Radioimmunotherapy of experimental head and neck squamous cell carcinoma (HNSCC) with E6-specific antibody using a novel HPV-16 positive HNSCC cell line.
Radioimmunotherapy of experimental head and neck squamous cell carcinoma (HNSCC) with E6-specific antibody using a novel HPV-16 positive HNSCC cell line.
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DOI：
10.1186/1758-3284-3-9
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发表时间：
2011-02-12
期刊：
影响因子：
--
通讯作者：
Dadachova E
中科院分区：
文献类型：
--
作者：
Harris M;Wang XG;Jiang Z;Goldberg GL;Casadevall A;Dadachova E
头颈部鳞状细胞癌（HNSCC）是全球第六大最常见的恶性肿瘤，预后较差。人乳头瘤病毒（HPV）感染与20%的HNSCC和50%的口咽癌相关。在90%的HPV+ HNSCC中检测到HPV16型。最近，我们提出了一种完全不同的治疗病毒源性癌症的方法，即用放射性标记抗体（mab）靶向癌细胞上的病毒抗原，这有望提供精确的治疗特异性。我们的目标是将这种方法扩展到hpv相关的头颈癌，通过使用放射标记的单克隆抗体对E6和E7癌基因进行放射免疫治疗（RIT）。由于目前还没有市售的HPV16+ HNSCC细胞系，而且在杜塞尔多夫、密歇根和图尔库的研究小组中只有一种HPV+细胞系，我们首先针对HNSCC的RIT建立了HPV16+细胞系和动物模型。用含有HPV16 E6和E7基因的pLXSN16E6E7载体转染市售HNSCC细胞株FaDu。采用PCR和western blot方法对生成的新细胞系进行评价，并对裸鼠进行致瘤性评价。使用未标记或188-铼（188Re）标记的C1P5单抗E6，在2A3载瘤裸鼠中进行了靶向E6癌蛋白的RIT原理验证。新型HPV16+ 2A3细胞系可靠表达E6癌蛋白。蛋白酶体抑制剂MG132以剂量依赖性的方式改变E6的表达。据估计，2A3细胞系中E6的表达水平约为每个细胞200个HPV拷贝。HPV16+ 2A3细胞系在裸鼠体内保留了100%的亲本FaDu细胞的致瘤性。在裸鼠2A3肿瘤的RIT过程中，相对低剂量的200 μCi 188Re-C1P5 mAb与未治疗的对照组相比，可以有效地抑制肿瘤的生长。未标记的C1P5单抗也引起肿瘤进展的一些减缓，但远不如188Re-C1P5单抗明显。我们在稳定转化的HPV16+ HNSCC细胞系和裸鼠肿瘤模型中描述了一项靶向HPV16 E6癌蛋白的RIT研究的原理验证，并证明了RIT作为HNSCC的一种新型分子靶向治疗的潜在效用。
Head and neck squamous cell carcinoma (HNSCC) is the sixth most common malignancy worldwide with a poor prognosis. Human papilloma virus (HPV) infection is associated with 20% HNSCC, and 50% of oropharyngeal carcinoma. HPV16 type is detected in 90% of all HPV+ HNSCC. Recently we suggested a fundamentally different approach to treatment of cancers of viral origin by targeting viral antigens on cancer cells with radiolabeled antibodies (mAbs) which promises exquisite specificity of treatment. We aimed at extending this approach to HPV-related head and neck cancer by performing radioimmunotherapy (RIT) targeting E6 and E7 oncogenes with radiolabeled mAbs. We first aimed at developing HPV16+ cell line and animal model for RIT of HNSCC as at present there are no commercially available HPV16+ HNSCC cell lines and there is only one HPV+ cell line among the collection maintained by Dusseldorf, Michigan and Turku groups. Commercially available HNSCC cell line FaDu was transfected with pLXSN16E6E7 vector containing HPV16 E6 and E7 genes. Generated novel cell lines were evaluated by PCR and western blot and the tumorigenecity was assessed in nude mice. Proof of principle RIT targeting E6 oncoprotein in 2A3 tumor-bearing nude mice was conducted using unlabeled or 188-Rhenium (188Re)-labeled C1P5 mAb to E6. Novel HPV16+ 2A3 cell line reliably expressed E6 oncoprotein. E6 expression was modifiable with proteasome inhibitor MG132 in a dose-dependent manner. The levels of E6 expression in 2A3 cell line were estimated to be around 200 HPV copies per cell. The HPV16+ 2A3 cell line preserved 100% tumorigenicity of parent FaDu cells in nude mice. During RIT of 2A3 tumors in nude mice the relatively low dose of 200 μCi 188Re-C1P5 mAb was effective in decreasing the tumor growth in comparison with untreated controls. Unlabeled C1P5 mAb also caused some decrease in tumor progression, however, much less pronounced than 188Re-C1P5 mAb. We describe a proof-of-principle RIT study targeting HPV16 E6 oncoprotein with radiolabeled mAb to E6 in a stably transformed HPV16+ HNSCC cell line and tumor model in nude mice, and demonstrate potential utility of RIT as a novel molecular targeted therapy for HNSCC.
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影响因子：
3.7
作者：
Wang XG;Revskaya E;Bryan RA;Strickler HD;Burk RD;Casadevall A;Dadachova E
通讯作者：
Dadachova E
影响因子：
7.3
作者：
Schlecht, N. F.;Burk, R. D.;Belbin, T. J.
通讯作者：
Belbin, T. J.
影响因子：
3.7
作者：
Kehmeier, E;Rühl, H;Stöppler, H
通讯作者：
Stöppler, H
影响因子：
3.8
作者：
KAUR, P;MCDOUGALL, JK;CONE, R
通讯作者：
CONE, R
影响因子：
64.8
作者：
Schatton, Tobias;Murphy, George F.;Frank, Markus H.
通讯作者：
Frank, Markus H.