上海郊区老年痴呆症病人α-雌激素受体及芳香烃受体基因多态性

目的：探索上海地区农民人群中α-雌激素受体基因(ER-α)及芳香烃受体基因(Ahr)不同基因形态和老年痴呆症高发风险的可能联系．方法：分别以PCR—RFLP和AS—PCR方法分析一组老年痴呆症患者(n=52)ER-α基因及Ahr基因的多态位点，同一地区的健康人群(n=125)为对照．结果：Alzheimer症病人ER-α基因两个位点突变形态频率显著高于对照人群(Pvu Ⅱ位点：P=0．023，OR=2．94，95％CI 1．13—7．71；Xba I位点：P=0．046，0R=2．28，95％ CI 1．003—5．17)．Ahr G1721A位点基因型频率在病人组和对照组间无显著差异．结论：ER-α基因多态性可能与Alzheimer症易感性个体差异有关，本工作不支持Ahr基因多态性与老年痴呆症高发风险间的可能关联．     

Synthetic peptide derived from α‐fetoprotein inhibits growth of human breast cancer: investigation of the pharmacophore and synthesis optimization

Abstract: A synthetic peptide that inhibits the growth of estrogen receptor positive (ER+) human breast cancers, growing as xenografts in mice, has been reported. The cyclic 9‐mer peptide, cyclo[EMTOVNOGQ], is derived from α‐fetoprotein (AFP), a safe, naturally occurring human protein produced during pregnancy, which itself has anti‐estrogenic and anti‐breast cancer activity. To determine the pharmacophore of the peptide, a series of analogs was prepared using solid‐phase peptide synthesis. Analogs were screened in a 1‐day bioassay, which assessed their ability to inhibit the estrogen‐stimulated growth of uterus in immature mice. Deletion of glutamic acid, Glu1, abolished activity of the peptide, but glutamine (Gln) or asparagine (Asn) could be substituted for Glu1 without loss of activity. Methionine (Met2) was replaced with lysine (Lys) or tyrosine (Tyr) with retention of activity. Substitution of Lys for Met2 in the cyclic molecule resulted in a compound with activity comparable with the Met2‐containing cyclic molecule, but with a greater than twofold increase in purity and corresponding increase in yield. This Lys analog demonstrated anti‐breast cancer activity equivalent to that of the original Met‐containing peptide. Therefore, Met2 is not essential for biologic activity and substitution of Lys is synthetically advantageous. Threonine (Thr3) is a nonessential site, and can be substituted with serine (Ser), valine (Val), or alanine (Ala) without significant loss of activity. Hydroxyproline (Hyp), substituted in place of the naturally occurring prolines (Pro4, Pro7), allowed retention of activity and increased stability of the peptide during storage. Replacement of the first Pro (Pro4) with Ser maintains the activity of the peptide, but substitution of Ser for the second Pro (Pro7) abolishes the activity of the peptide. This suggests that the imino acid at residue 7 is important for conformation of the peptide, and the backbone atoms are part of the pharmacophore, but Pro4 is not essential. Valine (Val5) can be substituted only with branched‐chain amino acids (isoleucine, leucine or Thr); replacement by d ‐valine or Ala resulted in loss of biologic activity. Thus, for this site, the bulky branched side chain is essential. Asparagine (Asn6) is essential for activity. Substitution with Gln or aspartic acid (Asp), resulted in reduction of biologic activity. Removal of glycine (Gly8) resulted in a loss of activity but nonconservative substitutions can be made at this site without a loss of activity indicating that it is not part of the pharmacophore. Cyclization of the peptide is facilitated by addition of Gln9, but this residue does not occur in AFP nor is it necessary for activity. Gln9 can be replaced with Asn, resulting in a molecule with similar activity. These data indicate that the pharmacophore of the peptide includes side chains of Val5 and Asn6 and backbone atoms contributed by Thr3, Val5, Asn6, Hyp7 and Gly8. Met2 and Gln9 can be modified or replaced. Glu1 can be replaced with charged amino acids, and is not likely to be part of the binding site of the peptide. The results of this study provide information that will be helpful in the rational modification of cyclo[EMTOVNOGQ] to yield peptide analogs and peptidomimetics with advantages in synthesis, pharmacologic properties, and biologic activity.     

Thioether side chain cyclization for helical peptide formation: inhibitors of estrogen receptor–coactivator interactions

Abstract: Cystine, lanthionine, and cystathionine containing cyclic peptides incorporating the signature nuclear receptor (NR) box (LXXLL) motif have been synthesized and the abilities of these peptides to inhibit estrogen receptor (ER)–coactivator interactions have been determined. We found that helicity of these peptides directly correlated with their bioactivity. Cystathionine proved to be a redox‐stable, isosteric replacement for the cystine disulfide. Cystathionine containing peptide 3 showed higher helical character and a lower inhibition constant (Ki, 7 nm ) when compared with its cystine counterpart.     

乳腺癌组织PS2与雌激素和孕激素受体的关系及预后意义

目的 :探讨PS2在乳腺癌中的表达及其与雌激素受体 (ER)、孕激素受体 (PR)关系和预后意义。方法 :采用链亲和素(LSAB)法检测 110例乳腺癌中PS2的表达。结果 :PS2在乳腺癌组织中的阳性表达率为3 9 0 9% ( 4 3 / 110 ) ,其表达与患者年龄无关 ,P >0 0 5 ;与乳腺癌瘤体大小、腋淋巴结转移呈负相关 ,P <0 0 5。在ER阳性组和阴性组 ,PS2阳性率分别为 48 5 3 % ( 3 3 / 68)和2 3 81% ( 10 / 42 ) ,P =0 0 1;在PR阳性组和阴性组 ,PS2阳性率分别为 49 15 % ( 2 9/ 5 9)和2 7 45 % ( 14 / 5 1) ,P =0 0 2 ,PS2表达与ER、PR呈正相关关系。结论 :PS2可作为判断乳腺癌预后及预测术后抗雌激素治疗效果的重要指标     

乳腺癌C-erbB-2癌基因与雌激素和孕激素受体的关系及其意义

目的　探讨乳腺癌C -erbB - 2癌基因与雌激素和孕激素受体的关系及其意义。方法　采用免疫组化方法 (二步法 ) ,检测 83例乳腺癌组织中C -erbB - 2、ER、PR的表达。结果　C -erbB - 2、ER、PR在乳腺癌组织中表达阳性率为 5 7 83%、71 0 8%、6 6 2 7%。C -erbB - 2表达 :在ER、PR阴性组高于ER、PR阳性组 (P <0 0 5 ) ;在淋巴结转移组的乳腺癌高于淋巴结未转移组 (P <0 0 5 )。结论　C -erbB - 2与ER、PR联合检测 ,对于乳腺癌患者术后选择个性化化疗具有指导意义 ,也是衡量预后的重要指标。     

胃癌的雌孕激素受体检测及应用三苯氧胺治疗的研究

目的　探讨胃癌的雌激素受体 (ER)、孕激素受体 (PR)表达情况及其对预后的影响 ,观察三苯氧胺 (TAM)在胃癌治疗中的作用。方法　从 1993年 2月到 2 0 0 0年 12月 ,用免疫组化SP法 ,对 12 3例胃癌术后标本进行了ER、PR检测 ,并将TAM应用于胃癌的内分泌治疗 ,追踪随访 5年。结果　①胃癌的ER、PR阳性率均为 36 5 9% ( 45 / 12 3) ;②分化好 (高、中分化 )的胃癌ER、PR阳性率18.5 7% ( 13/ 70 ) ,分化差 (低分化腺癌 ,粘液腺癌和印戒细胞癌 )的胃癌ER、PR阳性率 60 38% ( 32 / 5 3) ,统计学处理有显著差异 (P <0 .0 5 ) ;③ER、PR阳性表达与临床分期呈正相关 ,分期越晚阳性率越高 ,但统计学无显著差异 (P >0 .0 5 ) ;④接受化疗 34例 ,化疗同时辅以TAM内分泌治疗 31例 ,5年生存率分别为 2 6.47% ( 9/ 34 )、5 1.61% ( 16/ 31) ,二者有显著差异 (P <0 .0 5 )。结论　本研究表明 ,ER、PR阳性表达的胃癌是一种雌、孕激素依赖性肿瘤 ,化疗联合TAM内分泌治疗 ,可抑制胃癌细胞的生长 ,提高 5年生存率     

20例原发性输卵管癌组织中ER、PR与p~(53)蛋白的表达

目的：分析原发性输卵管腺癌的ＥＲ、ＰＲ及ｐ５３蛋白的表达，研究其与该肿瘤的临床分期、病理分级及患者预后的关系。方法：材料选自２０份原发性输卵管腺癌及１０份正常输卵管组织的存档石蜡包埋标本，采用免疫组化法检测。结果：在２０份原发性输卵管癌标本中，ＥＲ、ＰＲ的阳性表达率分别为２５％和１５％，稍高于正常输卵管组的１０％，但差异无显著性（Ｐ＞０．０５）；ｐ５３蛋白在癌症组的阳性表达率为４０％，对照组则无１例阳性表达，差异有显著性（Ｐ＜０．０５）；ｐ５３蛋白在晚期、分化差及预后不良的输卵管癌病例中的表达呈上升趋势，但未达到统计学意义（Ｐ＞０．０５）；对侧输卵管炎症的存在与ｐ５３蛋白的阳性表达呈负相关（Ｐ＜０．０５）。结论：在原发性输卵管癌中，ＥＲ、ＰＲ有一定程度的表达，但均较低；ｐ５３基因的突变可能参与了该肿瘤的发生，并可作为综合判断其恶性程度及患者预后的指标之一。     

CD44 variant expression and estrogen receptor status in breast cancer

To understand the relationship between CD44 gene expressionand an established variable associated with aggressive behaviourin human breast cancer, we have studied apanel of 6 breast cell lines and 40breast tumors selected primarily on the basis ofestrogen receptor (ER) status. CD44s (standard form) mRNAwas assessed by semi-quantitative RT-PCR, and CD44 variantsincorporating exon v7 or v10 were studied byRT-PCR and Southern blot. While CD44 expression wasnot influenced by estrogen in ER+ve MCF-7 cells,CD44s expression was slightly higher (up to 2fold) in ER–ve cells but there was amarked decrease in the range of CD44 variantsincorporating exons v7 or v10. In microdissected tumors,the levels of CD44s showed no correlation withER status but the pattern of expression oflarger forms of CD44 incorporating variant exons v7and v10 was significantly different (p=0.005and p=0.015, respectively) between ER+ve andER–ve tumors, reflecting the pattern seen in thecell lines. These findings suggest that the profileof CD44 expression in breast cancer may reflectcellular differentiation as indicated by the ER phenotype.The influence of these differences in CD44 expressionon the increased metastatic potential of ER negativebreast cancer remains to be determined.     

No association between immunohistochemical expression of p53, c-erbB-2, Ki-67, estrogen and progesterone receptors in female papillary thyroid cancer and ionizing radiation

An association has previously been reported between exposure to medical diagnostic ionizing radiation and papillary thyroid cancer in women. To further evaluate potential mechanisms in carcinogenesis, the expression of p53, c-erbB-2, as well as Ki-67, estrogen and progesterone receptors were analyzed by immunohistochemistry in 19 women exposed to X-rays and for comparison in nine women without such reported exposure. They all had papillary thyroid cancer. No difference was found between these groups. The results of this study showed that p53, c-erbB-2, Ki-67, estrogen and progesterone receptors are not involved in papillary thyroid cancer associated with exposure to medical diagnostic ionizing radiation.     

人胃癌SGC-7901细胞胞浆胞核性激素受体测定

 作者采用葡聚糖包被活性碳饱和分析法(DCC法)分别测定了培养的人胃低分化腺癌SGC-7901细胞的胞浆及胞核KCL抽提液中的雌激素受体(ER)、孕激素受体(PR)和雄激素受体(AR)的含量。 结果证明胃癌SGC-7901细胞的胞浆及胞核抽提液中ER含量为30.2和35.7fmol/mg蛋白，而PR的含量为20.3和22.7fmol/ng蛋白, 但AR均为阴性(<10fmol/mg蛋白), 这说明SGC-7901细胞为ER及PR阳性细胞, 其ER和PR在胞浆、胞核中均有分布。 提示胃癌可能为性激素依赖性肿瘤, 有内分泌治疗的可能。