XXXX -Based Strategy for Protection of Bone Marrow From Y-90 Ibritumomab Tiuxetan.

@entity1 @entity137 @entity24031 @entity706 @entity899 @entity5 @entity19 @entity1711 @entity2590 @entity1977 @entity29408 @entity236 @entity1778 @entity1710 @entity3494 @entity1487
PURPOSE: The main drawbacks of radioimmunotherapy have been severe hematological @entity137 and potential development of @entity2590 and @entity1778 . Activation of @entity899 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 @entity5 suppressor pathway of @entity899 . We have previously reported that use of low-dose @entity3494 (LDA) temporarily and reversibly suppresses @entity899 activation, thereby ameliorating normal tissue @entity137 from exposure to @entity1487 and X rays. We have also demonstrated that LDA-mediated protection requires functional @entity899 and thus is selective to normal tissues, as essentially every @entity5 cell has dysfunctional @entity899 . Here we tested the protective efficacy of LDA for bone marrow tissue against radioimmunotherapy through animal experiments. METHODS AND MATERIALS: @entity19 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   Ci) 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 NFkB, @entity29408 , and @entity24031 . Staining with @entity1710 and @entity1711 , y-H2AX, and terminal deoxynucleotidyl transferase @entity1977 nick end labeling (TUNEL) was used to examine morphology, DNA damage response, and apoptotic cell populations. RESULTS: Elevated levels of NFkB, @entity29408 , and @entity24031 were observed in bone marrow cells after LDA treatment. Bone @entity236 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 @entity19 . Furthermore, in the @entity19 xenograft model implanted with @entity1 @entity1 @entity706 cells, LDA pretreatment did not have any detectable effect on either @entity5 growth or Y-90 ibritumomab tiuxetan (200   Ci)-induced @entity5 suppression. CONCLUSIONS: LDA pretreatment protected bone marrow without compromising @entity5 control caused by Y-90 ibritumomab tiuxetan.
