背景:肿瘤杀伤复合物α1-油酸靶向膀胱癌细胞,快速触发,凋亡样肿瘤细胞死亡。最近在非肌层浸润性膀胱癌(NMIBC)患者中观察到了α1-油酸酯的临床效果,使用随机的,安慰剂对照研究方案。
目的:研究α1-油酸酯是否存在剂量依赖性效应。
方法:这里,NMIBC患者通过膀胱内滴注渐增浓度的α1-油酸酯(1.7,8.5或17mM)进行治疗,治疗反应定义为相对于安慰剂组.
结果:强,在α1-油酸酯治疗的患者中检测到分子和临床指标的剂量依赖性抗肿瘤作用;在接受8.5mM治疗的肿瘤中,88%检测到完全或部分缓解,而接受1.7mMα1-油酸酯治疗的肿瘤为47%.肿瘤对α1-油酸的摄取触发了肿瘤细胞快速脱落到尿液中,并通过凋亡样机制导致细胞死亡。组织活检的RNA测序证实了凋亡细胞死亡的激活和对癌症基因网络的强烈抑制,包括膀胱癌相关基因。没有记录药物相关的副作用,除了滴注部位的局部刺激。
结论:α1-油酸的这些剂量依赖性抗肿瘤作用是有希望的,并支持α1-油酸治疗NMIBC患者的潜力。
BACKGROUND: The tumoricidal complex alpha1-oleate targets bladder cancer cells, triggering rapid, apoptosis-like tumor cell death. Clinical effects of alpha1-oleate were recently observed in patients with non-muscle invasive bladder cancer (NMIBC), using a randomized, placebo-controlled study protocol.
OBJECTIVE: To investigate if there are dose-dependent effects of alpha1-oleate.
METHODS: Here, patients with NMIBC were treated by intravesical instillation of increasing concentrations of alpha1-oleate (1.7, 8.5, or 17 mM) and the treatment response was defined relative to a placebo group.
RESULTS: Strong, dose-dependent anti-tumor effects were detected in alpha1-oleate treated patients for a combination of molecular and clinical indicators; a complete or partial response was detected in 88% of tumors treated with 8.5 mM compared to 47% of tumors treated with 1.7 mM of alpha1-oleate. Uptake of alpha1-oleate by the tumor triggered rapid shedding of tumor cells into the urine and cell death by an apoptosis-like mechanism. RNA sequencing of tissue biopsies confirmed the activation of apoptotic cell death and strong inhibition of cancer gene networks, including bladder cancer related genes. Drug-related side effects were not recorded, except for local irritation at the site of instillation.
CONCLUSIONS: These dose-dependent anti-tumor effects of alpha1-oleate are promising and support the potential of alpha1-oleate treatment in patients with NMIBC.