Defining the mode of action of cisplatin combined with NUC-1031, a phosphoramidate modification of gemcitabine

IF 5 2区 医学 Q2 Medicine Translational Oncology Pub Date : 2024-09-18 DOI:10.1016/j.tranon.2024.102114
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Abstract

The combination of gemcitabine with platinum agents is a widely used chemotherapy regimen for a number of tumour types. Gemcitabine plus cisplatin remains the current therapeutic choice for biliary tract cancer. Gemcitabine is associated with multiple cellular drug resistance mechanisms and other limitations and has thereforelined in use. NUC-1031 (Acelarin) is a phosphorylated form of gemcitabine, protected by the addition of a phosphoramidate moiety, developed to circumvent the key limitations and generate high levels of the cytotoxic metabolite, dFdCTP. The rationale for combination of gemcitabine and cisplatin is determined by in vitro cytotoxicity. This, however, does not offer an explanation of how these drugs lead to cell death. In this study we investigate the mechanism of action for NUC-1031 combined with cisplatin as a rationale for treatment. NUC-1031 is metabolised to dFdCTP, detectable up to 72 h post-treatment and incorporated into DNA, to stall the cell cycle and cause DNA damage in biliary tract and ovarian cancer cell lines. In combination with cisplatin, DNA damage was increased and occurred earlier compared to monotherapy. The damage associated with NUC-1031 may be potentiated by a second mechanism, via binding the RRM1 subunit of ribonucleotide reductase and perturbing the nucleotide pools; however, this may be mitigated by increased RRM1 expression. The implication of this was investigated in case studies from a Phase I clinical trial to observe whether baseline RRM1 expression in tumour tissue at time of diagnosis correlates with patient survival.

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确定顺铂与 NUC-1031(吉西他滨的磷酰胺修饰物)的联合作用模式
吉西他滨联合铂类药物是一种广泛应用于多种肿瘤类型的化疗方案。吉西他滨加顺铂仍是目前治疗胆道癌的首选方案。吉西他滨与多种细胞耐药机制和其他限制因素有关,因此在使用中有所减少。NUC-1031(Acelarin)是吉西他滨的磷酸化形式,通过添加磷酰胺基团进行保护,以规避主要限制并产生高水平的细胞毒性代谢物 dFdCTP。吉西他滨与顺铂联用的理由是由体外细胞毒性决定的。然而,这并不能解释这些药物是如何导致细胞死亡的。在本研究中,我们研究了 NUC-1031 与顺铂联合治疗的作用机制。NUC-1031 在胆道癌和卵巢癌细胞系中代谢为 dFdCTP,在治疗后 72 小时内均可检测到,并结合到 DNA 中,使细胞周期停滞并造成 DNA 损伤。与单药治疗相比,与顺铂联合使用时,DNA损伤加剧,且发生时间更早。与 NUC-1031 相关的损伤可能会通过第二种机制加剧,即通过结合核糖核苷酸还原酶的 RRM1 亚基并扰乱核苷酸池;不过,RRM1 表达的增加可能会减轻这种损伤。在一项 I 期临床试验的病例研究中对这一影响进行了调查,以观察诊断时肿瘤组织中 RRM1 的基线表达是否与患者的存活率相关。
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来源期刊
CiteScore
8.40
自引率
2.00%
发文量
314
审稿时长
54 days
期刊介绍: Translational Oncology publishes the results of novel research investigations which bridge the laboratory and clinical settings including risk assessment, cellular and molecular characterization, prevention, detection, diagnosis and treatment of human cancers with the overall goal of improving the clinical care of oncology patients. Translational Oncology will publish laboratory studies of novel therapeutic interventions as well as clinical trials which evaluate new treatment paradigms for cancer. Peer reviewed manuscript types include Original Reports, Reviews and Editorials.
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