Department of Urology, Austin Health, Heidelberg, Vic., Australia.
Department of Surgery, University of Melbourne, Heidelberg, Vic., Australia.
BJU Int. 2019 May;123 Suppl 5:36-42. doi: 10.1111/bju.14709. Epub 2019 Apr 23.
To assess whether metformin reduces radio-resistance and increases survival in men undergoing external beam radiation therapy (EBRT) for prostate cancer (PCa), and to determine its effect on hypoxia inducible factor 1-α (HIF1α).
All patients treated with curative intent with EBRT for PCa at a major cancer centre between 2000 and 2007 were included in this study. The outcome measures of time to biochemical failure (BF), metastasis, PCa-specific mortality and overall survival (OS) were analysed in those taking metformin vs those not, using competing risk and Cox regression models. To determine metformin's effect on HIF1α expression and survival in vitro, PC3 cells with high basal HIF1α levels were subjected to increasing doses of metformin after H O -induced oxidative stress.
A total of 2055 eligible cases, including 113 who were on metformin, were identified, with a median follow-up of 95.7 months. There were no differences in age, initial prostate-specific antigen level, Gleason score, T-stage, D'Amico risk class or duration of androgen deprivation therapy (ADT) between patients who were or were not on metformin. Treatment with metformin did not result in any apparent improvement in time to BF, time to metastasis detection or OS, but there was a 1.5-fold increase in PCa-specific deaths (P = 0.045) in patients on metformin and ADT when adjusted for cancer risk and comorbidities. When comparing patients on high-dose metformin (>1 g/d) with those on low-dose metformin (≤1 g), there was no difference in either time to metastases or time to BF. In vitro metformin at a high concentration of 100 μM did not reduce HIF1α expression, nor did metformin affect the PC3 cell survival when exposed to oxidative stress (H O ).
No association was found between the use of metformin and time to metastasis detection, time to BF or OS in patients undergoing radiation therapy with or without ADT for PCa. In vitro, low therapeutic concentrations of metformin had no effect on HIF1α, and this observation could explain the conflicting evidence for the effectiveness of metformin in men undergoing EBRT for PCa. Higher, more toxic doses of metformin may be required to inhibit the mammalian target of rapamycin-HIF1α pathway in this patient group.
评估二甲双胍是否能降低男性接受前列腺癌外照射放射治疗（EBRT）后的放射抗性并提高生存率，并确定其对缺氧诱导因子 1-α（HIF1α）的影响。
本研究纳入了 2000 年至 2007 年期间在一家主要癌症中心接受根治性 EBRT 治疗的所有前列腺癌患者。使用竞争风险和 Cox 回归模型分析接受二甲双胍治疗与未接受治疗的患者的生化失败（BF）、转移、前列腺癌特异性死亡率和总生存率（OS）的时间。为了确定二甲双胍对体外 HIF1α表达和生存的影响，在 H2O2 诱导的氧化应激后，将 HIF1α 基础水平较高的 PC3 细胞用不同剂量的二甲双胍处理。
共确定了 2055 例符合条件的病例，其中 113 例正在服用二甲双胍，中位随访时间为 95.7 个月。接受或未接受二甲双胍治疗的患者在年龄、初始前列腺特异性抗原水平、Gleason 评分、T 分期、D'Amico 风险分类或雄激素剥夺治疗（ADT）持续时间方面无差异。与未接受 ADT 治疗的患者相比，接受二甲双胍联合 ADT 治疗的患者 BF 时间、转移检测时间或 OS 无明显改善，但二甲双胍联合 ADT 治疗的患者前列腺癌特异性死亡风险增加了 1.5 倍（P=0.045），这与癌症风险和合并症相关。比较高剂量（>1 g/d）和低剂量（≤1 g）二甲双胍患者，转移时间或 BF 时间无差异。高浓度（100 μM）二甲双胍体外并不降低 HIF1α 的表达，也不影响氧化应激（H2O2）下 PC3 细胞的存活。
在接受或不接受 ADT 的前列腺癌患者中，使用二甲双胍与转移检测时间、BF 时间或 OS 之间未发现关联。体外，低治疗浓度的二甲双胍对 HIF1α 没有影响，这一观察结果可以解释二甲双胍在接受前列腺癌 EBRT 治疗的男性中的疗效存在争议的原因。对于该患者组，可能需要更高、更具毒性的二甲双胍剂量来抑制哺乳动物雷帕霉素靶蛋白-HIF1α 通路。
