Abstract
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.
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Funding
This study was funded by EpicentRx.
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P Cabrales designed the experiments, acquired and analyzed data, and participated in the drafting of the manuscript. All authors analyzed data and participated in the drafting of the manuscript. All authors read and approved the final manuscript.
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EpicentRx Inc funds research of molecule RRx-001. B. Oronsky is an employee of EpicentRx. P. Cabrales and the other authors have no conflicts of interest to declare.
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All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.
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Oronsky, B., Reid, T.R., Larson, C. et al. RRx-001 protects against cisplatin-induced toxicities. J Cancer Res Clin Oncol 143, 1671–1677 (2017). https://doi.org/10.1007/s00432-017-2416-4
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DOI: https://doi.org/10.1007/s00432-017-2416-4