Sharma Ashish, Broggini-Tenzer Angela, Vuong Van, Messikommer Alessandra, Nytko Katarzyna J, Guckenberger Matthias, Bachmann Felix, Lane Heidi A, Pruschy Martin
Department for Radiation Oncology, University Hospital Zurich, CH-8091 Zurich, Switzerland.
Basilea Pharmaceutica International Ltd, CH-4005 Basel, Switzerland.
Radiother Oncol. 2017 Sep;124(3):433-438. doi: 10.1016/j.radonc.2017.07.024. Epub 2017 Aug 7.
Resistance to microtubule targeting agents (MTA) represents a major drawback in successful cancer therapy with MTAs. Here we investigated the combined treatment modality of the novel MTA BAL101553 in combination with radiotherapy in paclitaxel and epothilone-resistant tumor models.
Multiple regimens of BAL101553, or its active moiety BAL27862 for in vitro experiments, were probed in combination with radiotherapy in P-glycoprotein-overexpressing, human colon adenocarcinoma cells (SW480) and in tubulin-mutated human NSCLC cells (A549EpoB40) and tumors thereof.
BAL27862 reduced the proliferative activity of SW480 and A549EpoB40 tumor cells with similar potency as in A549 wildtype cells. Combined treatment of BAL27862 with ionizing radiation in vitro resulted in an additive reduction of clonogenicity. Moreover, treatment of paclitaxel- and epothilone-resistant tumors with fractionated irradiation and different regimens of BAL101553 (a single i.v. bolus vs. oral daily) suppressed tumor growth and resulted in an extended additive tumor growth delay with strong reduction of tumor proliferation and mean tumor vessel density.
BAL101553 is a promising alternative in taxane- and epothilone-refractory tumors as part of a combined treatment modality with ionizing radiation. Its potent antitumor effect is not only tumor cell-directed but also targets the tumor microenvironment.
对微管靶向药物（MTA）产生耐药性是MTA用于癌症治疗取得成功的一个主要障碍。在此，我们在紫杉醇和埃坡霉素耐药肿瘤模型中研究了新型MTA BAL101553与放疗联合的治疗方式。
在过表达P-糖蛋白的人结肠腺癌细胞（SW480）以及微管蛋白突变的人非小细胞肺癌细胞（A549EpoB40）及其肿瘤模型中，探究了多种BAL101553方案或其活性部分BAL27862（用于体外实验）与放疗联合的效果。
BAL27862降低SW480和A549EpoB40肿瘤细胞增殖活性的效力与在A549野生型细胞中相似。BAL27862与体外电离辐射联合治疗导致克隆形成能力进一步降低。此外，用分次照射和不同方案的BAL101553（单次静脉推注与每日口服）治疗紫杉醇和埃坡霉素耐药肿瘤，可抑制肿瘤生长，并导致肿瘤生长延迟进一步延长，肿瘤增殖和平均肿瘤血管密度显著降低。
作为与电离辐射联合治疗方式的一部分，BAL101553在紫杉烷和埃坡霉素难治性肿瘤中是一种有前景的替代药物。其强大的抗肿瘤作用不仅针对肿瘤细胞，还靶向肿瘤微环境。
