title: p53-Based Strategy for Protection of Bone Marrow From Y-90 Ibritumomab Tiuxetan.
abstract: OBJECTIVE
  The main drawbacks of radioimmunotherapy have been severe hematological toxicity and potential development of myelodysplastic syndrome and secondary leukemia. Activation of p53 follows a major pathway by which normal tissues respond to DNA-damaging agents, such as chemotherapy and radiation therapy, that result in injuries and pathological consequences. This pathway is separate from the tumor suppressor pathway of p53. We have previously reported that use of low-dose arsenic (LDA) temporarily and reversibly suppresses p53 activation, thereby ameliorating normal tissue toxicity from exposure to 5-fluorouracil and X rays. We have also demonstrated that LDA-mediated protection requires functional p53 and thus is selective to normal tissues, as essentially every cancer cell has dysfunctional p53. Here we tested the protective efficacy of LDA for bone marrow tissue against radioimmunotherapy through animal experiments.
  
  
  METHODS
  Mice were subjected to LDA pretreatment for 3 days, followed by treatment with Y-90 ibritumomab tiuxetan. Both dose course (10, 25, 50, 100, and 200 μCi) and time course (6, 24, and 72 hours and 1 and 2 weeks) experiments were performed. The response of bone marrow cells to LDA was determined by examining the expression of NFκB, Glut1, and Glut3. Staining with hematoxylin and eosin, γ-H2AX, and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) was used to examine morphology, DNA damage response, and apoptotic cell populations.
  
  
  RESULTS
  Elevated levels of NFκB, Glut1, and Glut3 were observed in bone marrow cells after LDA treatment. Bone marrow damage levels induced by Y-90 ibritumomab tiuxetan were greatly reduced by LDA pretreatment. Consistent with this observation, significantly less DNA damage and fewer apoptotic cells were accumulated after Y-90 ibritumomab tiuxetan treatment in LDA-pretreated mice. Furthermore, in the mouse xenograft model implanted with human Karpas-422 lymphoma cells, LDA pretreatment did not have any detectable effect on either tumor growth or Y-90 ibritumomab tiuxetan (200 μCi)-induced tumor suppression.
  
  
  CONCLUSIONS
  LDA pretreatment protected bone marrow without compromising tumor control caused by Y-90 ibritumomab tiuxetan.
authors.affiliation: Department of Radiation Oncology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas. Electronic address: suh3@uthscsa.edu.
authors.forename: Hang
authors.initials: H
authors.lastname: Su
authors.affiliation: Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, Massachusetts.
authors.forename: Suthakar
authors.initials: S
authors.lastname: Ganapathy
authors.affiliation: Department of Radiation Oncology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas.
authors.forename: Xiaolei
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, Massachusetts.
authors.forename: Zhi-Min
authors.initials: ZM
authors.lastname: Yuan
authors.affiliation: Department of Radiation Oncology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas.
authors.forename: Chul S
authors.initials: CS
authors.lastname: Ha
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000009:adverse effects*; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D001151:Arsenic / Q000008:administration & dosage*; D015415:Biomarkers / Q000378:metabolism; D001853:Bone Marrow / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects*; D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D004249:DNA Damage / Q000187:drug effects*; D005260:Female; D016158:Genes, p53 / Q000187:drug effects*; D051272:Glucose Transporter Type 1 / Q000378:metabolism; D051274:Glucose Transporter Type 3 / Q000378:metabolism; D064593:Heterografts; D006657:Histones / Q000378:metabolism; D020287:In Situ Nick-End Labeling; D016393:Lymphoma, B-Cell / Q000378:metabolism / Q000532:radiotherapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D016328:NF-kappa B / Q000378:metabolism; D011829:Radiation Dosage; D011833:Radiation Injuries, Experimental / Q000235:genetics / Q000517:prevention & control*; D011836:Radiation Tolerance / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D011837:Radiation-Protective Agents / Q000008:administration & dosage*; D016499:Radioimmunotherapy / Q000009:adverse effects; D015533:Transcriptional Activation / Q000187:drug effects; D015021:Yttrium Radioisotopes / Q000009:adverse effects*
chemical_list: D000911:Antibodies, Monoclonal; D015415:Biomarkers; D051272:Glucose Transporter Type 1; D051274:Glucose Transporter Type 3; D006657:Histones; D016328:NF-kappa B; D011837:Radiation-Protective Agents; C495678:Slc2a1 protein, mouse; C495689:Slc2a3 protein, mouse; D015021:Yttrium Radioisotopes; C475961:gamma-H2AX protein, mouse; C422802:ibritumomab tiuxetan; D001151:Arsenic