A novel tumor-derived mediator that sensitizes cytokine-resistant tumors to tumor necrosis factor.
A novel tumor-derived mediator that sensitizes cytokine-resistant tumors to tumor necrosis factor.
复制标题
一种新型肿瘤衍生介质，可使细胞因子抗性肿瘤对肿瘤坏死因子敏感。
DOI：
10.1006/jsre.1996.0256
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发表时间：
1996
期刊：
影响因子：
--
通讯作者：
Chabot,J
中科院分区：
文献类型：
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作者：
Marvin,MR;Libutti,SK;Kayton,M;Kao,J;Hayward,J;Grikscheit,T;Fan,Y;Brett,J;Weinberg,A;Nowygrod,R;LoGerfo,P;Feind,C;Hansen,KS;Schwartz,M;Stern,D;Chabot,J
用肿瘤坏死因子-α (TNF)治疗小鼠肿瘤后的治疗成功还不容易应用于临床肿瘤学，因为人体所需的TNF浓度会引起全身毒性。这使我们确定了可以使肿瘤对TNF的作用敏感的介质，允许较低剂量的施用，并可能实现这种细胞因子的治疗潜力。我们的研究报告了一种新的细胞因子，内皮单核细胞激活多肽II (EMAP II)，能够在小鼠模型中使最初耐药的小鼠和人类肿瘤对tnf诱导的退化敏感。重组(r) EMAP II是从大肠杆菌中纯化的，用表达成熟EMAP II的质粒转化。在C57BL/6小鼠中生长的B16黑色素瘤或免疫功能低下小鼠中生长的人纤维肉瘤（HT-1080），在瘤内注射载体或rEMAP II/热处理的EMAP II (50-100 μg)，然后注射全身TNF/热处理TNF (5 μg)，并评估肿瘤体积、出血和组织学外观。B16黑色素瘤和HT-1080人纤维肉瘤在给予肿瘤内EMAP II和全身TNF后，均发生血栓出血性和急性炎症改变，并伴有消退或显著减缓生长。任何一种细胞因子的遗漏或失活都消除了这种作用。这些结果表明，用EMAP II局部治疗某些肿瘤可增强对tnf介导的血栓出血和消退的易感性。
Therapeutic successes following treatment of murine tumors with tumor necrosis factor-α (TNF) have not been easily applied to clinical oncology because the concentrations of TNF required in humans induces systemic toxicity. This has led us to identify mediators which could sensitize tumors to the effects of TNF, permitting administration of lower doses and possible realization of the therapeutic potential of this cytokine. Our study reports the ability of a novel cytokine, endothelial-monocyte-activating polypeptide II (EMAP II), to sensitize initially resistant murine and human tumors to TNF-induced regression employing a murine model. Recombinant (r) EMAP II was purified fromEscherichia colitransformed with a plasmid expressing mature EMAP II. The B16 melanoma, raised in C57BL/6 mice, or a human fibrosarcoma (HT-1080), grown in immunocompromised mice, was injected intratumorally with either vehicle or rEMAP II/heat-treated EMAP II (50–100 μg) followed by systemic TNF/heat-treated TNF (5 μg) and assessed for tumor volume, hemorrhage, and histologic appearance. Both the B16 melanoma and the HT-1080 human fibrosarcoma underwent thrombohemorrhagic and acute inflammatory changes concomitant with regression or significantly slowed growth after administration of intratumor EMAP II followed by systemic TNF. Omission or inactivation of either cytokine abrogated this effect. These results demonstrate that local treatment of certain tumors with EMAP II results in enhanced susceptibility to TNF-mediated induction of thrombohemorrhage and regression.