评估二甲双胍对李-弗劳梅尼综合征患者耐受性和代谢影响的初步研究。
Pilot Study Assessing Tolerability and Metabolic Effects of Metformin in Patients With Li-Fraumeni Syndrome.
作者信息
Walcott Farzana L, Wang Ping-Yuan, Bryla Christine M, Huffstutler Rebecca D, Singh Neha, Pollak Michael N, Khincha Payal P, Savage Sharon A, Mai Phuong L, Dodd Kevin W, Hwang Paul M, Fojo Antonio T, Annunziata Christina M
机构信息
Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
Cardiovascular Branch, National Heart Lung Blood Institute, Bethesda, MD, USA.
出版信息
JNCI Cancer Spectr. 2020 Jul 18;4(6):pkaa063. doi: 10.1093/jncics/pkaa063. eCollection 2020 Dec.
BACKGROUND
Li-Fraumeni syndrome (LFS) is a highly penetrant autosomal dominant cancer predisposition disorder caused by germline pathogenic variants. Patients with LFS have increased oxidative phosphorylation capacity in skeletal muscle and oxidative stress in blood. Metformin inhibits oxidative phosphorylation, reducing available energy for cancer cell proliferation and decreasing production of reactive oxygen species that cause DNA damage. Thus, metformin may provide pharmacologic risk reduction for cancer in patients with LFS, but its safety in nondiabetic patients with germline pathogenic variants has not been documented.
METHODS
This study assessed safety and tolerability of metformin in nondiabetic LFS patients and measured changes in metabolic profiles. Adult patients with LFS and germline variant received 14 weeks of metformin. Blood samples were obtained for measurement of serum insulin-like growth factor-1, insulin, and insulin-like growth factor binding protein 3. Hepatic mitochondrial function was assessed with fasting exhaled CO after ingestion of C-labeled methionine. Changes in serum metabolome were measured. All statistical tests were 2-sided.
RESULTS
We enrolled 26 participants: 20 females and 6 males. The most common adverse events were diarrhea (50.0%) and nausea (46.2%). Lactic acidosis did not occur, and there were no changes in fasting glucose. Cumulative mean C exhalation was statistically significantly suppressed by metformin ( = .001). Mean levels of insulin-like growth factor binding protein 3 and insulin-like growth factor-1 were statistically significantly lowered ( = .02). Lipid metabolites and branched-chain amino acids accumulated.
CONCLUSIONS
Metformin was safe and tolerable in patients with LFS. It suppressed hepatic mitochondrial function as expected in these individuals. This study adds to the rationale for development of a pharmacologic risk-reduction clinical trial of metformin in LFS.
背景
李-佛美尼综合征（LFS）是一种由种系致病性变异引起的高外显率常染色体显性遗传性癌症易感疾病。LFS患者骨骼肌中的氧化磷酸化能力增强，血液中的氧化应激增加。二甲双胍可抑制氧化磷酸化，减少癌细胞增殖所需的能量，并减少导致DNA损伤的活性氧的产生。因此，二甲双胍可能为LFS患者降低患癌的药理学风险，但其在携带种系致病性变异的非糖尿病患者中的安全性尚无文献记载。
方法
本研究评估了二甲双胍在非糖尿病LFS患者中的安全性和耐受性，并测量了代谢谱的变化。患有LFS和种系变异的成年患者接受了14周的二甲双胍治疗。采集血样以测量血清胰岛素样生长因子-1、胰岛素和胰岛素样生长因子结合蛋白3。摄入C标记的蛋氨酸后，通过空腹呼出的CO评估肝脏线粒体功能。测量血清代谢组的变化。所有统计检验均为双侧检验。
结果
我们招募了26名参与者：20名女性和6名男性。最常见的不良事件是腹泻（50.0%）和恶心（46.2%）。未发生乳酸性酸中毒，空腹血糖也无变化。二甲双胍使累积平均C呼出量受到统计学显著抑制（P = .001）。胰岛素样生长因子结合蛋白3和胰岛素样生长因子-1的平均水平在统计学上显著降低（P = .02）。脂质代谢物和支链氨基酸蓄积。
结论
二甲双胍在LFS患者中安全且耐受性良好。它如预期那样抑制了这些个体的肝脏线粒体功能。本研究为开展二甲双胍降低LFS患者癌症风险的药理学临床试验提供了依据。
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