Institute of Chemical Sciences and Engineering, Swiss Federal Institute of Technology (EPFL), 1015, Lausanne, Switzerland.
Service of Thoracic Surgery, Centre Hospitalier Universitaire Vaudois, 1011, Lausanne, Switzerland.
Sci Rep. 2018 Jul 6;8(1):10263. doi: 10.1038/s41598-018-28589-2.
Human pleural mesothelioma is an incurable and chemoresistant cancer. Using a nude mouse xenograft model of human pleural mesothelioma, we show that RAPTA-T, a compound undergoing preclinical evaluation, enhances tumor vascular function by decreasing blood vessel tortuosity and dilation, while increasing the coverage of endothelial cells by pericytes and vessel perfusion within tumors. This in turn significantly reduces the interstitial fluid pressure and increases oxygenation in the tumor. Consequently, RAPTA-T pre-treatment followed by the application of cisplatin or liposomal cisplatin (Lipoplatin) leads to increased levels of the cytotoxin in the tumor and enhanced mesothelioma growth inhibition. We demonstrate that the vascular changes induced by RAPTA-T are related, in part, to the inhibition of poly-(ADP-ribose) polymerase 1 (PARP-1) which is associated to tumor vascular stabilization. These findings suggest novel therapeutic implications for RAPTA-T to create conditions for superior drug uptake and efficacy of approved cytotoxic anti-cancer drugs in malignant pleural mesothelioma and potentially other chemoresistant tumors.
人胸膜间皮瘤是一种无法治愈且对化疗有抗性的癌症。我们使用人胸膜间皮瘤的裸鼠异种移植模型表明，RAPTA-T，一种正在进行临床前评估的化合物，通过降低血管扭曲和扩张程度，增加周细胞覆盖内皮细胞的程度和肿瘤内血管灌注，从而增强肿瘤血管功能。这反过来又显著降低了肿瘤内的间质液压力并增加了氧合作用。因此，RAPTA-T 预处理后再应用顺铂或脂质体顺铂（Lipoplatin）会导致肿瘤内细胞毒素水平升高，并增强间皮瘤的生长抑制。我们证明，RAPTA-T 诱导的血管变化部分与聚（ADP-核糖）聚合酶 1（PARP-1）的抑制有关，PARP-1 与肿瘤血管稳定有关。这些发现表明，RAPTA-T 具有新的治疗意义，可以为批准的细胞毒性抗癌药物在恶性胸膜间皮瘤和潜在的其他化疗抗性肿瘤中的更高药物摄取和疗效创造条件。
