范可尼贫血 (FA) 是一种由 DNA 修复缺陷引起的疾病，表现为骨髓衰竭、癌症倾向和发育缺陷。 FA 通路中一个或多个基因含有失活突变的小鼠部分模拟了人类疾病。我们之前报道过二甲双胍（MET）或羟甲龙（OXM）单一疗法可改善 Fancd2-/- 小鼠的外周血（PB）计数以及骨髓（BM）造血干祖细胞（HSPC）数量和功能。为了评估这些药物的联合治疗是否具有预防 FA 骨髓衰竭的协同作用，我们用单独的 MET、单独的 OXM、MET OXM 或安慰剂饮食治疗 Fancd2-/- 小鼠和野生型对照组。雄性和雌性小鼠均在 3 周至 18 个月大期间接受治疗。 OXM 治疗的动物显示出血液参数的适度改善，包括血小板计数 (p=0.01) 和血红蛋白水平 (p<0.05)。此外，长期单独使用 MET 治疗，静态 HSC (LSK) 的百分比显着增加 (p=0.001)。然而，通过 LSK 频率或 CFU-S 测量的祖细胞绝对数量并没有因 MET 治疗而显着改变。二甲双胍和羟甲龙的组合并未对任何参数产生显着的协同效应。无论基因型如何，服用 MET OXM 或单独服用 MET 的雄性动物在 18 个月时明显比对照组瘦。对这些动物肝组织的基因表达分析表明，由 Fancd2 缺失引起的一些表达变化通过二甲双胍治疗部分正常化。重要的是，尽管长期给药，但没有观察到单独或联合疗法的不良反应。

Fanconi Anemia (FA) is a disease caused by defective DNA repair which manifests as bone marrow failure, cancer predisposition, and developmental defects. Mice containing inactivating mutations in one or more genes in the FA pathway partially mimic the human disease. We previously reported that monotherapy with either metformin (MET) or oxymetholone (OXM) improved peripheral blood (PB) counts and the number and functionality of bone marrow (BM) hematopoietic stem progenitor cells (HSPCs) number in Fancd2-/- mice. To evaluate whether the combination treatment of these drugs has a synergistic effect to prevent bone marrow failure in FA, we treated cohorts of Fancd2-/- mice and wild-type controls with either MET alone, OXM alone, MET+OXM or placebo diet. Both male and female mice were treated from age 3 weeks to 18 months. The OXM treated animals showed modest improvements in blood parameters including platelet count (p=0.01) and hemoglobin levels (p<0.05). In addition, the percentage of quiescent HSC (LSK) was significantly increased (p=0.001) by long-term treatment with MET alone. However, the absolute number of progenitors, measured by LSK frequency or CFU-S, was not significantly altered by MET therapy. The combination of metformin and oxymetholone did not result in a significant synergistic effect on any parameter. Male animals on MET+OXM or MET alone were significantly leaner than controls at 18 months, regardless of genotype. Gene expression analysis of liver tissue from these animals showed that some of the expression changes caused by Fancd2 deletion were partially normalized by metformin treatment. Importantly, no adverse effects of the individual or combination therapies were observed, despite the long-term administration.