Buchsbaum Donald J, Khazaeli M B, Axworthy Donald B, Schultz Jody, Chaudhuri Tandra R, Zinn Kurt R, Carpenter Mark, LoBuglio Albert F
Department of Radiation Oncology, University of Alabama at Birmingham, Alabama 35294-6832, USA.
Clin Cancer Res. 2005 Nov 15;11(22):8180-5. doi: 10.1158/1078-0432.CCR-05-0607.
This study examined a pretarget radioimmunotherapy strategy for treatment of an i.p. tumor model (LS174T).
The strategy used regional administration (i.p.) of a novel targeting molecule composed of four CC49 anti-tumor-associated glycoprotein 72 (TAG-72) single-chain antibodies linked to streptavidin as a fusion protein (CC49 fusion protein); 24 hours later, a synthetic clearing agent was administered i.v. to produce hepatic clearance of unbound CC49 fusion protein/synthetic clearing agent complexes. Four hours later, a low molecular weight radiolabeled reagent composed of biotin conjugated to the chelating agent 7,10-tetra-azacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA) complexed with (111)In-, (90)Y-, or (177)Lu-DOTA-biotin was injected.
Radiolocalization to tumor sites was superior with i.p. administration of radiolabeled DOTA-biotin as compared with i.v. administration. Imaging and biodistribution studies showed excellent tumor localization of radioactivity with (111)In- or (177)Lu-DOTA-biotin. Tumor localization of (111)In-DOTA-biotin was 43% ID/g and 44% ID/g at 4 and 24 hours with the highest normal tissue localization in the kidney with 6% ID/g at 48 and 72 hours. Therapy studies with (90)Y-DOTA-biotin at doses of 400 to 600 microCi or (177)Lu-DOTA-biotin at doses of 600 to 800 microCi produced significant prolongation of survival compared with controls (P = 0.03 and P < 0.01).
Pretarget radioimmunotherapy using regional administration of CC49 fusion protein and i.p. (90)Y- or (177)Lu-DOTA-biotin represents a successful therapeutic strategy in the LS174T i.p. tumor model and this strategy may be applicable to human trials in patients with i.p. ovarian cancer.
本研究考察了一种预靶向放射免疫治疗策略用于治疗腹腔肿瘤模型（LS174T）。
该策略采用区域给药（腹腔内）一种新型靶向分子，其由四个与链霉亲和素连接的CC49抗肿瘤相关糖蛋白72（TAG - 72）单链抗体组成的融合蛋白（CC49融合蛋白）；24小时后，静脉注射一种合成清除剂以清除未结合的CC49融合蛋白/合成清除剂复合物。4小时后，注射一种低分子量放射性标记试剂，其由与螯合剂7,10 - 四氮杂环十二烷 - N,N',N'',N'''-四乙酸（DOTA）共轭的生物素与（111）In -、（90）Y - 或（177）Lu - DOTA - 生物素络合而成。
与静脉注射相比，腹腔内注射放射性标记的DOTA - 生物素时肿瘤部位的放射性定位更佳。成像和生物分布研究显示（111）In - 或（177）Lu - DOTA - 生物素在肿瘤部位有良好的放射性定位。（111）In - DOTA - 生物素在4小时和24小时时肿瘤定位分别为43% ID/g和44% ID/g，在48小时和72小时时正常组织中定位最高的是肾脏，为6% ID/g。用剂量为400至600微居里的（90）Y - DOTA - 生物素或剂量为600至800微居里的（177）Lu - DOTA - 生物素进行治疗研究，与对照组相比显著延长了生存期（P = 0.03和P < 0.01）。
使用区域给药CC49融合蛋白和腹腔内注射（90）Y - 或（177）Lu - DOTA - 生物素的预靶向放射免疫治疗在LS174T腹腔肿瘤模型中是一种成功的治疗策略，并且该策略可能适用于腹腔卵巢癌患者的人体试验。
