Comparison of 225actinium chelates: tissue distribution and radiotoxicity

Davis, Ila A.; Glowienka, Kirsten A; Boll, R. A.; Deal, Kim A.; Brechbiel, Martin W.; Stabin, Michael G.; Bochsler, Philip N.; Mirzadeh, Saed; Kennel, Stephen J.

doi:10.1016/s0969-8051(99)00024-4

Cited by 83 publications

(94 citation statements)

References 13 publications

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“…The use of 212 Bi-antiTac monoclonal antibody resulted in marrow toxicity (42). Studies with 225 Ac showed that a dose of 1 Ci resulted in a wasting syndrome with marrow ablation, splenic atrophy, and some gastrointestinal toxicity (49,50).…”

mentioning

confidence: 99%

Pretargeted α Emitting Radioimmunotherapy Using 213Bi 1,4,7,10-Tetraazacyclododecane-N,N′,N″,N‴-Tetraacetic Acid-Biotin

Yao¹,

Zhang²,

Garmestani³

et al. 2004

Clinical Cancer Research

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Purpose: The use of an ␣ emitter for radioimmunotherapy has potential advantages compared with ␤ emitters. When administered systemically optimal targeting of intact antibodies requires >24 h, therefore limiting the use of shortlived ␣ emitters. This study investigated the biodistribution of bismuth-labeled biotin in A431 tumor-bearing mice pretargeted with antibody B3-streptavidin (B3-SA) and examined the therapeutic efficacy of the ␣ emitter, 213Bi-labeled biotin. Experimental Design: Biotinidase-resistant 7,10-tetraazacyclododecane-N,N,N؆,Nٟ-tetraacetic acid (DOTA)-biotin was radiolabeled with 205,206 Bi or 213 Bi. Treatment of tumor-bearing mice began by administration of B3-SA (400 g) to target the tumor sites for 24 h. Then, an agent containing biotin and galactose groups was used to clear the conjugate from the circulation. Four h later, bismuth-radiolabeled DOTA-biotin was given, and biodistribution or therapy was evaluated. Dose escalation treatment from 3.7-74 MBq was performed, and the effects on tumors of different sizes were investigated. Tumor growth, complete blood cell counts, toxicity, and survival were monitored.Results: Radiolabeled biotin cleared rapidly. Rapid tumor uptake resulted in much higher tumor:nontumor targeting ratios than achieved with the directly labeled monoclonal antibody. Dose escalation revealed that 74 MBq caused acute death of mice, whereas 0.37-37 MBq doses inhibited tumor growth and prolonged survival significantly. Evidence of mild hematological toxicity was noted.At therapeutically effective doses renal toxicity was observed. Conclusions:213 Bi-DOTA-biotin, directed by the Pretarget method to tumor-targeted B3-SA, showed a therapeutic effect, although the therapeutic index was low. The source of the toxicity was most likely related to the renal toxicity.

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mentioning

confidence: 99%

Pretargeted α Emitting Radioimmunotherapy Using 213Bi 1,4,7,10-Tetraazacyclododecane-N,N′,N″,N‴-Tetraacetic Acid-Biotin

Yao¹,

Zhang²,

Garmestani³

et al. 2004

Clinical Cancer Research

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“…Th has been linked by p-benzyl-DOTA to rituximab. The resulting compound is stable, with a similar retention time and immunoreactivity to unlabeled rituximab [30]. Compared to free thorium, 227 Th-p-nitrobenzyl-DOTA had a lower uptake and increased clearance in all organs studied except for the large intestines.…”

Section: Targeted Radioimmunotherapymentioning

confidence: 93%

“…It has 10 days half life and may have more potent effects on cancer cells as compared to 213 Bi [27,28]. In order to optimize the therapeutic potential this molecule has been linked to antibodies to allow specific cell targeting but even with the most attempts to deliver a stable internalization, a significant release of alpha emitting daughters was encountered causing toxicity with radiation nephropathy being a particular issue [28][29][30]. Radon, a gaseous product that would pose a serious challenge to control in vivo [31,32].…”

Section: Terbium (Tb)mentioning

confidence: 99%

“…Further investigation into other potential chelators revealed 1,4,7,10,13,16-Hexaazocyclooctadecane-N,N',N'',N''',N'''',N'''''-Hexaacetic Acid, (HEHA) to be a stable carrier of 225 Ac, which also allowed for the most rapid clearance and lowest accumulation within the liver, bone, kidneys and heart [46]. HEHA has been synthesized, radiolabeled to 225 Ac, and conjugated to three different monoclonal antibodies with reasonable yields thus providing a reasonable approach to targeted alpha particles via radioimmunotherapy [30]. Th has been linked by p-benzyl-DOTA to rituximab.…”

Section: Targeted Radioimmunotherapymentioning

confidence: 99%

“…Compared to free thorium, 227 Th-p-nitrobenzyl-DOTA had a lower uptake and increased clearance in all organs studied except for the large intestines. Free thorium deposits predominantly in bone, and the uptake in the bone of 227 Th-p-nitrobenzyl-DOTA has been demonstrated to be seven times lower than that of free thorium [30]. Subsequent efforts have also succeeded in creating a similar radioimmunoconjugate by binding 227 Th to trastuzumab via p-iso-thiocyanato-benzyl-DOTA [29,[47][48][49].…”

Section: Targeted Radioimmunotherapymentioning

confidence: 99%

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