RRx-001 protects against cisplatin-induced toxicities

Bryan Oronsky, Tony R. Reid, Christopher Larson, Corey A. Carter, Christina E. Brzezniak, Arnold Oronsky, Pedro Cabrales

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)1-7
Number of pages7
JournalJournal of Cancer Research and Clinical Oncology
DOIs
StateAccepted/In press - Apr 17 2017
Externally publishedYes

Fingerprint

Cisplatin
Creatinine
Metaphase
RRx-001
Sarcoma 180
Kidney
Phase II Clinical Trials
Femoral Vein
Poisons
Blood Urea Nitrogen
Carboplatin
Platinum
Leukocyte Count
Heterografts
Chromosome Aberrations
Bone Marrow Cells
Doxorubicin
Urea
Neoplasms
Hemoglobins

Keywords

  • Chemoprotection
  • Cisplatin
  • Myeloprotection
  • RRx-001
  • Toxicity sparing

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Oronsky, B., Reid, T. R., Larson, C., Carter, C. A., Brzezniak, C. E., Oronsky, A., & Cabrales, P. (Accepted/In press). RRx-001 protects against cisplatin-induced toxicities. Journal of Cancer Research and Clinical Oncology, 1-7. https://doi.org/10.1007/s00432-017-2416-4

RRx-001 protects against cisplatin-induced toxicities. / Oronsky, Bryan; Reid, Tony R.; Larson, Christopher; Carter, Corey A.; Brzezniak, Christina E.; Oronsky, Arnold; Cabrales, Pedro.

In: Journal of Cancer Research and Clinical Oncology, 17.04.2017, p. 1-7.

Research output: Contribution to journalArticle

Oronsky, B, Reid, TR, Larson, C, Carter, CA, Brzezniak, CE, Oronsky, A & Cabrales, P 2017, 'RRx-001 protects against cisplatin-induced toxicities', Journal of Cancer Research and Clinical Oncology, pp. 1-7. https://doi.org/10.1007/s00432-017-2416-4
Oronsky, Bryan ; Reid, Tony R. ; Larson, Christopher ; Carter, Corey A. ; Brzezniak, Christina E. ; Oronsky, Arnold ; Cabrales, Pedro. / RRx-001 protects against cisplatin-induced toxicities. In: Journal of Cancer Research and Clinical Oncology. 2017 ; pp. 1-7.
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T1 - RRx-001 protects against cisplatin-induced toxicities

AU - Oronsky, Bryan

AU - Reid, Tony R.

AU - Larson, Christopher

AU - Carter, Corey A.

AU - Brzezniak, Christina E.

AU - Oronsky, Arnold

AU - Cabrales, Pedro

PY - 2017/4/17

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N2 - 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.

AB - 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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KW - Toxicity sparing

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