RRx-001 protects against cisplatin-induced toxicities
RRx-001 protects against cisplatin-induced toxicities
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DOI：
10.1007/s00432-017-2416-4
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发表时间：
2017-09-01
影响因子：
3.6
通讯作者：
Cabrales, Pedro
中科院分区：
文献类型：
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作者：
Oronsky, Bryan;Reid, Tony R.;Cabrales, Pedro
目的RRx-001是一种毒性最低的肿瘤相关巨噬细胞和嗜中性粒细胞复极化剂，正在II期临床试验中作为顺铂和卡铂的增敏剂/再增敏剂进行研究。基于在使用RRx-001的引发期之后改善的铂耐受性的轶事临床观察以及先前已经证明肠干细胞的辐射保护和来自阿霉素的心脏保护的临床前研究，研究了RRx-001预处理对抗顺铂诱导的骨髓抑制和肾毒性的体内细胞保护潜力。（1）无治疗，（2）仅媒介物和顺铂，和（3）RRx-001和顺铂。在顺铂给药前3天开始RRx-001治疗（每隔一天5 mg/kg，持续3天）。以不同的时间间隔从股静脉采集血液，以测量总血红蛋白和白细胞计数以及肾功能标志物（血清尿素、肌酐和肌酐清除率）。结果RRx-001预处理可显著降低小鼠血尿素氮和肌酐水平（P < 0.05）; RRx-001和顺铂组的平均总染色体畸变频率在每个中期相的统计学显着（P < 0.05）的减少相比，cisplatin-only group.Conclusions本研究是第一次证明，RRx-001在体内具有肾，基因和骨髓保护作用。重要的是，RRx-001不能保护肉瘤-180实体瘤异种移植物免受顺铂诱导的细胞毒性。这些结果可能支持使用RRx-001作为针对顺铂诱导的毒性的化学保护剂。
Purpose RRx-001, a minimally toxic tumor-associated macrophage and neutrophil-repolarizing agent, is under investigation in Phase II clinical trials as a sensitizer/resensitizer to cisplatin and carboplatin. On the basis of anecdotal clinical observations of improved platinum tolerability following a priming period with RRx-001 as well as preclinical studies that have previously demonstrated radioprotection of intestinal stem cells and cardioprotection from doxorubicin, the in vivo cytoprotective potential of RRx-001 pretreatment against cisplatin-induced bone marrow suppression and renal toxicity was investigated.Methods BALB/c mice were divided into three groups: (1) no treatment, (2) vehicle and cisplatin only, and (3) RRx-001 and cisplatin. RRx-001 treatment (5 mg/kg every other day for 3 days) was initiated 3 days prior to cisplatin administration. Blood was collected from the femoral vein at different intervals to measure total hemoglobin and leukocyte counts as well as renal functional markers (serum urea, creatinine and creatinine clearance). Metaphase spreads were prepared from whole bone marrow cells as markers of clastogenicity.Results RRx-001 pretreatment significantly decreased (P < 0.05) the blood urea nitrogen and creatinine levels. A statistically significant (P < 0.05) reduction in the mean total chromosome aberration frequency per metaphase in the RRx-001 and cisplatin group compared to the cisplatin-only group was observed.Conclusions This study is the first to demonstrate that RRx-001 has nephro-, geno- and myeloprotective effects in vivo. Importantly, RRx-001 did not protect sarcoma-180 solid tumor xenografts against cisplatin-induced cytotoxicity. These results potentially support the use of RRx-001 as a chemoprotector against cisplatin-induced toxicities.