Chen Thomas C, Cho Hee-Yeon, Wang Weijun, Wetzel Stephanie J, Singh Anupam, Nguyen Jenny, Hofman Florence M, Schönthal Axel H
Department of Neurosurgery, University of Southern California, Los Angeles, CA, USA.
Department of Molecular Microbiology & Immunology, University of Southern California, Los Angeles, CA, USA.
J Biomed Sci. 2015 Aug 19;22(1):71. doi: 10.1186/s12929-015-0175-6.
Many patients with nasopharyngeal carcinoma (NPC) face poor prognosis. Due to its hidden anatomical location, the tumor is usually diagnosed quite late, and despite initially successful treatment with radiation and cisplatin, many patients will relapse and succumb to the disease. New treatment options are urgently needed. We have performed preclinical studies to evaluate the potential NPC therapeutic activity of a newly developed analog of temozolomide (TMZ), an alkylating agent that is the current chemotherapeutic standard of care for patients with malignant glioma.
TMZ was covalently conjugated to the natural monoterpene perillyl alcohol (POH), creating the novel fusion compound NEO212. Its impact on two NPC cell lines was studied through colony formation assays, cell death ELISA, immunoblots, and in vivo testing in tumor-bearing mice. In vitro, NEO212 effectively triggered tumor cell death, and its potency was significantly greater than that of its individual components, TMZ or POH alone. Intriguingly, merely mixing TMZ with POH also was unable to achieve the superior potency of the conjugated compound NEO212. Treatment of NPC cells with NEO212 inactivated the chemoprotective DNA repair protein MGMT (O6-methylguanine methyltransferase), resulting in significant chemosensitization of cells to a second round of drug treatment. When tested in vivo, NEO212 reduced tumor growth in treated animals.
Our results demonstrate anticancer activity of NEO212 in preclinical NPC models, suggesting that this novel compound should be evaluated further for the treatment of patients with NPC.
许多鼻咽癌（NPC）患者预后较差。由于其解剖位置隐匿，肿瘤通常在较晚阶段才被诊断出来，尽管最初采用放疗和顺铂治疗取得了成功，但许多患者仍会复发并死于该疾病。迫切需要新的治疗选择。我们进行了临床前研究，以评估一种新开发的替莫唑胺（TMZ）类似物对NPC的潜在治疗活性，TMZ是一种烷化剂，目前是恶性胶质瘤患者化疗的标准治疗药物。
TMZ与天然单萜紫苏醇（POH）共价结合，形成新型融合化合物NEO212。通过集落形成试验、细胞死亡酶联免疫吸附测定、免疫印迹以及在荷瘤小鼠体内进行测试，研究了其对两种NPC细胞系的影响。在体外，NEO212有效触发肿瘤细胞死亡，其效力明显大于其单个成分TMZ或单独的POH。有趣的是，仅仅将TMZ与POH混合也无法达到共轭化合物NEO212的优越效力。用NEO212处理NPC细胞可使化学保护DNA修复蛋白MGMT（O6-甲基鸟嘌呤甲基转移酶）失活，从而使细胞对第二轮药物治疗产生显著的化学增敏作用。在体内测试时，NEO212可减少治疗动物的肿瘤生长。
我们的结果证明了NEO212在临床前NPC模型中的抗癌活性，表明这种新型化合物应进一步评估用于治疗NPC患者。
