Daylami Rouzbeh, Muilenburg Diego J, Virudachalam Subbulakshmi, Bold Richard J
Department of Surgery, University of California, Davis Medical Center, Sacramento, CA, USA.
Division of Surgical Oncology, Suite 3010, University of California, Davis Cancer Center, 4501 X Street, Sacramento, CA, 95817, USA.
J Exp Clin Cancer Res. 2014 Dec 12;33(1):102. doi: 10.1186/s13046-014-0102-9.
Pancreatic ductal adenocarcinoma has proven to be one of the most chemo-resistant among all solid organ malignancies. Several mechanisms of resistance have been described, though few reports of strategies to overcome this chemo-resistance have been successful in restoring sensitivity to the primary chemotherapy (gemcitabine) and enter the clinical treatment arena.
We examined the ability of cellular arginine depletion through treatment with PEG-ADI to alter in vitro and in vivo cytotoxicity of gemcitabine. The effect on levels of key regulators of gemcitabine efficacy (e.g. RRM2, hENT1, and dCK) were examined.
Combination of PEG-ADI and gemcitabine substantially increases growth arrest, leading to increased tumor response in vivo. PEG-ADI is a strong inhibitor of the gemcitabine-induced overexpression of ribonucleotide reductase subunit M2 (RRM2) levels both in vivo and in vitro, which is associated with gemcitabine resistance. This mechanism is through the abrogation of the gemcitabine-mediated inhibitory effect on E2F-1 function, a transcriptional repressor of RRM2.
The ability to alter gemcitabine resistance in a targeted manner by inducing metabolic stress holds great promise in the treatment of advanced pancreatic cancer.
胰腺导管腺癌已被证明是所有实体器官恶性肿瘤中对化疗耐药性最强的肿瘤之一。虽然已经描述了几种耐药机制，但很少有克服这种化疗耐药性的策略能成功恢复对一线化疗药物（吉西他滨）的敏感性并进入临床治疗领域的报道。
我们研究了通过聚乙二醇化精氨酸脱亚氨酶（PEG-ADI）处理使细胞内精氨酸耗竭，从而改变吉西他滨在体外和体内细胞毒性的能力。检测了其对吉西他滨疗效关键调节因子（如核糖核苷酸还原酶M2亚基（RRM2）、人等效核苷转运体1（hENT1）和脱氧胞苷激酶（dCK））水平的影响。
PEG-ADI与吉西他滨联合使用可显著增强生长停滞，导致体内肿瘤反应增加。PEG-ADI在体内和体外均是吉西他滨诱导的核糖核苷酸还原酶亚基M2（RRM2）水平过表达的强效抑制剂，而RRM2过表达与吉西他滨耐药相关。这一机制是通过消除吉西他滨介导的对RRM2转录抑制因子E2F-1功能的抑制作用实现的。
通过诱导代谢应激以靶向方式改变吉西他滨耐药性的能力在晚期胰腺癌治疗中具有巨大潜力。
