URINARY HCGB SUBUNIT/CORE FRAGMENT IN GYNECOLOGIC CANCER

妇科癌症中的尿液 HCGB 亚基/核心片段

• 批准号: 3190264
• 负责人: LAURENCE Anthony COLE
• 金额: $ 24.35万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-03-01 至 1996-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3190264
• 关键词: biomarker; cervix neoplasms; chemoprevention; chorionic gonadotropin; diagnosis design /evaluation; diagnostic tests; female reproductive system neoplasm; high performance liquid chromatography; human subject; monoclonal antibody; neoplasm /cancer classification /staging; neoplasm /cancer immunodiagnosis; neoplasm /cancer relapse /recurrence; ovary neoplasms; radioimmunoassay; urine

Beta-Core fragment (synonyms: BetaCF, urinary gonadotropin fragment, UGF) is a small dimeric protein (Mr=10,300) composed of 2 short peptides (35 and 38 amino acids) linked by disulfide bridges. The two peptides each have sequence homology with segments of the Beta-subunit of hCG (145 amino acids). BetaCF can be detected by assays using BetaCF or hCGBeta antibodies in trophoblast/placenta tissue in pregnancy, and at relatively high levels in pregnancy urines, however, it cannot be detected by this means in blood. Thus, we initially selected urine samples for measuring BetaCF. In 1986-7 we found that hCG or its Beta-subunit were present in serum or urine of 18%, but BetaCF was present in the urine of 74%, of women with gynecologic cancers (n=68). Since then we have demonstrated with much larger populations, BetaCF is useful in monitoring the therapy of patients with gynecologic malignancies, and in the early detection of recurrent disease. BetaCF measurements are particularly useful in complementing plasma CA125 determinations. While CA125 is specific for epithelial carcinomas, BetaCF has equal sensitivity for this and other histologic subtypes. Urine BetaCF levels may also be useful in the differential diagnosis of benign disease and malignancy in patients presenting with a pelvic mass. Recently, many of these findings were confirmed, generally with larger populations, by independent laboratories. As a result of these and confirmatory studies, BetaCF is now being developed commercially and tested as a marker of gynecologic cancers, at centers in the U.S., U.K. and Japan. In this renewal we turn our attention to other yet-explored applications of BetaCF measurements: 1. To investigate the use of urinary BetaCF measurements in screening groups at high risk for ovarian cancer. 2. BetaCF is a secretory product of cancers, CA125 a membrane component sloughed-off dead cells. BetaCF, but not CA125, levels correlate with tumor grade, thus maybe indicative of cellular differentiation and chemistry. We propose investigating the use of BetaCF measurements in predicting the prognosis (mortality, persistence of disease, resistance to therapy) of ovarian cancers. 3. Preliminary studies suggest further uses for BetaCF in the diagnosis and management of breast and colon cancers (sensitivities 69% and 63%). Collaborative studies are proposed to evaluate these new applications. There has been some reluctance by physicians to use urine, rather than a plasma tumor markers. We asked ourselves "why can't BetaCF be detected in blood?". We considered the possibility that BetaCF is masked by associated molecules in serum. Studies using ammonium thiocyanate, a chaotropic agent, and gel filtration separation methods revealed this to be the case, and have now demonstrated the presence of BetaCF, as a specific BetaCF- macromolecule complex (Mr~65,000) in serum. Initial results are that this complex is present in all serum samples from women with pregnancy and form patients with gynecologic cancers with elevated parallel urine specimens (0.5-85 nmol/1, n=8). Initial indications are that serum measurements could replace, supplement or surpass (higher level detected in cancer serum) those of urine. We are currently trying to raise antibodies, and develop more-rapid HPLC methods for detecting the serum BetaCF complex. 4. We have parallel serum samples for most urines in our library. Wee propose, firstly, to establish the sensitivity and specificity of serum BetaCF complex measurements for gynecologic cancers (cancer samples n=300- 400, no evidence of disease and benign disease n=200-300), and then the efficacy in the differential diagnosis of benign and malignant disease, and in the management of therapy and detection of recurrences. Finally, to parallel Objectives 1, 2 and 3, described above, examining serum rather than urine samples and compare the utilities of serum and urine measurements.

β-核心片段(同义词：BetaCF，尿促性腺激素片段，UGF) 是一种小的二聚体蛋白(Mr=10,300)，由2个短肽(35和 38个氨基酸)通过二硫键连接。这两种多肽都有 人绒毛膜促性腺激素β亚基片段(145个氨基酸)的序列同源性 酸)。可以通过使用BetaCF或hCGBeta的检测来检测BetaCF 妊娠滋养细胞/胎盘组织中的抗体 然而，在怀孕的尿液中，它不能被检测到 意思是用血。因此，我们最初选择了尿样进行测量 BetaCF.在1986-2007年，我们发现hCG或其β亚基存在于 血清或尿液中有18%，但74%的妇女尿液中存在BetaCF 妇科肿瘤(n=68)。从那时起，我们已经展示了很多 在更大的人群中，BetaCF对监测患者的治疗是有用的 妇科恶性肿瘤，并在早期发现复发 疾病。BetaCF测量在补充 血浆CA125测定。而CA125是上皮细胞特有的 癌症，BetaCF对这一点和其他组织学有同样的敏感性 子类型。尿β-CF水平对鉴别诊断也有帮助 诊断良性疾病和恶性疾病患者的临床表现 盆腔肿块。最近，这些发现中的许多都得到了普遍的证实 有更多的人口，由独立的实验室。由于这些原因， 和验证性研究，BetaCF现在正在商业化开发和 在美国、英国和英国的中心进行的妇科癌症标志物检测 日本。在这次更新中，我们将注意力转向其他尚未探索的 BetaCF测量的应用： 1.探讨尿β-CF测定在筛查中的应用 卵巢癌高危人群。 2.BetaCF是肿瘤的分泌产物，CA125是膜成分 将死亡的细胞剥离。BetaCF，而不是CA125，水平与 肿瘤分级，因此可能指示细胞分化和 化学反应。我们建议调查BetaCF测量在以下方面的使用 预测预后(死亡率、疾病持久性、对 卵巢癌的治疗)。 3.初步研究建议进一步使用BetaCF进行诊断 乳腺癌和结肠癌的治疗(敏感度分别为69%和63%)。 建议进行协作研究来评估这些新的应用。 医生们一直不太愿意使用尿液，而不是 血浆肿瘤标志物。我们问自己“为什么BetaCF不能在 我们考虑了BetaCF被关联的 血清中的分子。利用硫氰酸铵的研究 试剂和凝胶过滤分离方法揭示了这种情况， 现在已经证明了BetaCF的存在，作为一种特定的BetaCF- 血清中大分子复合体(Mr~65,000)。初步结果是，这是 在所有怀孕和形体妇女的血清样本中都存在复合体 妇科肿瘤患者平行尿标本升高的临床分析 (0.5~85nmol/1，n=8)。初步迹象是血清检测结果 可以取代、补充或超过(在癌症中检测到的更高水平 血清)尿液。我们目前正在努力提高抗体水平， 建立更快速的检测血清BetaCF复合体的高效液相色谱方法。4. 我们图书馆里的大多数尿液都有平行的血清样本。小不点 首先，建议建立血清的敏感性和特异性 妇科癌症的BetaCF综合测量(癌症样本n=300) 400，没有疾病和良性疾病的证据)，然后 在良、恶性疾病的鉴别诊断中的作用 在治疗管理和复发检测方面发挥重要作用。最后，为了 上面描述的平行目标1、2和3，检查血清而不是 并比较血清和尿液的效用 测量。