有丝分裂
体内
放射治疗
癌症研究
细胞周期
人口
脑瘤
生物
有丝分裂指数
病理
医学
药理学
细胞
内科学
细胞生物学
生物化学
生物技术
环境卫生
作者
Mark C. de Gooijer,Hilal Çolakoğlu,Ceren H. Çitirikkaya,Daria Fedorushkova,Amal El Ouazani,Rohan Shah,Michaël H. Meel,Esther Hulleman,Gerben R. Borst,Olaf van Tellingen
出处
期刊:Neuro-oncology
[Oxford University Press]
日期:2023-09-01
卷期号:25 (Supplement_2): ii38-ii39
标识
DOI:10.1093/neuonc/noad137.122
摘要
Abstract BACKGROUND Radiotherapy remains one of the most effective modalities for anticancer treatment and part of standard of care for many primary and metastatic brain tumors. Boosting the efficacy of radiotherapy is therefore a logical avenue to improve patient survival. We have developed a radiosensitization strategy called ‘induction of mitotic enrichment’. It has long been known that the radiosensitivity of a cell depends on the phase of the cell cycle and that mitotic cells are especially vulnerable. Enriching the tumor for mitotic cells by arresting them during division prior to each radiotherapy fraction should therefore render the tumor population more sensitive to irradiation. Ideally, induction of mitotic enrichment should be reversible and non-cytotoxic to prevent healthy tissue toxicity and be compatible with clinically applied fractionated radiotherapy regimens. MATERIAL AND METHODS Mitotic enrichment in vitro is established using flow cytometry and radiosensitization is assessed using colony formation assays. In vivo, several independent luciferase-tagged orthotopic brain tumor models are used to investigate mitotic enrichment (phospho-histone 3 immunohistochemistry), tumor growth, survival and healthy tissue toxicity (body weight, blood liver enzymes, γH2AX and cleaved-caspase 3 immunohistochemistry). Pharmacokinetic studies are quantified using LC-MS/MS. All experiments on primary brain tumors included serum-free neurosphere culture models. RESULTS We have now identified an orally available targeted tubulin polymerization inhibitor that can achieve repeated and reversible mitotic enrichment for up to 10 hours prior to radiotherapy, without causing cytotoxicity in vitro or healthy tissue toxicity in vivo. This tubulin inhibitor (ABT-751) efficiently radiosensitizes a range of preclinical tumor models representing adult and pediatric, primary and metastatic brain tumors. Importantly, ABT-751 also improves survival in mouse models of adult glioblastoma (GBM), but only in a mitotic enrichment setup when given several hours prior to radiotherapy to allow accumulation in mitosis. Of note, induction of mitotic enrichment does not exacerbate healthy tissue toxicity. CONCLUSION Induction of mitotic enrichment by ABT-751 radiosensitizes adult GBM to fractionated radiotherapy. We are currently expanding our preclinical development of mitotic enrichment as a radiosensitization strategy to other targets and cancers and have designed a phase 0/I trial for adult GBM to demonstrate induction of mitotic enrichment and tolerability when combined with radiotherapy. We expect to start enrollment in this trial soon.
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