title: p53-based strategy to reduce hematological toxicity of chemotherapy: A proof of principle study.
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.
authors.affiliation: Department of Radiation Oncology, 7703 Floyd Curl Drive, University of Texas Health Science Center at San Antonio, TX 78229, United States. Electronic address: HAC@UTHSCSA.EDU.
authors.forename: Chul S
authors.initials: CS
authors.lastname: Ha
authors.affiliation: Department of Epidemiology and Biostatistics, 7703 Floyd Curl Drive, University of Texas Health Science Center at San Antonio, TX 78229, United States.
authors.forename: Joel E
authors.initials: JE
authors.lastname: Michalek
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, 7703 Floyd Curl Drive, University of Texas Health Science Center at San Antonio, TX 78229, United States.
authors.forename: Richard
authors.initials: R
authors.lastname: Elledge
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, 7703 Floyd Curl Drive, University of Texas Health Science Center at San Antonio, TX 78229, United States.
authors.forename: Kevin R
authors.initials: KR
authors.lastname: Kelly
authors.affiliation: Department of Radiation Oncology, 7703 Floyd Curl Drive, University of Texas Health Science Center at San Antonio, TX 78229, United States.
authors.forename: Suthakar
authors.initials: S
authors.lastname: Ganapathy
authors.affiliation: Department of Radiation Oncology, 7703 Floyd Curl Drive, University of Texas Health Science Center at San Antonio, TX 78229, United States.
authors.forename: Hang
authors.initials: H
authors.lastname: Su
authors.affiliation: Department of Radiation Oncology, 7703 Floyd Curl Drive, University of Texas Health Science Center at San Antonio, TX 78229, United States.
authors.forename: Carol A
authors.initials: CA
authors.lastname: Jenkins
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, 7703 Floyd Curl Drive, University of Texas Health Science Center at San Antonio, TX 78229, United States.
authors.forename: Athanassios
authors.initials: A
authors.lastname: Argiris
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, 7703 Floyd Curl Drive, University of Texas Health Science Center at San Antonio, TX 78229, United States.
authors.forename: Ronan
authors.initials: R
authors.lastname: Swords
authors.affiliation: Department of Radiation Oncology, 7703 Floyd Curl Drive, University of Texas Health Science Center at San Antonio, TX 78229, United States.
authors.forename: Tony Y
authors.initials: TY
authors.lastname: Eng
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, 7703 Floyd Curl Drive, University of Texas Health Science Center at San Antonio, TX 78229, United States.
authors.forename: Anand
authors.initials: A
authors.lastname: Karnad
authors.affiliation: Department of Radiation Oncology, 7703 Floyd Curl Drive, University of Texas Health Science Center at San Antonio, TX 78229, United States.
authors.forename: Richard L
authors.initials: RL
authors.lastname: Crownover
authors.affiliation: Department of Radiation Oncology, 7703 Floyd Curl Drive, University of Texas Health Science Center at San Antonio, TX 78229, United States.
authors.forename: Gregory P
authors.initials: GP
authors.lastname: Swanson
authors.affiliation: Department of Epidemiology and Biostatistics, 7703 Floyd Curl Drive, University of Texas Health Science Center at San Antonio, TX 78229, United States.
authors.forename: Martin
authors.initials: M
authors.lastname: Goros
authors.affiliation: Department of Epidemiology and Biostatistics, 7703 Floyd Curl Drive, University of Texas Health Science Center at San Antonio, TX 78229, United States.
authors.forename: Brad H
authors.initials: BH
authors.lastname: Pollock
authors.affiliation: Department of Radiation Oncology, 7703 Floyd Curl Drive, University of Texas Health Science Center at San Antonio, TX 78229, United States.
authors.forename: Zhi-Min
authors.initials: ZM
authors.lastname: Yuan
mesh_terms: D000970:Antineoplastic Agents / Q000009:adverse effects*; D001151:Arsenic / Q000008:administration & dosage*; D001853:Bone Marrow / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors*
chemical_list: D000970:Antineoplastic Agents; D016159:Tumor Suppressor Protein p53; D001151:Arsenic
keywords: Arsenic; Chemoprotection; Hematological toxicity; Myelosuppression; p53