Vallabhajosula Shankar, Smith-Jones Peter M, Navarro Vincent, Goldsmith Stanley J, Bander Neil H
Department of Radiology, New York Presbyterian Hospital, Weill Medical College of Cornell University, New York, New York 10021, USA.
Prostate. 2004 Feb 1;58(2):145-55. doi: 10.1002/pros.10281.
Prostate specific membrane antigen (PSMA), expressed by virtually all prostate cancers is an ideal target for targeted therapy of prostate cancer. Radiolabeled J591 monoclonal antibody (MAb) binds with high affinity to an extracellular epitope of PSMA and localizes specifically in PSMA positive LNCaP tumors in vivo.
Pre-clinical radioimmunotherapy (RIT) studies using (131)I-huJ591 and (90)Y-1,4,7,10-tetraazacyclododecane-N,N',N",N"'-tetraacetic acid (DOTA)-huJ591 MAbs were studied in nude mice bearing LNCaP xenografts.
A 15-90% reduction in mean tumor volume was observed after a single dose of (131)I-huJ591 (3.7-11.1 MBq) or (90)Y-DOTA-huJ591 (3.7-7.4 MBq). The median survival time increased 2-3 times relative to untreated controls. Multiple administrations of fractionated doses of (90)Y-DOTA-huJ591 were even more effective with minimal toxicity. Radiation dose to blood and tumor was higher with (90)Y than with (131)I. The maximum tolerated dose (MTD) is 5.55 MBq for (90)Y-DOTA-huJ591 and more than 11.1 MBq for (131)I-huJ591. For (90)Y-DOTA-huJ591 at MTD, dose to the tumor was 2,753 cGy.
In nude mice bearing PSMA positive tumors, radiation dose to the tumor with (90)Y-DOTA-J591 is greater for large tumors than with (131)I-J591. The theoretical and practical considerations strongly suggest that (90)Y-DOTA-huJ591 may be a suitable radiopharmaceutical for the treatment of prostate cancer.
几乎所有前列腺癌都表达前列腺特异性膜抗原（PSMA），它是前列腺癌靶向治疗的理想靶点。放射性标记的J591单克隆抗体（MAb）与PSMA的细胞外表位具有高亲和力结合，并在体内特异性定位于PSMA阳性的LNCaP肿瘤。
使用（131）I-huJ591和（90）Y-1,4,7,10-四氮杂环十二烷-N,N',N",N"'-四乙酸（DOTA）-huJ591单克隆抗体在携带LNCaP异种移植瘤的裸鼠中进行临床前放射免疫治疗（RIT）研究。
单次给予（131）I-huJ591（3.7-11.1 MBq）或（90）Y-DOTA-huJ591（3.7-7.4 MBq）后，观察到平均肿瘤体积减少了15%-90%。中位生存时间相对于未治疗的对照组增加了2-3倍。多次给予分次剂量的（90）Y-DOTA-huJ591甚至更有效，且毒性最小。（90）Y对血液和肿瘤的辐射剂量高于（131）I。（90）Y-DOTA-huJ591的最大耐受剂量（MTD）为5.55 MBq，（131）I-huJ591的最大耐受剂量超过11.1 MBq。对于处于MTD的（90）Y-DOTA-huJ591，肿瘤剂量为2753 cGy。
在携带PSMA阳性肿瘤的裸鼠中对于大肿瘤，（90）Y-DOTA-J591对肿瘤的辐射剂量大于（131）I-J591。理论和实际考虑强烈表明，（90）Y-DOTA-huJ591可能是一种适合治疗前列腺癌的放射性药物。
