Ozawa Tomoko, Rodriguez Mirna, Zhao Guisheng, Yao Tsun Wen, Fischer Wolf-Nicolas, Jandeleit Bernd, Koller Kerry, Nicolaides Theodore
Neurological Surgery, University of California San Francisco, San Francisco, USA.
Science, Quadriga BioSciences, Los Altos, USA.
Cureus. 2021 Aug 31;13(8):e17595. doi: 10.7759/cureus.17595. eCollection 2021 Aug.
Introduction The standard treatment for glioblastoma (GBM) patients is surgical tumor resection, followed by radiation and chemotherapy with temozolomide (TMZ). Unfortunately, 60% of newly diagnosed GBM patients express high levels of the DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT) and are TMZ-resistant, and all patients eventually become refractory to treatment. The blood-brain barrier (BBB) is an obstacle to the delivery of chemotherapeutic agents to GBM, and BBB-permeable agents that are efficacious in TMZ-resistant and refractory patients are needed. The large amino acid transporter 1 (LAT1) is expressed on the BBB and in GBM and is detected at much lower levels in normal brain tissue. A LAT1-selective therapeutic would potentially target brain tumors while avoiding uptake by healthy tissue. Methods We report a novel chemical entity (QBS10072S) that combines a potent cytotoxic chemotherapeutic domain (tertiary N-bis(2-chloroethyl)amine) with the structural features of a selective LAT1 substrate and tested it against GBM models and . For studies, DNA damage was assessed with a gamma H2A.X antibody and cell viability was assessed by WST-1 assay and/or CellTiter-Glo assay. For studies, QBS10072S (with or without radiation) was tested in orthotopic glioblastoma xenograft models, using overall survival and tumor size (as measured by bioluminescence), as endpoints. Results QBS10072S is 50-fold more selective for LAT1 vs. LAT2 in transport assays and demonstrates significant growth suppression of LAT1-expressing GBM cell lines. Unlike TMZ, QBS10072S is cytotoxic to cells with both high and low levels of MGMT expression. In orthotopic GBM xenografts, QBS10072S treatment significantly delayed tumorigenesis and prolonged animal survival compared to the vehicle without adverse effects. Conclusion QBS10072S is a novel BBB-permeable chemotherapeutic agent with the potential to treat TMZ-resistant and recurrent GBM as monotherapy or in combination with radiation treatment.
引言 胶质母细胞瘤（GBM）患者的标准治疗方法是手术切除肿瘤，随后进行放疗和替莫唑胺（TMZ）化疗。不幸的是，60%新诊断的GBM患者表达高水平的DNA修复酶O6-甲基鸟嘌呤-DNA甲基转移酶（MGMT），对TMZ耐药，并且所有患者最终都会对治疗产生耐药。血脑屏障（BBB）是化疗药物递送至GBM的障碍，因此需要对TMZ耐药和难治性患者有效的可穿透BBB的药物。大中性氨基酸转运体1（LAT1）在BBB和GBM中表达，而在正常脑组织中的表达水平要低得多。一种LAT1选择性治疗药物可能会靶向脑肿瘤，同时避免被健康组织摄取。方法 我们报告了一种新型化学实体（QBS10072S），它将一种强效细胞毒性化疗结构域（叔氮双（2-氯乙基）胺）与一种选择性LAT1底物的结构特征相结合，并在GBM模型 和 上进行了测试。对于 研究，用γH2A.X抗体评估DNA损伤，并用WST-1测定法和/或CellTiter-Glo测定法评估细胞活力。对于 研究，在原位胶质母细胞瘤异种移植模型中测试QBS10072S（有或无放疗），以总生存期和肿瘤大小（通过生物发光测量）作为终点。结果 在转运试验中，QBS10072S对LAT1的选择性比对LAT2高50倍，并对表达LAT1的GBM细胞系显示出显著的生长抑制作用。与TMZ不同，QBS10072S对MGMT表达水平高和低的细胞均具有细胞毒性。在原位GBM异种移植模型中，与赋形剂相比，QBS10072S治疗显著延迟了肿瘤发生并延长了动物生存期，且无不良反应。结论 QBS10072S是一种新型的可穿透BBB的化疗药物，有潜力作为单一疗法或与放疗联合治疗TMZ耐药和复发性GBM。
