P53-Based strategy to reduce hematological toxicity of chemotherapy: A proof of principle study

Chul S Ha, Joel E Michalek, Richard M Elledge, Kevin R. Kelly, Suthakar Ganapathy, Hang Su, Carol A. Jenkins, Athanassios Argiris, Ronan Swords, Tony Y. Eng, Anand B Karnad, Richard L Crownover, Gregory P Swanson, Martin Goros, Brad H. Pollock, Zhi Min Yuan

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

p53 activation is a primary mechanism underlying pathological responses to DNA damaging agents such as chemotherapy and radiotherapy. Our recent animal studies showed that low dose arsenic (LDA)-induced transient p53 inhibition selectively protected normal tissues from chemotherapy-induced toxicity.Study objectives were to: 1) define the lowest safe dose of arsenic trioxide that transiently blocks p53 activation in patients and 2) assess the potential of LDA to decrease hematological toxicity from chemotherapy.Patients scheduled to receive minimum 4 cycles of myelosuppressive chemotherapy were eligible. For objective 1, dose escalation of LDA started at 0.005 mg/kg/day for 3 days. This dose satisfied objective 1 and was administered before chemotherapy cycles 2, 4, and 6 for objective 2. p53 level in peripheral lymphocytes was measured on day 1 of each cycle by ELISA assay. Chemotherapy cycles 1, 3, and 5 served as the baseline for the subsequent cycles of 2, 4, and 6 respectively. If p53 level for the subsequent cycle was lower (or higher) than the baseline cycle, p53 was defined as "suppressed" (or "activated") for the pair of cycles. Repeated measures linear models of CBC in terms of day, cycle, p53 activity and interaction terms were used.Twenty-six patients treated with 3 week cycle regimens form the base of analyses. The mean white blood cell, hemoglobin and absolute neutrophil counts were significantly higher in the "suppressed" relative to the "activated" group.These data support the proof of principle that suppression of p53 could lead to protection of bone marrow in patients receiving chemotherapy.This trial is registered in ClinicalTrials.gov. Identifier: NCT01428128.

Original languageEnglish (US)
JournalMolecular Oncology
DOIs
StateAccepted/In press - Jul 29 2015

Fingerprint

Drug Therapy
Arsenic
Activity Cycles
Linear Models
Hemoglobins
Neutrophils
Leukocytes
Radiotherapy
Bone Marrow
Enzyme-Linked Immunosorbent Assay
Lymphocytes
DNA

Keywords

  • Arsenic
  • Chemoprotection
  • Hematological toxicity
  • Myelosuppression
  • P53

ASJC Scopus subject areas

  • Cancer Research
  • Genetics
  • Molecular Medicine

Cite this

P53-Based strategy to reduce hematological toxicity of chemotherapy : A proof of principle study. / Ha, Chul S; Michalek, Joel E; Elledge, Richard M; Kelly, Kevin R.; Ganapathy, Suthakar; Su, Hang; Jenkins, Carol A.; Argiris, Athanassios; Swords, Ronan; Eng, Tony Y.; Karnad, Anand B; Crownover, Richard L; Swanson, Gregory P; Goros, Martin; Pollock, Brad H.; Yuan, Zhi Min.

In: Molecular Oncology, 29.07.2015.

Research output: Contribution to journalArticle

Ha, CS, Michalek, JE, Elledge, RM, Kelly, KR, Ganapathy, S, Su, H, Jenkins, CA, Argiris, A, Swords, R, Eng, TY, Karnad, AB, Crownover, RL, Swanson, GP, Goros, M, Pollock, BH & Yuan, ZM 2015, 'P53-Based strategy to reduce hematological toxicity of chemotherapy: A proof of principle study', Molecular Oncology. https://doi.org/10.1016/j.molonc.2015.09.004
Ha, Chul S ; Michalek, Joel E ; Elledge, Richard M ; Kelly, Kevin R. ; Ganapathy, Suthakar ; Su, Hang ; Jenkins, Carol A. ; Argiris, Athanassios ; Swords, Ronan ; Eng, Tony Y. ; Karnad, Anand B ; Crownover, Richard L ; Swanson, Gregory P ; Goros, Martin ; Pollock, Brad H. ; Yuan, Zhi Min. / P53-Based strategy to reduce hematological toxicity of chemotherapy : A proof of principle study. In: Molecular Oncology. 2015.
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AU - Ganapathy, Suthakar

AU - Su, Hang

AU - Jenkins, Carol A.

AU - Argiris, Athanassios

AU - Swords, Ronan

AU - Eng, Tony Y.

AU - Karnad, Anand B

AU - Crownover, Richard L

AU - Swanson, Gregory P

AU - Goros, Martin

AU - Pollock, Brad H.

AU - Yuan, Zhi Min

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