Pretargeted alpha emitting radioimmunotherapy using (213)Bi 1,4,7,10-tetraazacyclododecane-N,N',N",N"'-tetraacetic acid-biotin.

Autor:	Yao Z; Department of Nuclear Medicine, Warren G. Magnuson Clinical Center, NIH, Bethesda, Maryland 20892, USA., Zhang M, Garmestani K, Axworthy DB, Mallett RW, Fritzberg AR, Theodore LJ, Plascjak PS, Eckelman WC, Waldmann TA, Pastan I, Paik CH, Brechbiel MW, Carrasquillo JA
Jazyk:	angličtina
Zdroj:	Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2004 May 01; Vol. 10 (9), pp. 3137-46.
DOI:	10.1158/1078-0432.ccr-03-0171
Abstrakt:	Purpose: The use of an alpha emitter for radioimmunotherapy has potential advantages compared with beta emitters. When administered systemically optimal targeting of intact antibodies requires >24 h, therefore limiting the use of short-lived alpha 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 alpha emitter, (213)Bi-labeled biotin. Experimental Design: Biotinidase-resistant 7,10-tetraazacyclododecane-N,N',N",N"'-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 micro 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.
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu