizing 125 I-mAbs were more harmful than internalizing ones. Although the strongest toxicity of 125 I is observed when the isotope is incorporated within the DNA molecule (17,23,24), these results suggest that the cell membrane also is a sensitive target (25). Here, we investigated the efficacy of noninternalizing and internalizing 125 I-mAbs in the treatment of mice with tumor cell xenografts.…”

mentioning

confidence: 99%

Noninternalizing Monoclonal Antibodies Are Suitable Candidates for ¹²⁵I Radioimmunotherapy of Small-Volume Peritoneal Carcinomatosis

Santoro¹,

Boutaleb²,

Garambois³

et al. 2009

J Nucl Med

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We have previously shown that, in vitro, monoclonal antibodies (mAbs) labeled with the Auger electron emitter 125 I are more cytotoxic if they remain at the cell surface and do not internalize in the cytoplasm. Here, we assessed the in vivo biologic efficiency of internalizing and noninternalizing 125 I-labeled mAbs for the treatment of small solid tumors. Methods: Swiss nude mice bearing intraperitoneal tumor cell xenografts were injected with 37 MBq (370 MBq/mg) of internalizing (anti-HER1) 125 I-m225 or noninternalizing (anti-CEA) 125 I-35A7 mAbs at days 4 and 7 after tumor cell grafting. Nonspecific toxicity was assessed using the irrelevant 125 I-PX mAb, and untreated controls were injected with NaCl. Tumor growth was followed by bioluminescence imaging. Mice were sacrificed when the bioluminescence signal reached 4.5 · 10 7 photons/s. Biodistribution analysis was performed to determine the activity contained in healthy organs and tumor nodules, and total cumulative decays were calculated. These values were used to calculate the irradiation dose by the MIRD formalism. Results: Median survival (MS) was 19 d in the NaCltreated group. Similar values were obtained in mice treated with unlabeled PX (MS, 24 d) and 35A7 (MS, 24 d) or with 125 I-PX mAbs (MS, 17 d). Conversely, mice treated with unlabeled or labeled internalizing m225 mAb (MS, 76 and 77 d, respectively) and mice injected with 125 I-35A7 mAb (MS, 59 d) showed a significant increase in survival. Irradiation doses were comparable in all healthy organs, independently from the mAb used, whereas in tumors the irradiation dose was 7.4-fold higher with 125 I-labeled noninternalizing than with internalizing mAbs. This discrepancy might be due to iodotyrosine moiety release occurring during the catabolism of internalizing mAbs associated with high turnover rate. Conclusion: This study indicates that 125 I-labeled noninternalizing mAbs could be suitable for radioimmunotherapy of small solid tumors and that the use of internalizing mAbs should not be considered as a requirement for the success of treatments with 125 I Auger electrons.

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confidence: 99%

Noninternalizing Monoclonal Antibodies Are Suitable Candidates for ¹²⁵I Radioimmunotherapy of Small-Volume Peritoneal Carcinomatosis

Santoro¹,

Boutaleb²,

Garambois³

et al. 2009

J Nucl Med

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“…These findings reiterate the importance of matching the physical half-life of an isotope with that of the carrier molecule. 36 Tumor environment is yet another factor to be considered. A tumor is usually surrounded by or adjacent to normal tissue with normal vasculature.…”

Section: Discussionmentioning

confidence: 99%

Solid‐tumor radionuclide therapy dosimetry: New paradigms in view of tumor microenvironment and angiogenesis

et al. 2010

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Purpose: The objective of this study is to evaluate requirements for radionuclide-based solid tumor therapy by assessing the radial dose distribution of beta-particle-emitting and alpha-particleemitting molecules localized either solely within endothelial cells of tumor vasculature or diffusing from the vasculature throughout the adjacent viable tumor cells. Methods: Tumor blood vessels were modeled as a group of microcylindrical layers comprising endothelial cells ͑one-cell thick, 10 m diameter͒, viable tumor cells ͑25-cell thick, 250 m radius͒, and necrotic tumor region ͑Ͼ250 m from any blood vessel͒. Sources of radioactivity were assumed to distribute uniformly in either endothelial cells or in concentric cylindrical 10 m shells within the viable tumor-cell region. The EGSnrc Monte Carlo simulation code system was used for beta particle dosimetry and a dose-point kernel method for alpha particle dosimetry. The radioactive decays required to deposit cytocidal doses ͑Ն100 Gy͒ in the vascular endothelial cells ͑endothelial cell mean dose͒ or, alternatively, at the tumor edge ͓tumor-edge mean dose ͑TEMD͔͒ of adjacent viable tumor cells were then determined for six beta ͑ 32 P, 33 Re can be effective even when the radionuclide is confined to the blood vessel ͑i.e., no diffusion into the tumor͒. Furthermore, the increase in tumor-edge dose consequent to beta emitter diffusion is dependent on the energy of the emitted beta particles, being much greater for lower-energy emitters 131 I, 67 Cu, and 33 P relative to higher-energy emitters 90 Y, 32 P, and 188 Re. Compared to alpha particle emitters, a ϳ150-400 times higher number of beta-particle-emitting radioactive atoms is required to deposit the same dose in tumor neovasculature. However, for the alpha particle emitters 211 At and 213 Bi to be effective in irradiating viable tumor-cell regions in addition to the vasculature, the carrier molecules must diffuse substantially from the vasculature into the viable tumor. Conclusion: The presented data enable comparison of radionuclides used for antiangiogenic therapy on the basis of their radioactive decay properties, tumor neovasculature geometry, and tumor-cell viability. For alpha particle emitters or low-energy beta particle emitters, the targeting carrier molecule should be chosen to permit the radiopharmaceutical to diffuse from the endothelial wall of the blood vessel, while for long-range energetic beta particle emitters that target neovasculature, a radiopharmaceutical that binds to newly formed endothelial cells and does not diffuse is preferable. The work is a first approximation to modeling of tumor neovasculature that ignores factors such as pharmacokinetics and targeting capability of carrier molecules. The calculations quantify the interplay between irradiation of neovasculature, the surrounding viable tumor cells, and the physical properties of commonly used radionuclides and can be used to assist estimation of radioactivity to be administered for neovasculature-targeted tumor therapy.

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“…[14] Every treatment using external radiation therapy has to be rigorously planned. The planning process consists of three phases: 1.…”

Section: External Radiation Therapymentioning

confidence: 99%

External and internal radiation therapy: Past and future directions

2010

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Cancer is a leading cause of morbidity and mortality in the modern world. Treatment modalities comprise radiation therapy, surgery, chemotherapy and hormonal therapy. Radiation therapy can be performed by using external or internal radiation therapy. However, each method has its unique properties which undertakes special role in cancer treatment, this question is brought up that: For cancer treatment, whether external radiation therapy is more efficient or internal radiation therapy one? To answer this question, we need to consider principles and structure of individual methods. In this review, principles and application of each method are considered and finally these two methods are compared with each other.

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Radiotargeting agents for cancer therapy

Cited by 19 publications

References 33 publications

Noninternalizing Monoclonal Antibodies Are Suitable Candidates for ¹²⁵I Radioimmunotherapy of Small-Volume Peritoneal Carcinomatosis

Noninternalizing Monoclonal Antibodies Are Suitable Candidates for ¹²⁵I Radioimmunotherapy of Small-Volume Peritoneal Carcinomatosis

Solid‐tumor radionuclide therapy dosimetry: New paradigms in view of tumor microenvironment and angiogenesis

External and internal radiation therapy: Past and future directions

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Radiotargeting agents for cancer therapy

Cited by 19 publications

References 33 publications

Noninternalizing Monoclonal Antibodies Are Suitable Candidates for 125I Radioimmunotherapy of Small-Volume Peritoneal Carcinomatosis

Noninternalizing Monoclonal Antibodies Are Suitable Candidates for 125I Radioimmunotherapy of Small-Volume Peritoneal Carcinomatosis

Solid‐tumor radionuclide therapy dosimetry: New paradigms in view of tumor microenvironment and angiogenesis

External and internal radiation therapy: Past and future directions

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Noninternalizing Monoclonal Antibodies Are Suitable Candidates for ¹²⁵I Radioimmunotherapy of Small-Volume Peritoneal Carcinomatosis

Noninternalizing Monoclonal Antibodies Are Suitable Candidates for ¹²⁵I Radioimmunotherapy of Small-Volume Peritoneal Carcinomatosis