Capecitabine-Based Chemoendocrine Combination as First-Line Treatment for Metastatic Hormone-Positive Metastatic Breast Cancer: Phase 2 Study

BackgroundPreclinical studies have suggested a synergistic effect of tamoxifen and capecitabine in estrogen receptor–positive cell lines. We evaluated the safety and efficacy of first-line chemoendocrine treatment in patients with metastatic breast cancer. Biochemical assessment was performed of serum levels of thymidine phosphorylase enzyme (TP), serum tamoxifen, hydroxytamoxifen, and 5-fluorouracil in relationship to efficacy.Patients and MethodsThis prospective phase 2 interventional study studied patients with estrogen receptor-positive, HER2⁻ metastatic breast cancer who received either tamoxifen/capecitabine or letrozole/capecitabine as first-line treatment. The dose of capecitabine provided at 2000 mg per day continuously as a fixed dose.ResultsForty women with a median age of 49.3 years were enrolled. For the whole study group, median progression-free survival (PFS) was 10 months and median overall survival (OS) was 23.3 months. The overall response rate was 60% and the clinical benefit rate 82.5%. Progesterone receptor positivity was associated with significantly longer PFS (12 vs. 7 months, P = .021). The most frequent adverse events were palmar–plantar erythrodysesthesia (62.5%), fatigue (62.5%), diarrhea (30%), abdominal pain (12.5%), and constipation (10%). Changes in serum level of TP were not correlated to response to treatment, PFS, or OS. Higher serum levels of tamoxifen and hydroxytamoxifen were correlated with higher response rates and longer PFS but not OS.ConclusionChemoendocrine treatment is well tolerated, with no evidence of contradictory effects between the combination components. However, the efficacy data need more validation.     

Exercising with blocked muscle glycogenolysis: Adaptation in the McArdle mouse

Background

McArdle disease (glycogen storage disease type V) is an inborn error of skeletal muscle metabolism, which affects glycogen phosphorylase (myophosphorylase) activity leading to an inability to break down glycogen. Patients with McArdle disease are exercise intolerant, as muscle glycogen-derived glucose is unavailable during exercise. Metabolic adaptation to blocked muscle glycogenolysis occurs at rest in the McArdle mouse model, but only in highly glycolytic muscle. However, it is unknown what compensatory metabolic adaptations occur during exercise in McArdle disease.

转染胸苷磷酸化酶基因对5'-脱氧氟脲苷抗结肠癌细胞株活性的影响

目的 探讨人结肠癌细胞系SW480和LOVO细胞株转染胸苷磷酸化酶(TP)基因后转化5′-脱氧氟脲苷(5′-DFUR)为氟尿嘧啶(5-FU)能力的变化及5′-DFUR抗癌细胞株活性的变化.方法 构建包含TP cDNA的真核表达载体,用慢病毒包装后转染结肠癌细胞株SW480和LOVO.转染5代后以免疫荧光法和流式细胞技术检测转染效率;RT-PCR和Western blot法分别检测2株细胞的TP mRNA和TP蛋白表达.然后以高效液相色谱法(HPLC)检测2株细胞转染前后转化5′-DFUR为5-FU的量;MTT法检测5′-DFUR对2株细胞转染前后半数抑制浓度(IC50).结果 转染TP基因后SW480-TP与LOVO-TP 5代细胞转染效率稳定在95％左右.2株转染细胞的TP mRNA表达分别比野生型细胞增加(695±172)倍(t=-7.00,P=0.002)和(282±87)倍(t=-5.61,P=0.030),Western blot显示TP蛋白表达也明显增强.转染后的SW480-TP与LOVO-TP在培养基中分别使5′-DFUR转化为5-FU的量增加(t=19.406 ～66.921,P＜0.01).5′-DFUR对SW480的IC50由(1641±53) μmol/L降至(587±17) μmol/L(t=-32.59,P＜0.01);对LOVO的IC50由(1607±57) μmol/L降至(1088±89) μmol/L(t=-8.52,P＜0.01).结论 慢病毒载体能够高效地将TP cDNA转染至人结肠癌细胞SW480和LOVO并稳定传代,转染后2株细胞的TP mRNA和TP蛋白表达明显增高,使5′-DFUR转化为5-FU的量增加,对结肠癌细胞株SW480和LOVO的抑制作用增强.     

TP在子宫内膜癌中的表达及其临床意义

目的检测子宫内膜癌中胸苷磷酸化酶(TP)的表达情况,探讨它与子宫内膜癌预后的相关性及临床意义。方法采用免疫组化SP法检测15例正常内膜,10例不典型增生内膜,48例子宫内膜癌石蜡标本中的TP蛋白表达情况。结果子宫内膜癌TP表达显著高于正常内膜(PTP=0.029)。TP表达与肿瘤分化程度、浸润深度、淋巴结转移及临床病理分期无相关性(P>0.05)。结论 TP的过度表达可能与子宫内膜癌的预后有关。     

干扰素α2a对人结肠癌细胞胸苷磷酸化酶表达和5′-脱氧氟尿苷抗癌活性的影响

目的 探讨干扰素-α2a(IFN-α2a)对人结肠癌细胞胸苷磷酸化酶(TP)mRNA表达水平以及5′-脱氧氟尿苷(5′-DFUR)和氟尿嘧啶(5-FU)抗癌效应的影响.方法 不同剂量IFN-α2a分别处理人结肠癌细胞LOVO和SW480,荧光定量PCR检测TP mRNA表达水平;MTT法检测联合应用IFN-α2a前后5-FU和5′-DFUR对LOVO和SW480抑制作用的半数有效浓度(IC50)变化情况.结果 与0 U/ml IFN-α2a浓度组相比,500 U/ml及5000 U/ml组可明显上调LOVO和SW480细胞TPmRNA表达(P＜0.01),而50 U/ml则对上述两种细胞TPmRNA表达水平无明显影响(P＞0.05).联合应用浓度为20 U/ml的IFN-α2a后,5-FU对LOVO和SW480细胞的IC50无明显改变(P＞0.05),但5′-DFUR的IC50则明显降低(P＜0.05).结论 IFN-α2a能上调结肠癌细胞TP mRNA的表达水平,并可使5′-DFUR对结肠癌细胞的IC50明显下降,而对5-FU则无明显影响.     

Pentacyclic Triterpenoids from Spikes of Prunella vulgaris L. Inhibit Glycogen Phosphorylase and Improve Insulin Sensitivity in 3T3‐L1 Adipocytes

Phytochemical investigation of methanol extract from the spikes of Prunella vulgaris L. led to the isolation of two new pentacyclic triterpenoid glycosides Vulgasides I (1) and II (2) along with 13 known compounds (3–15). Their structures were established on the basis of nuclear magnetic resonance (1D and 2D) and mass spectroscopic data analysis. All the isolated compounds were screened for glycogen phosphorylase inhibitory activity and also evaluated for their effect on insulin sensitivity in 3T3‐L1 adipocytes. Two new compounds (1, 2) did not demonstrate the glycogen phosphorylase inhibitory activity, but other compounds (3–11) exhibited varying degrees of glycogen phosphorylase inhibitory activity with IC₅₀ values in the range from 30.69 to 68.85 μM. Compounds 3, 6, 7, 11, and 13 demonstrated markedly increased insulin‐mediated glucose consumption in 3T3‐L1 adipocytes. Copyright © 2014 John Wiley & Sons, Ltd.     

缺血性脑卒中患者甲硫腺苷磷酸化酶基因的表达

目的：研究甲硫腺苷磷酸化酶（methylthioadenonine phosphorylase,MTAP）基因在缺血性脑卒中患者中的表达,探讨MTAP基因与缺血性脑卒中发病的关系。方法：采用聚合酶链式反应（ PCR）方法,检测并比较50例缺血性脑卒中患者和50例对照组人群 MTAP基因的表达情况,分析MTAP表达与缺血性脑卒中的相关性。结果：MTAP基因在缺血性脑卒中患者与正常对照组比较,差异无统计学意义（ P ＞0．05）。结论：缺血性脑卒中的发病机制可能与MTAP基因表达无关。     

Potential role of polymorphisms in the transporter genes ENT1 and MATE1/OCT2 in predicting TAS-102 efficacy and toxicity in patients with refractory metastatic colorectal cancer

BackgroundTrifluridine (FTD) is an active cytotoxic component of the metastatic colorectal cancer (mCRC) drug TAS-102, and thymidine phosphorylase inhibitor (TPI) inhibits the rapid degradation of FTD. We tested whether single nucleotide polymorphisms (SNPs) in genes involved in FTD metabolism and TPI excretion could predict outcome in patients with mCRC treated with TAS-102.Patients and methodsWe investigated three different cohorts: a training cohort (n = 52) and a testing cohort (n = 129) both receiving TAS-102 and a control cohort (n = 52) receiving regorafenib. SNPs of TK1, ENT1, CNT1, MATE1, MATE2 and OCT2 were analysed by polymerase chain reaction-based direct DNA sequencing.ResultsIn the training cohort, patients with any ENT1 rs760370 G allele had a significantly longer progression-free survival (PFS; 3.5 versus 2.1 months, respectively, hazard ratio [HR] 0.44, P = 0.004) and overall survival (OS; 8.7 versus 5.3 months, respectively, HR 0.27, P = 0.003) than the A/A genotype. These findings were validated in the testing cohort (P = 0.021 and 0.009 for PFS and OS, respectively). In addition, the combination of ENT1 rs760370, MATE1 rs2289669 and OCT2 rs316019 SNPs significantly stratified patients with the risk of PFS and OS in both cohorts (P < 0.001 for PFS and OS in the training cohort; P = 0.053 and 0.025 for PFS and OS, respectively, in the testing cohort). No significant differences were observed in the control group.ConclusionsThe combination of ENT1, MATE1 and OCT2 SNPs may serve as a predictive and prognostic marker in mCRC patients treated with TAS-102.