Engler S, Thiel C, Förster K, David K, Bredehorst R, Juhl H
Clinic for General and Thoracic Surgery, Christian-Albrechts University, Kiel, Germany.
Cancer Res. 2001 Apr 1;61(7):2968-73.
Neuroblastoma (NB), the most common extracranial solid tumor in childhood is associated with poor prognosis in patients with advanced tumor stages. Natural human cytotoxic anti-NB IgM antibodies present in the serum of healthy humans are discussed as a potential novel immunotherapeutic regimen against human NB because these antibodies have been shown to affect growth arrest of solid s.c. xenografts of human NB in nude rats. Subcutaneously induced tumors, however, exhibit a different growth pattern compared with the typical growth pattern of NB tumors in humans. Therefore, we developed in this study a novel metastatic tumor model in nude rats that reflects the clinical appearance of human NB and used this model to study the therapeutic efficacy of human anti-NB IgM. Intra-aortal injection of human NB cells in nude rats resulted in the development of large invasive adrenal gland tumors and micrometastases in the liver and bones. Apparently, adrenal glands provide most favorable growth conditions for human NB cells, as documented by the preferential and rapid growth of NB cells in this location. We studied three different treatment protocols of natural human anti-NB IgM. Anti-NB IgM completely inhibited tumor formation and metastases when injected simultaneously with human LAN-1 NB cells (P < 0.05). When antibody treatment was started 6 days after tumor cell injection (i.e., micrometastatic stage), tumor growth was inhibited by 90% (P < 0.05). An anti-NB IgM therapy directed against established tumors (14 days after tumor cell injection) shrank adrenal gland tumors by 90% (P < 0.05). Analysis of the tumors revealed both complement activation and an induction of apoptosis as two independent mechanisms of antitumor function. This study strongly suggests human anti-NB IgM antibodies as new agents for the therapy of neuroblastoma.
神经母细胞瘤(NB)是儿童期最常见的颅外实体瘤,晚期肿瘤患者预后较差。健康人血清中存在的天然人细胞毒性抗NB IgM抗体被认为是一种潜在的新型抗人NB免疫治疗方案,因为这些抗体已被证明可影响裸鼠体内人NB皮下实体异种移植物的生长停滞。然而,皮下诱导的肿瘤与人类NB肿瘤的典型生长模式相比表现出不同的生长模式。因此,我们在本研究中建立了一种反映人类NB临床表现的裸鼠新型转移瘤模型,并使用该模型研究人抗NB IgM的治疗效果。在裸鼠主动脉内注射人NB细胞导致大的侵袭性肾上腺肿瘤以及肝脏和骨骼中的微转移灶形成。显然,肾上腺为人类NB细胞提供了最有利的生长条件,这一点已被NB细胞在该部位的优先快速生长所证实。我们研究了天然人抗NB IgM的三种不同治疗方案。当与人LAN-1 NB细胞同时注射时,抗NB IgM完全抑制了肿瘤形成和转移(P<0.05)。当在肿瘤细胞注射后6天(即微转移阶段)开始抗体治疗时,肿瘤生长被抑制了90%(P<0.05)。针对已形成肿瘤(肿瘤细胞注射后14天)的抗NB IgM疗法使肾上腺肿瘤缩小了90%(P<0.05)。对肿瘤的分析揭示了补体激活和凋亡诱导是抗肿瘤功能的两种独立机制。这项研究强烈表明人抗NB IgM抗体是治疗神经母细胞瘤的新型药物。