Bryan Oronsky1, Tony R Reid2, Christopher Larson2, Corey A Carter3, Christina E Brzezniak3, Arnold Oronsky4, Pedro Cabrales5. 1. EpicentRx Inc, 4445 Eastgate Mall, Suite 200, San Diego, CA, 92121, USA. boronsky@epicentrx.com. 2. Moores Cancer Center, University of California San Diego, 3855 Health Sciences Dr, La Jolla, CA, USA. 3. Walter Reed National Military Medical Center, 8901 Wisconsin Ave, Bethesda, MD, USA. 4. InterWest Partners, 2710 Sand Hill Road #200, Menlo Park, CA, USA. 5. Department of Bioengineering, University of California San Diego, 9500 Gilman Dr, La Jolla, CA, USA.
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.
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 ureanitrogen 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.
Authors: Michelle M Kim; Hemant Parmar; Yue Cao; Susan J Knox; Bryan Oronsky; Jan Scicinski; Theodore S Lawrence; Christopher D Lao Journal: Neuro Oncol Date: 2016-01-13 Impact factor: 12.300
Authors: Tony Reid; Bryan Oronsky; Jan Scicinski; Curt L Scribner; Susan J Knox; Shoucheng Ning; Donna M Peehl; Ron Korn; Meaghan Stirn; Corey A Carter; Arnold Oronsky; Michael J Taylor; William L Fitch; Pedro Cabrales; Michelle M Kim; Howard A Burris; Christopher D Lao; Nacer E D Abrouk; Gary R Fanger; Jeffrey R Infante Journal: Lancet Oncol Date: 2015-08-19 Impact factor: 41.316
Authors: Pedro Cabrales; Jan Scicinski; Tony Reid; Frans Kuypers; Sandra Larkin; Marcel Fens; Arnold Oronsky; Bryan Oronsky Journal: Med Oncol Date: 2016-05-26 Impact factor: 3.064
Authors: Shoucheng Ning; Mark Bednarski; Bryan Oronsky; Jan Scicinski; Gordon Saul; Susan J Knox Journal: Cancer Res Date: 2012-05-15 Impact factor: 12.701
Authors: Corey A Carter; Karen Zeman; Regina M Day; Patrick Richard; Arnold Oronsky; Neil Oronsky; Michelle Lybeck; Jan Scicinski; Bryan Oronsky Journal: Oncotarget Date: 2016-06-28
Authors: Corey A Carter; Bryan T Oronsky; Scott Z Caroen; Jan J Scicinski; Aiste Degesys; Michelle M Kim; Arnold L Oronsky; Harry Lybeck; Pedro Cabrales; Neil Oronsky; Tony Reid; Joseph Roswarski; Christina Brzezniak Journal: Case Rep Oncol Date: 2016-03-11
Authors: Bryan Oronsky; Jan Scicinski; Shoucheng Ning; Donna Peehl; Arnold Oronsky; Pedro Cabrales; Mark Bednarski; Susan Knox Journal: Invest New Drugs Date: 2016-02-03 Impact factor: 3.850
Authors: Kimberly J Jurgensen; William K J Skinner; Bryan Oronsky; Nacer D Abrouk; Andrew E Graff; Reid D Landes; William E Culp; Thomas A Summers; Lynnette H Cary Journal: Front Pharmacol Date: 2021-04-22 Impact factor: 5.810