Kroger L A, DeNardo G L, Gumerlock P H, Xiong C Y, Winthrop M D, Shi X B, Mack P C, Leshchinsky T, DeNardo S J
Division of Hematology/Oncology, University of California Davis Medical Center, Sacramento, CA, USA.
Cancer Biother Radiopharm. 2001 Jun;16(3):213-25. doi: 10.1089/10849780152389401.
Despite low radiation dose rates, radioimmunotherapy (RIT) has proven particularly effective in the treatment of malignancies, such as lymphoma. Apoptosis has been suggested to be a major mechanism for cell death from continuous low-dose rate radiation from radioimmunotherapy. The goal of this study was to examine Raji lymphoma xenografts for induction of apoptosis and modulation of apoptosis-related gene and protein expression in response to 67Cu-2IT-BAT-Lym-1 RIT. In preclinical and clinical trials, 67Cu-2IT-BAT-Lym-1 has shown an exceptionally long tumor residence time associated with substantial cumulated radiation doses. The Raji model mirrors human lymphomas that have mutant p53 and increased BCL2 expression. Untreated athymic BALB/c nu/nu mice and mice treated with 400 micrograms Lym-1, or 335-500 microCi 67Cu on less than 400 micrograms Lym-1 antibody, were observed for toxicity and response over 84 days. Subgroups of 4-5 mice were sacrificed at 3, 6 and 24 h after therapy so that tumors could be examined for poly(ADP-ribose) polymerase (PARP) and DNA ladder evidence for apoptosis and for BCL2, p53, p21, GADD45, TGF-beta 1 and c-MYC gene and protein expression. Untreated tumors had little evidence of apoptosis and Lym-1 had no effect on apoptosis or gene expression. 67Cu-2IT-BAT-Lym-1 RIT induced an overall response rate of 50% with tolerable toxicity, and 29% of the tumors were cured at cumulated tumor radiation doses of about 1800 cGy. Apoptosis was greatly increased in the RIT treated Raji xenografts as evidenced by cleavage of PARP to the characteristic 85 kD fragment at 3 and 6 h and by the DNA cleavage pattern. BCL2 gene and protein expression were substantially decreased at 3 and 24 h, respectively, after 67Cu-2IT-BAT-Lym-1 RIT despite only modest cumulated radiation doses (56 cGy at 3 h). Evidence for apoptosis preceded tumor regression by 4-6 days. In these therapy-resistant, human lymphoma tumors treated with 67Cu-2IT-BAT-Lym-1, apoptosis was convincingly demonstrated to be a major mechanism for the effectiveness of RIT and occurred by p53-independent mechanisms.
尽管放射免疫疗法（RIT）的辐射剂量率较低，但已证明其在治疗恶性肿瘤（如淋巴瘤）方面特别有效。细胞凋亡被认为是放射免疫疗法持续低剂量率辐射导致细胞死亡的主要机制。本研究的目的是检测Raji淋巴瘤异种移植瘤在接受67Cu-2IT-BAT-Lym-1放射免疫疗法后凋亡的诱导情况以及凋亡相关基因和蛋白表达的调节情况。在临床前和临床试验中，67Cu-2IT-BAT-Lym-1显示出异常长的肿瘤滞留时间，并伴有大量累积辐射剂量。Raji模型反映了具有p53突变和BCL2表达增加的人类淋巴瘤。观察未治疗的无胸腺BALB/c nu/nu小鼠以及用400微克Lym-1或小于400微克Lym-1抗体联合335 - 500微居里67Cu治疗的小鼠在84天内的毒性和反应。在治疗后3、6和24小时处死4 - 5只小鼠的亚组，以便检查肿瘤中聚（ADP - 核糖）聚合酶（PARP）和DNA梯状条带以证明凋亡，以及检查BCL2、p53、p21、GADD45、TGF - β1和c - MYC基因及蛋白表达。未治疗的肿瘤几乎没有凋亡证据，Lym-1对凋亡或基因表达没有影响。67Cu-2IT-BAT-Lym-1放射免疫疗法诱导的总体反应率为50%，毒性可耐受，在累积肿瘤辐射剂量约为1800 cGy时，29%的肿瘤被治愈。在接受放射免疫疗法治疗的Raji异种移植瘤中，凋亡显著增加，这通过PARP在3和6小时裂解为特征性的85 kD片段以及DNA裂解模式得以证明。在67Cu-2IT-BAT-Lym-1放射免疫疗法后3和24小时，BCL2基因和蛋白表达分别大幅下降，尽管累积辐射剂量仅适度（3小时时为56 cGy）。凋亡证据比肿瘤消退提前4 - 6天出现。在这些用67Cu-2IT-BAT-Lym-1治疗的耐药人类淋巴瘤肿瘤中，令人信服地证明细胞凋亡是放射免疫疗法有效性的主要机制，并且通过p53非依赖机制发生。
Cancer Biother Radiopharm. 1998-10
Oncol Lett. 2017-1
World J Gastroenterol. 2015-1-7
Adv Urol. 2012
Biomed Imaging Interv J. 2006-7
Semin Nucl Med. 2011-1
Zotero 插件