In vivo antitumor activity of the NF-κB inhibitor dehydroxymethylepoxyquinomicin in a mouse model of adult T-cell leukemia
In vivo antitumor activity of the NF-κB inhibitor dehydroxymethylepoxyquinomicin in a mouse model of adult T-cell leukemia
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DOI：
10.1093/carcin/bgi095
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发表时间：
2005-08-01
期刊：
影响因子：
4.7
通讯作者：
Urano, T
中科院分区：
文献类型：
--
作者：
Ohsugi, T;Horie, R;Urano, T
成人T细胞白血病（ATL）是由人T细胞白血病病毒I型（HTLV-I）引起的侵袭性肿瘤。核转录因子NF-κ B由HTLV-I诱导，是随后肿瘤形成的中心。为了研究一种新的NF-κ B抑制剂，去羟甲基表氧喹诺霉素（DHMEQ），在体内对ATL的影响，我们开发了一种改进的严重联合免疫缺陷（SCID）小鼠模型的ATL。将其中自然杀伤（NK）细胞活性已被消除的五周龄SCID小鼠腹膜内接种HTLV-1感染的细胞系TL-Om 1、MT-1、MT-2和HUT-102。注射后40天未检测到TL-Om 1细胞的植入和MT-1细胞的少量成瘤。与此相反，接种MT-2和HUT-102细胞的小鼠引起高死亡率，100%的总肿瘤形成和肿瘤细胞浸润的各种器官的频率，所有这些都减少了DHMEQ在接种过程中的共同管理。此外，来自用DHMEQ处理的小鼠的肿瘤具有高的细胞凋亡频率。这些结果表明，DHMEQ在体内诱导HTLV-I转化细胞的凋亡，导致抑制肿瘤形成和器官浸润，从而提高存活率。
Adult T-cell leukemia (ATL) is an aggressive neoplasm caused by human T-cell leukemia virus type I (HTLV-I). The nuclear transcription factor, NF-kappa B, is induced by HTLV-I and is central to the ensuing neoplasia. To examine the effect of a novel NF-kappa B inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ), on ATL in vivo, we developed an improved severe combined immunodeficiency (SCID) mouse model for ATL. Five-week-old SCID mice in which natural killer (NK) cell activity had been eliminated were inoculated intraperitoneally with the HTLV-I-infected cell lines, TL-Om1, MT-1, MT-2 and HUT-102. No engraftment of TL-Om1 cells and little tumorigenesis of MT-1 cells were detected 40 days after injection. In contrast, inoculation of mice with MT-2 and HUT-102 cells elicited high mortality, 100% frequency of gross tumor formation and tumor cell infiltration of various organs, all of which were reduced by coadministration of DHMEQ during the inoculation. Moreover, tumors from mice treated with DHMEQ had a high frequency of apoptosis. These results suggest that DHMEQ induces apoptosis in HTLV-I-transformed cells in vivo, resulting in inhibition of tumor formation and organ infiltration, thereby enhancing survival.