TARGETING OF GM2-BEARING TUMOR-CELLS WITH THE CYTOLYTIC CLOSTRIDIUM-PERFRINGENS DELTA TOXIN
TARGETING OF GM2-BEARING TUMOR-CELLS WITH THE CYTOLYTIC CLOSTRIDIUM-PERFRINGENS DELTA TOXIN
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DOI：
10.1097/00001813-199302000-00009
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发表时间：
1993-02-01
影响因子：
2.3
通讯作者：
CHEDID, L
中科院分区：
文献类型：
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作者：
JOLIVETREYNAUD, C;ESTRADA, J;CHEDID, L
溶细胞性产气荚膜梭菌Delta毒素选择性地裂解表达神经节苷脂GM2的细胞。在这项研究中，我们研究了Delta毒素是否可以用来表征肿瘤细胞膜上的GM2，并作为抗肿瘤药物。用铬-51释放法测定了不同的小鼠和人恶性细胞系以及正常组织对Delta毒素裂解的敏感性。细胞毒效价与敏感和不敏感细胞的I-125标记毒素结合能力相关。在测试的8个人类黑色素瘤中，有7个被这种毒素溶解，其中4个非常敏感(细胞毒性滴度低于12纳克的毒素)。所有神经母细胞瘤、胶质瘤和视网膜母细胞瘤均用3-18 ng毒素溶解。6例肿瘤中的3例和2例肉瘤中的1例也非常敏感(细胞毒滴度为0.6-15 ng)，而白血病和淋巴瘤细胞则不敏感。正常人体组织是不敏感的(红细胞、皮肤成纤维细胞)或不敏感的(脑、肺、脾)。用荷瘤小鼠检测Delta毒素的体内抗肿瘤活性。荷瘤裸鼠和神经母细胞瘤C1300荷瘤A/J小鼠每天瘤内注射0.5~1 mg毒素，连续4~5天，可显著抑制肿瘤生长12~36天。在荷Mel80裸鼠和C1300 A/J小鼠中，每天静脉注射毒素100 ng，连续5天，仅在治疗期间对肿瘤生长有显著抑制作用，而对缺乏GM2的肿瘤SK-MEL28，10次注射同样剂量的毒素对肿瘤生长无显著影响。
The cytolytic Clostridium perfringens delta toxin lyses selectively cells which express ganglioside GM2. In this study, we investigated whether delta toxin can be used to characterize GM2 on tumor cell membranes and as an antitumor agent. The sensitivity to lysis by delta toxin of various murine and human malignant cell lines and also normal tissues was quantified using a Cr-51-release assay. The cytotoxicity titers were correlated with the I-125-labeled toxin binding capacity of sensitive and insensitive cells. Seven of eight human melanomas tested were lysed by the toxin and, of these, four were very sensitive (cytotoxicity titers below 12 ng of toxin). All neuroblastomas, gliomas and the retinoblastoma tested were lysed with 3-18 ng of toxin. Three of six carcinomas and one of two sarcomas were also very sensitive (cytotoxicity titers 0.6-15 ng) whereas leukemias and lymphoma cells were insensitive. Normal human tissues were insensitive (erythrocytes, skin fibroblasts) or poorly sensitive (brain, lung, spleen). The in vivo antitumor activity of delta toxin was tested in tumor-bearing mice. Daily intra-tumor injections of 0.5-1 mg of toxin for 4-5 days in carcinoma Mel80- and melanoma A375-bearing nude mice, and neuroblastoma C1300-bearing A/J mice significantly inhibited tumor growth for 12-36 days. Intravenous administration of 100 ng of toxin per day for 5 days in Mel80-bearing nude mice and C1300-bearing A/J mice gave significant inhibition of tumor growth only during the treatment period, and 10 injections of the same dose of toxin had no significant effect on SK-MEL28, a tumor lacking GM2.