APOMAB, a La-specific monoclonal antibody, detects the apoptotic tumor response to life-prolonging and DNA-damaging chemotherapy.
APOMAB, a La-specific monoclonal antibody, detects the apoptotic tumor response to life-prolonging and DNA-damaging chemotherapy.
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DOI：
10.1371/journal.pone.0004558
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发表时间：
2009
期刊：
影响因子：
3.7
通讯作者：
Brown MP
中科院分区：
文献类型：
--
作者：
Al-Ejeh F;Darby JM;Tsopelas C;Smyth D;Manavis J;Brown MP
抗肿瘤治疗可能会损害恶性细胞的存活，导致细胞死亡。因此，体内肿瘤细胞死亡的直接测量是治疗反应监测的高度期望的组成部分。我们之前已经证明，代表La/SSB特异性鼠单克隆自身抗体的DAB 4克隆的APOMAB®是一种恶性细胞死亡配体，其在DNA损伤化疗后以抗原特异性和剂量依赖性方式优先在肿瘤中积累。在这里，我们的目标是对APOMAB®（DAB 4）的肿瘤摄取进行成像，并确定其生物学相关性。DNA损伤性环磷酰胺/依托泊苷化疗荷瘤小鼠后，在同基因EL 4淋巴瘤模型中诱导了快速的肿瘤细胞凋亡。在荷瘤小鼠中，通过全身静态成像和器官测定来定量铟111（111 In）标记的La特异性DAB 4 mAb作为完整IgG或IgG片段的肿瘤和正常器官蓄积。肿瘤半胱天冬酶-3活化和PARP-1裂解的免疫组织化学测量结果（分别为早期和晚期凋亡的指标）与肿瘤中DAB 4的积累相关。增加的肿瘤蓄积的DAB 4与化疗诱导的肿瘤细胞死亡的程度和每个死亡肿瘤细胞的DAB 4结合直接相关。肿瘤DAB 4蓄积与作为细胞凋亡肿瘤生物标志物的累积半胱天冬酶-3活化和PARP-1裂解相关，并与荷瘤小鼠的中位生存时间延长直接相关。放射性标记的La特异性单克隆抗体DAB 4检测化疗后死亡的肿瘤细胞，而不是化疗敏感的肠和骨髓正常组织。DAB 4在体内鉴定晚期凋亡肿瘤细胞。因此，放射性标记的DAB 4可以有效地成像对人类癌症治疗的反应，因为DAB 4可以捕获癌症的延长的细胞死亡。我们认为，放射性标记的DAB 4的能力，迅速评估凋亡肿瘤反应，从而有可能预测延长生存证明其未来的临床发展作为一个放射免疫闪烁剂。本文是两部分系列的第一部分，为La特异性单克隆抗体的诊断和治疗用途提供概念验证，其DAB 4克隆由注册商标APOMAB®代表。
Antineoplastic therapy may impair the survival of malignant cells to produce cell death. Consequently, direct measurement of tumor cell death in vivo is a highly desirable component of therapy response monitoring. We have previously shown that APOMAB® representing the DAB4 clone of a La/SSB-specific murine monoclonal autoantibody is a malignant cell-death ligand, which accumulates preferentially in tumors in an antigen-specific and dose-dependent manner after DNA-damaging chemotherapy. Here, we aim to image tumor uptake of APOMAB® (DAB4) and to define its biological correlates. Brisk tumor cell apoptosis is induced in the syngeneic EL4 lymphoma model after treatment of tumor-bearing mice with DNA-damaging cyclophosphamide/etoposide chemotherapy. Tumor and normal organ accumulation of Indium 111 (111In)-labeled La-specific DAB4 mAb as whole IgG or IgG fragments was quantified by whole-body static imaging and organ assay in tumor-bearing mice. Immunohistochemical measurements of tumor caspase-3 activation and PARP-1 cleavage, which are indicators of early and late apoptosis, respectively, were correlated with tumor accumulation of DAB4. Increased tumor accumulation of DAB4 was associated directly with both the extent of chemotherapy-induced tumor cell death and DAB4 binding per dead tumor cell. Tumor DAB4 accumulation correlated with cumulative caspase-3 activation and PARP-1 cleavage as tumor biomarkers of apoptosis and was directly related to the extended median survival time of tumor-bearing mice. Radiolabeled La-specific monoclonal antibody, DAB4, detected dead tumor cells after chemotherapy, rather than chemosensitive normal tissues of gut and bone marrow. DAB4 identified late apoptotic tumor cells in vivo. Hence, radiolabeled DAB4 may usefully image responses to human carcinoma therapy because DAB4 would capture the protracted cell death of carcinoma. We believe that the ability of radiolabeled DAB4 to rapidly assess the apoptotic tumor response and, consequently, to potentially predict extended survival justifies its future clinical development as a radioimmunoscintigraphic agent. This article is part I of a two-part series providing proof-of-concept for the the diagnostic and therapeutic use of a La-specific monoclonal antibody, the DAB4 clone of which is represented by the registered trademark, APOMAB®.
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影响因子：
158.5
作者：
Cristofanilli, M;Budd, GT;Hayes, DF
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78.5
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作者：
Ayukawa, K;Taniguchi, S;Sagara, J
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