3137 - P53 Downregulation-Based Strategy to Reduce Radiation-Induced Secondary Malignancies: A Pilot Study with RF Mice

Purpose/Objective(s): Genomic instability and impaired DNA repair following exposure to DNA-damaging agents (DDA) such as radiation and chemotherapy contribute to the development of therapy-related secondary malignancies, including myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). p53 activation is a key pathway leading to normal tissue injury in response to DDA, triggering senescence or cell death. We have demonstrated that low-dose arsenic trioxide (LDA) administered prior to DDA treatment mitigates normal tissue injury without compromising tumor response by temporarily and reversibly downregulating p53. This protective effect is selective to normal tissues as it requires intact p53. Most cancer cells are not protected as they have either mutated or dysfunctional p53. Building on our findings that LDA pretreatment reduces Spi-1/PU.1 gene deletion -- associated with 95% of radiation-induced AML in CBA/Ca mouse model – this study investigates whether LDA pretreatment reduces the incidence of radiation-induced leukemia or lymphoma in RF mice, which have a higher and earlier incidence of these malignancies (50-90% incidence of AML or thymic lymphoma after 4.25 Gy of TBI with latency of 4-6 months compared to 15-25% incidence and 18-24 month latency for CBA/Ca mice).

Materials/Methods: RF mice were assigned to either the LDA pretreatment group (n=24, 14 male/10 female) or the control group receiving PBS (n=23, 13 male/10 female). LDA (0.4 mg/kg) or PBS was administered via intraperitoneal injection for 3 days, followed by 4.25 Gy TBI at a dose rate of 0.9 Gy/min using the Faxitron X-ray System. Mice were monitored for six months post-irradiation and examined for leukemia or lymphoma upon sacrifice or morbidity.

Results: Due to breeding and health challenges, final group sizes were 21 mice in the LDA group (13 male/8 female) and 16 in the control group (9 male/7 female) at the time of LDA or PBS treatments. Their ages ranged from 10 to 26 weeks. In the LDA group, one female mouse exhibited morbidity at 18 weeks post-TBI, while in the control group, one female and one male exhibited morbidity at 20 weeks post-TBI. All other mice were sacrificed at the study endpoint. Leukemia or lymphoma was observed to be numerically reduced in LDA-treated mice [LDA 61.9% (13/21), control 81.3% (13/16), p=0.28, Fisher’s Exact Test]. A stronger protective effect was suggested in male mice, with 53.8% (7/13) affected in the LDA group versus 88.9% (8/9) in controls (p=0.16). Incidences for female were similar between groups (75% vs. 71.4%, p=1).

Conclusion: Despite limited sample size, LDA pretreatment suggested reduced radiation-induced leukemia/lymphoma, particularly in male mice. Given LDA’s previously demonstrated genome-protective effects, further studies with larger cohorts are warranted to confirm its potential in mitigating radiation-induced secondary malignancies such as MDS and AML.