背景:青蒿琥酯,黄花蒿中活性成分青蒿素的衍生物,在传统中药中使用了几个世纪,正被用作疟疾治疗的一线药物。因为它对癌细胞有细胞毒性,试验正在进行中,包括这种药物作为癌症治疗的补充。在胶质母细胞瘤细胞中,青蒿琥酯被证明能诱导氧化应激,DNA碱基损伤和双链断裂(DSB),凋亡,和坏死。它还抑制DNA修复功能并具有抗衰老活性。与电离辐射相比,DNA损伤在整个暴露期间累积,这使得该试剂的基因毒性特征独一无二。青蒿琥酯已用于各种癌症的辅助治疗。
目的:由于青蒿琥酯已被用于不同类型癌症的辅助治疗,并且缺乏脑癌的临床试验,我们调查了其在神经胶质瘤患者中的活性,重点是可能的副作用。
方法:2014年至2020年,12例患者接受青蒿琥酯治疗,其中男8例,女4例。中位年龄45岁。
结果:4个胶质母细胞瘤WHO4级,5个星形细胞瘤WHO3级,3个少突胶质细胞瘤2级或3级。所有患者均接受放疗和替莫唑胺为基础的化疗。每日两次口服青蒿琥酯100mg联合剂量密集的替莫唑胺(100mg/m2第1-5天/7,10例患者)或替莫唑胺(50mg/m2第1-5天/7)加洛莫司汀(CCNU,40毫克第6/7天)。血细胞计数,C反应蛋白(CRP),肝酶,每周监测肾脏参数。
结果:除了一个短暂的3级血液学毒性,青蒿琥酯耐受性良好。没有观察到肝毒性。虽然8例晚期患者在开始青蒿琥酯治疗后的中位生存期为5个月,4例接受缓解维持治疗的患者的中位生存期为46个月。我们还回顾了在治疗方案中包括青蒿琥酯的其他癌症中进行的临床试验。
结论:青蒿琥酯以2×100mg/天的剂量给药没有有害的副作用,即使与用于神经胶质瘤治疗的烷化剂联合使用。因此,植物化学物质,它也被用作食品补充剂,是一个有趣的,耐受性良好的支持剂可用于长期维持治疗。本身对胶质母细胞瘤细胞具有细胞毒性,并增强替莫唑胺的细胞毒性以及鉴于其衰老活性,青蒿琥酯显然有可能提高恶性脑癌治疗的疗效。
BACKGROUND: Artesunate, a derivative of the active ingredient artemisinin from Artemisia annua L. used for centuries in the traditional Chinese medicine, is being applied as front-line drug in malaria treatment. As it is cytotoxic for cancer cells, trials are ongoing to include this drug as supplement in cancer therapy. In glioblastoma cells, artesunate was shown to induce oxidative stress, DNA base damage and double-strand breaks (DSBs), apoptosis, and necroptosis. It also inhibits DNA repair functions and bears senolytic activity. Compared to ionizing radiation, DNA damages accumulate over the whole exposure period, which makes the agent unique in its genotoxic profile. Artesunate has been used in adjuvant therapy of various cancers.
OBJECTIVE: As artesunate has been used in adjuvant therapy of different types of cancer and clinical trials are lacking in brain cancer, we investigated its activity in glioma patients with focus on possible side effects.
METHODS: Between 2014 and 2020, twelve patients were treated with artesunate for relapsing glioma and analyzed retrospectively: 8 males and 4 females, median age 45 years.
RESULTS: 4 glioblastomas WHO grade 4, 5 astrocytomas WHO grade 3, 3 oligodendrogliomas grade 2 or 3. All patients were pretreated with radiation and temozolomide-based chemotherapy. Artesunate 100 mg was applied twice daily p.o. combined with dose-dense temozolomide alone (100 mg/m2 day 1-5/7, 10 patients) or with temozolomide (50 mg/m2 day 1-5/7) plus lomustine (CCNU, 40 mg day 6/7). Blood count, C-reactive protein (CRP), liver enzymes, and renal parameters were monitored weekly.
RESULTS: Apart from one transient grade 3 hematological toxicity, artesunate was well tolerated. No liver toxicity was observed. While 8 patients with late stage of the disease had a median survival of 5 months after initiation of artesunate treatment, 4 patients with treatment for remission maintenance showed a median survival of 46 months. We also
review clinical trials that have been performed in other cancers where artesunate was included in the treatment regimen.
CONCLUSIONS: Artesunate administered at a dose of 2 × 100 mg/day was without harmful side effects, even if combined with alkylating agents used in glioma therapy. Thus, the phytochemical, which is also utilized as food supplement, is an interesting, well tolerated supportive agent useful for long-term maintenance treatment. Being itself cytotoxic on glioblastoma cells and enhancing the cytotoxicity of temozolomide as well as in view of its senolytic activity, artesunate has clearly a potential to enhance the efficacy of malignant brain cancer therapy.