Department of Urology, Leiden University Medical Center, The Netherlands.
Cell Death and Metabolism, Center for Autophagy, Recycling and Disease, Danish Cancer Society Research Center, Copenhagen, Denmark.
Mol Oncol. 2020 Dec;14(12):3121-3134. doi: 10.1002/1878-0261.12793. Epub 2020 Oct 16.
More effective therapy for patients with either muscle-invasive or high-risk non-muscle-invasive urothelial carcinoma of the bladder (UCB) is an unmet clinical need. For this, drug repositioning of clinically approved drugs represents an interesting approach. By repurposing existing drugs, alternative anticancer therapies can be introduced in the clinic relatively fast, because the safety and dosing of these clinically approved pharmacological agents are generally well known. Cationic amphiphilic drugs (CADs) dose-dependently decreased the viability of a panel of human UCB lines in vitro. CADs induced lysosomal puncta formation, a hallmark of lysosomal leakage. Intravesical instillation of the CAD penfluridol in an orthotopic mouse xenograft model of human UCB resulted in significantly reduced intravesical tumor growth and metastatic progression. Furthermore, treatment of patient-derived ex vivo cultured human UCB tissue caused significant partial or complete antitumor responses in 97% of the explanted tumor tissues. In conclusion, penfluridol represents a promising treatment option for bladder cancer patients and warrants further clinical evaluation.
对于肌肉浸润性或高危非肌肉浸润性膀胱癌（UCB）患者，更有效的治疗方法是一种未满足的临床需求。为此，重新定位临床批准药物的用途代表了一种有趣的方法。通过重新利用现有的药物，可以相对较快地将替代抗癌疗法引入临床，因为这些临床批准的药物的安全性和剂量通常是众所周知的。阳离子两亲性药物（CAD）在体外剂量依赖性地降低了一系列人 UCB 系的活力。CAD 诱导溶酶体斑点形成，这是溶酶体渗漏的一个标志。CAD 戊氟醇在人 UCB 原位异种移植模型中的膀胱内灌注导致膀胱内肿瘤生长和转移进展明显减少。此外，对患者来源的离体培养的人 UCB 组织进行治疗，导致 97%的离体肿瘤组织出现明显的部分或完全抗肿瘤反应。总之，戊氟醇为膀胱癌患者提供了一种有前途的治疗选择，值得进一步临床评估。
