p53-Based Strategy for Protection of Bone Marrow From Y-90 Ibritumomab Tiuxetan

Abstract

Purpose The main drawbacks of radioimmunotherapy have been severe hematological toxicity and potential development of myelodysplastic syndrome and secondary leukemia. p53 activation is a major pathway by which normal tissues respond to DNA damaging agents such as chemotherapy and radiotherapy, resulting in injuries and pathological consequences. This pathway is separate from the tumor suppressor pathway of p53. We have previously reported that the use of low-dose arsenic (LDA) temporarily and reversibly suppresses p53 activation, thereby ameliorating normal tissue toxicity from 5-FU and X-ray. 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. Method and Materials Mice were subject to LDA pretreatment for three days, followed by Y-90 ibritumomab tiuxetan treatment. Both dose-course (10, 25, 50, 100 and 200 μCi) and time-course (6h, 24h, 72h, 1wk and 2wk) experiments were performed. The response of bone marrow cells to LDA was examined by examining the expression of NFκB, Glut1 and Glut3. H&E, γ-H2AX, and TUNEL staining was employed 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 damages 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.

Regulation of the Mdm2-p53 signaling axis in the DNA damage response and tumorigenesis

“…In another approach that exploits the propensity for p53 inactivation in tumor cells, Yuan and colleagues have identified a phenomenon in which pre-treatment of cells with low-dose arsenic induces p53 stabilization and a p53-dependent metabolic shift from oxidative phosphorylation to anaerobic glycolysis which confers protection to normal tissues from 5FU and radiation-induced toxicities (257–259). This approach has recently shown hematopoietic protection in humans receiving myelosuppressive chemotherapy in a recently reported clinical trial (260).…”

Acute DNA damage activates the tumour suppressor p53 to promote radiation-induced lymphoma

“…In certain tissues, such as the haematopoietic system, acute toxicity from chemoradiation primarily results from the activation of the intrinsic pathway of apoptosis mediated by the tumour suppressor p53 (refs 2 , 3 , 4 , 5 , 6 ). Thus, blocking p53-mediated apoptosis during genotoxic therapies has been suggested as a promising approach to ameliorate acute toxicity in normal tissues that are wild type (WT) for p53 without compromising the therapeutic response of p53 mutant tumours 3 7 8 .…”

p53‐Based strategy to reduce hematological toxicity of chemotherapy: A proof of principle study

“…An example is radioimmunotherapy where the patients are usually treated with one dose instead of multiple repeated doses. We have recently presented preclinical data that demonstrate that suppression of p53 through pretreatment with LDA leads to protection of bone marrow from radioimmunotherapy using Y‐90 ibritumomab tiuxetan for B‐cell lymphoma as a model (Su et al., 2015). The same study also demonstrated much less double strand DNA damage as measured by pH2AX staining in mice pretreated with LDA.…”