Li Fengzhi, Ling Xiang, Harris Danni L, Liao Jianqun, Wang Yuping, Westover David, Jiang Guohui, Xu Bo, Boland Patrick M, Jin Chunyang
Department of Pharmacology & Therapeutics, Roswell Park Cancer Institute Buffalo, New York, USA.
Department of Pharmacology & Therapeutics, Roswell Park Cancer InstituteBuffalo, New York, USA; Canget BioTekpharma LLCBuffalo, New York, USA.
Am J Cancer Res. 2017 Feb 1;7(2):370-382. eCollection 2017.
FL118 is a novel camptothecin (CPT) analogue that possesses exceptional antitumor efficacy in human tumor animal models. To date, two CPT analogues, irinotecan and topotecan, have been approved by the FDA for cancer treatment. FL118 exhibits superior antitumor activity over irinotecan and topotecan, and effectively overcomes the irinotecan- or topotecan-resistant human tumors in animal models. Accordingly, FL118 selectively inhibits the expression of multiple cancer-associated proteins (survivin, Mcl-1, XIAP, cIAP2, MdmX). However, FL118 has hematopoietic toxicity similar to irinotecan and topotecan, suggesting that FL118's hematopoietic toxicity may share a mechanism similar to irinotecan and topotecan. It is known that CPTs including irinotecan, SN-38 (active metabolite of irinotecan) and topotecan are topoisomerase I (Top1) inhibitors. However, the evidence from our studies failed to reveal that FL118 is a better Top1 inhibitor than SN-38. It was documented that Top1 expression level is positively associated with CPTs' sensitivity. Low Top1 expression links to CPTs' resistance. In contrast to these findings, we found that human colorectal tumor sensitivity to FL118 is irrelevant to the expression level of Top1 protein. FL118 can show high antitumor efficacy in Top1-negative tumors, while Top1 highly positive tumors can exhibit FL118 resistance. This suggests that the presence of Top1 target is not critical for FL118 antitumor activity. In other words, targeting Top1 by FL118 may not play a major role for its antitumor efficacy. However, studies indicate that FL118 can bind to, and inhibit Top1 activity. This raises the possibility that inhibition of Top1 by FL118 may predominantly be involved in hematopoietic toxicity, but not in FL118 antitumor activity. In this article, we will summarize existing observations and provide our up-to-date research results to support our opinion on this important topic.
FL118是一种新型喜树碱（CPT）类似物，在人类肿瘤动物模型中具有卓越的抗肿瘤功效。迄今为止，两种CPT类似物，伊立替康和拓扑替康，已获美国食品药品监督管理局（FDA）批准用于癌症治疗。FL118展现出优于伊立替康和拓扑替康的抗肿瘤活性，并在动物模型中有效克服了对伊立替康或拓扑替康耐药的人类肿瘤。因此，FL118选择性抑制多种癌症相关蛋白（生存素、髓细胞白血病-1蛋白、X连锁凋亡抑制蛋白、细胞凋亡抑制蛋白2、小鼠双微体蛋白X）的表达。然而，FL118具有与伊立替康和拓扑替康相似的造血毒性，这表明FL118的造血毒性可能与伊立替康和拓扑替康有相似的机制。已知包括伊立替康、SN-38（伊立替康的活性代谢物）和拓扑替康在内的CPT是拓扑异构酶I（Top1）抑制剂。然而，我们的研究证据未能表明FL118是比SN-38更好的Top1抑制剂。有文献记载，Top1表达水平与CPT的敏感性呈正相关。低Top1表达与CPT耐药相关。与这些发现相反，我们发现人类结直肠肿瘤对FL118的敏感性与Top1蛋白的表达水平无关。FL118在Top1阴性肿瘤中可显示出高抗肿瘤功效，而Top1高度阳性的肿瘤可表现出对FL118耐药。这表明Top1靶点的存在对FL118的抗肿瘤活性并非至关重要。换句话说，FL118靶向Top1可能对其抗肿瘤功效不起主要作用。然而，研究表明FL118能够结合并抑制Top1活性。这增加了一种可能性，即FL118对Top1的抑制可能主要与造血毒性有关，而与FL118的抗肿瘤活性无关。在本文中，我们将总结现有观察结果，并提供我们最新的研究成果以支持我们对这一重要课题的观点。
