Importance of receptor density in alpha radioimmunotherapy in B cell malignancies: an in-vitro study

Vandenbulcke, Katia; Thierens, Hubert; Offner, Fritz; Janssens, Ann; Gelder, Virginie de; Bacher, Klaus; Philippé, Jan; Vos, Filip De; Dierckx, Rudi; Apostolidis, Christos; Morgenstern, Alfred; Slegers, Guido

doi:10.1097/00006231-200411000-00011

Cited by 8 publications

(5 citation statements)

References 23 publications

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“…In the current study, significant (P < 0.0001) induction of apoptosis as assessed by DNA fragmentation was observed after treatment with 213 Bi-hu3S193 and was most apparent following 72-h incubation. These results agree with several other studies assessing a-particle radioimmunotherapy in lymphoma and prostate cancers, where treatment was shown to induce cellular apoptosis (12,44). Phosphorylation of histone H2AX (g-H2AX) is known to occur in response to double-stranded DNA breaks and was assessed via immunoblotting (28).…”

Section: Discussionsupporting

confidence: 90%

“…It is thought that high linear energy transfer radiation from a-emitter radiation results in irreparable double-stranded DNA breaks and severe chromosomal damage leading to the rapid and irreversible induction of apoptosis and cell death (8,12,43). In the current study, significant (P < 0.0001) induction of apoptosis as assessed by DNA fragmentation was observed after treatment with 213 Bi-hu3S193 and was most apparent following 72-h incubation.…”

Section: Discussionmentioning

confidence: 99%

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Radioimmunotherapy with α-Particle–Emitting 213Bi-C-Functionalized trans-Cyclohexyl-Diethylenetriaminepentaacetic Acid-Humanized 3S193 Is Enhanced by Combination with Paclitaxel Chemotherapy

Kelly

Lee

Tahtis

et al. 2007

Clinical Cancer Research

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Purpose: Previous experience in solid tumor radioimmunotherapy studies has indicated that greatest therapeutic efficacy is achieved in the treatment of small-volume disease. a-Particleê mitting radioisotopes possess several physical characteristics ideally suited to the treatment of minimal residual disease. Therefore, we have investigated the efficacy of the a-particle^emitting bismuth-213 ( Bi-hu3S193 causes specific and significant retardation of tumor growth even in established tumors, and efficacy was enhanced by paclitaxel to produce defined complete responses. Conclusions: These studies show the potency of a-particle radioimmunotherapy and warrant its further exploration in the treatment of micrometastatic disease in Le y -positive malignancies.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Radioimmunotherapy with α-Particle–Emitting 213Bi-C-Functionalized trans-Cyclohexyl-Diethylenetriaminepentaacetic Acid-Humanized 3S193 Is Enhanced by Combination with Paclitaxel Chemotherapy

Kelly

Lee

Tahtis

et al. 2007

Clinical Cancer Research

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“…Several studies have shown the successful use of high-LET a-emitters for targeted radionuclide therapy, suggesting their superiority over low-LET h-emitters in the treatment of solid tumors (21,22). In this study, we aim to evaluate the quantitative radiolabeling methods, stability, biodistribution, safety, and therapeutic efficacy of 213 Bi labeled to DOTATOC in the treatment of somatostatin receptor -expressing pancreatic tumors.…”

Section: Discussionmentioning

confidence: 99%

213Bi-[DOTA0, Tyr3]Octreotide Peptide Receptor Radionuclide Therapy of Pancreatic Tumors in a Preclinical Animal Model

Norenberg¹,

Krenning

Konings

et al. 2006

Clinical Cancer Research

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Bi-DOTATOC (specific activity 7.4 MBq/Ag) were investigated. Biodistribution studies to determine somatostatin receptor specificity were done in Lewis rats at 1and 3 hours postinjection. Histopathology of various organs was used to evaluated toxicity and safety. Therapeutic efficacy of 4 to 22 MBq Bi-DOTATOC showed significantly greater tumor reduction when compared with animals receiving <11MBq (P < 0.02). Conclusions:213 Bi-DOTATOC showed dose-related antitumor effects with minimal treatmentrelated organ toxicity. No acute or chronic hematologic toxicities were observed. Mild, acute nephrotoxicity was observed without evidence of chronic toxicity. 213Bi-DOTATOC is a promising therapeutic radiopharmaceutical for further evaluation.

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“…These data are in line with previously published studies. Vandenbulcke [ 28 ] could show that [Bi-213]anti-CD20 induced significantly higher cell death rates in cells to which the antibody had a higher binding capacity. In a second study [ 27 ], they demonstrated that [Bi-213]anti-CD20 killed chronic lymphatic leukaemia cells more effectively than external gamma-irradiation underlining the importance of this novel therapeutic approach [ 27 ].…”

Section: Discussionmentioning

confidence: 99%

Targeted alpha-therapy using [Bi-213]anti-CD20 as novel treatment option for radio- and chemoresistant non-Hodgkin lymphoma cells

et al. 2013

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Radioimmunotherapy (RIT) is an emerging treatment option for non-Hodgkin lymphoma (NHL) producing higher overall response and complete remission rates compared with unlabelled antibodies. However, the majority of patients treated with conventional or myeloablative doses of radiolabelled antibodies relapse. The development of RIT with alpha-emitters is attractive for a variety of cancers because of the high linear energy transfer (LET) and short path length of alpha-radiation in human tissue, allowing higher tumour cell kill and lower toxicity to healthy tissues. In this study, we investigated the molecular effects of the alpha-emitter Bi-213 labelled to anti-CD20 antibodies ([Bi-213]anti-CD20) on cell cycle and cell death in sensitive and radio-/chemoresistant NHL cells. [Bi-213]anti-CD20 induced apoptosis, activated caspase-3, caspase-2 and caspase-9 and cleaved PARP specifically in CD20-expressing sensitive as well as in chemoresistant, beta-radiation resistant and gamma-radiation resistant NHL cells. CD20 negative cells were not affected by [Bi-213]anti-CD20 and unspecific antibodies labelled with Bi-213 could not kill NHL cells. Breaking radio-/chemoresistance in NHL cells using [Bi-213]anti-CD20 depends on caspase activation as demonstrated by complete inhibition of [Bi-213]anti-CD20-induced apoptosis with zVAD.fmk, a specific inhibitor of caspases activation. This suggests that deficient activation of caspases was reversed in radioresistant NHL cells using [Bi-213]anti-CD20. Activation of mitochondria, resulting in caspase-9 activation was restored and downregulation of Bcl-xL and XIAP, death-inhibiting proteins, was found after [Bi-213]anti-CD20 treatment in radio-/chemosensitive and radio-/chemoresistant NHL cells. [Bi-213]anti-CD20 seems to be a promising radioimmunoconjugate to improve therapeutic success by breaking radio- and chemoresistance selectively in CD20-expressing NHL cells via re-activating apoptotic pathways through reversing deficient activation of caspases and the mitochondrial pathway and downregulation of XIAP and Bcl-xL.

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Importance of receptor density in alpha radioimmunotherapy in B cell malignancies: an in-vitro study

Cited by 8 publications

References 23 publications

Radioimmunotherapy with α-Particle–Emitting 213Bi-C-Functionalized trans-Cyclohexyl-Diethylenetriaminepentaacetic Acid-Humanized 3S193 Is Enhanced by Combination with Paclitaxel Chemotherapy

Radioimmunotherapy with α-Particle–Emitting 213Bi-C-Functionalized trans-Cyclohexyl-Diethylenetriaminepentaacetic Acid-Humanized 3S193 Is Enhanced by Combination with Paclitaxel Chemotherapy

213Bi-[DOTA0, Tyr3]Octreotide Peptide Receptor Radionuclide Therapy of Pancreatic Tumors in a Preclinical Animal Model

Targeted alpha-therapy using [Bi-213]anti-CD20 as novel treatment option for radio- and chemoresistant non-Hodgkin lymphoma cells

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