Hang Su1, Suthakar Ganapathy2, Xiaolei Li3, Zhi-Min Yuan2, Chul S Ha3. 1. Department of Radiation Oncology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas. Electronic address: suh3@uthscsa.edu. 2. Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, Massachusetts. 3. Department of Radiation Oncology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas.
Abstract
PURPOSE: 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 AND MATERIALS: 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.
PURPOSE: 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 AND MATERIALS: 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 transferasedUTP 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: Maria A Christophorou; Dionisio Martin-Zanca; Laura Soucek; Elizabeth R Lawlor; Lamorna Brown-Swigart; Emmy W Verschuren; Gerard I Evan Journal: Nat Genet Date: 2005-05-29 Impact factor: 38.330
Authors: Steven H Lamm; Arnold Engel; Michael B Kruse; Manning Feinleib; Daniel M Byrd; Shenghan Lai; Richard Wilson Journal: J Occup Environ Med Date: 2004-03 Impact factor: 2.162
Authors: Angeline S Andrew; Amy J Warren; Aaron Barchowsky; Kaili A Temple; Linda Klei; Nicole V Soucy; Kimberley A O'Hara; Joshua W Hamilton Journal: Environ Health Perspect Date: 2003-05 Impact factor: 9.031
Authors: Chul S Ha; Joel E Michalek; Richard Elledge; Kevin R Kelly; Suthakar Ganapathy; Hang Su; Carol A Jenkins; Athanassios Argiris; Ronan Swords; Tony Y Eng; Anand Karnad; Richard L Crownover; Gregory P Swanson; Martin Goros; Brad H Pollock; Zhi-Min Yuan Journal: Mol Oncol Date: 2015-09-18 Impact factor: 6.603
Authors: Chang-Lung Lee; Katherine D Castle; Everett J Moding; Jordan M Blum; Nerissa Williams; Lixia Luo; Yan Ma; Luke B Borst; Yongbaek Kim; David G Kirsch Journal: Nat Commun Date: 2015-09-24 Impact factor: 14.919