Safety and antitumor activity of recombinant soluble Apo2 ligand
Safety and antitumor activity of recombinant soluble Apo2 ligand
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DOI：
10.1172/jci6926
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发表时间：
1999-07-01
影响因子：
15.9
通讯作者：
Schwall, RH
中科院分区：
文献类型：
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作者：
Ashkenazi, A;Pai, RC;Schwall, RH
TNF和Fas配体诱导肿瘤细胞凋亡；然而，它们对正常组织的严重毒性阻碍了它们在癌症治疗中的应用。Apo2配体（Apo2L，或TRAIL）是引发肿瘤细胞凋亡的相关分子。Apo2L mRNA在许多组织中表达，表明该配体可能对正常细胞无毒。为了研究Apo2L的治疗潜力，我们在细菌中产生了一种天然人类蛋白的强活性可溶性版本。几种正常细胞类型对Apo2L诱导的细胞凋亡具有体外抗性。在非人灵长类动物中反复静脉注射Apo2L对所检查的组织和器官没有引起可检测到的毒性。Apo2L对39种结肠癌、肺癌、乳腺癌、肾癌、脑癌和皮肤癌细胞系中的32种具有细胞抑制或细胞毒性作用。异种肿瘤移植后不久用Apo2L治疗胸腺肥大小鼠可显著降低肿瘤发生率。Apo2L治疗实体瘤小鼠可诱导肿瘤细胞凋亡，抑制肿瘤进展，提高生存率。Apo2L与化疗药物5-氟尿嘧啶或CPT-11协同作用，使肿瘤显著消退或完全消融。因此，Apo2L可能具有强大的抗癌活性，而对正常组织没有明显的毒性。
TNF and Fas ligand induce apoptosis in tumor cells; however, their severe toxicity toward normal tissues hampers their application to cancer therapy. Apo2 Ligand (Apo2L, or TRAIL) is a related molecule that triggers tumor cell apoptosis. Apo2L mRNA is expressed in many tissues, suggesting that the ligand may be nontoxic to normal cells. To investigate Apo2L's therapeutic potential, we generated in bacteria a potently active soluble version of the native human protein. Several normal cell types were resistant in vitro to apoptosis induction by Apo2L. Repeated intravenous injections of Apo2L in nonhuman primates did not cause detectable toxicity to tissues and organs examined. Apo2L exerted cytostatic or cytotoxic effects in vitro on 32 of 39 cell lines from colon, lung, breast, kidney, brain, and skin cancer. Treatment of athymic mice with Apo2L shortly after tumor xenograft injection markedly reduced tumor incidence. Apo2L treatment of mice bearing solid tumors induced tumor cell apoptosis, suppressed tumor progression, and improved survival. Apo2L cooperated synergistically with the chemotherapeutic drugs 5-fluorouracil or CPT-11, causing substantial tumor regression or complete tumor ablation. Thus, Apo2L may have potent anticancer activity without significant toxicity toward normal tissues.