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: 3190260
• 负责人: LAURENCE Anthony COLE
• 金额: $ 23.65万
• 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 1996-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3190260
• 关键词: biomarker; cervix neoplasms; 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.

Beta-Core 片段（同义词：BetaCF、尿促性腺激素片段、UGF） 是一种小二聚蛋白 (Mr=10,300)，由 2 个短肽（35 和 38 个氨基酸）通过二硫桥连接。 这两种肽各有 与 hCG β 亚基片段（145 个氨基酸）具有序列同源性 酸）。 BetaCF 可以通过使用 BetaCF 或 hCGBeta 进行检测来检测 妊娠期滋养层/胎盘组织中存在抗体，相对而言 妊娠尿液中含量较高，但无法通过此方法检测到 是指在血液中。 因此，我们首先选择尿液样本进行测量 贝塔CF。 1986 年 7 月，我们发现 hCG 或其 Beta 亚基存在于 18% 的女性血清或尿液中存在 BetaCF，但 74% 的女性尿液中存在 BetaCF 患有妇科癌症（n=68）。 从那时起，我们已经展示了很多 对于较大的人群，BetaCF 可用于监测患者的治疗 妇科恶性肿瘤，以及复发性早期发现 疾病。 BetaCF 测量对于补充特别有用 血浆CA125测定。 虽然 CA125 对上皮细胞具有特异性 癌症，BetaCF 对此和其他组织学具有相同的敏感性 亚型。 尿液 BetaCF 水平也可能有助于鉴别 对患有以下疾病的患者进行良性疾病和恶性肿瘤的诊断 盆腔肿块。 最近，这些发现中的许多都得到了证实，一般来说 人口较多，由独立实验室进行。 由于这些 和验证性研究，BetaCF 目前正在商业化开发中 作为妇科癌症的标志物，在美国、英国和美国的中心进行了测试 日本。 在这次更新中，我们将注意力转向其他尚未探索的领域 BetaCF 测量的应用： 1. 研究尿 BetaCF 测量在筛查中的应用 卵巢癌高危人群。 2. BetaCF是癌症的分泌产物，CA125是膜成分 脱落的死细胞。 BetaCF，但不是 CA125，水平与 肿瘤等级，因此可能表明细胞分化和 化学。 我们建议研究 BetaCF 测量的使用 预测预后（死亡率、疾病持续性、耐药性 治疗）卵巢癌。 3. 初步研究表明BetaCF在诊断中的进一步用途 乳腺癌和结肠癌的治疗（敏感性分别为 69% 和 63%）。 建议开展合作研究来评估这些新应用。 医生有些不愿意使用尿液，而不是使用尿液。 血浆肿瘤标志物。 我们问自己“为什么 BetaCF 不能在 血液？”。我们考虑了 BetaCF 被相关物质掩盖的可能性。 血清中的分子。 使用硫氰酸铵（一种离液剂）进行的研究 剂和凝胶过滤分离方法表明情况确实如此， 现在已经证明了 BetaCF 的存在，作为一种特定的 BetaCF- 血清中的大分子复合物（Mr~65,000）。 初步结果是，这 复合物存在于怀孕妇女的所有血清样本中 平行尿液标本升高的妇科癌症患者 （0.5-85 nmol/1，n=8）。 初步迹象是血清测量 可以替代、补充或超越（在癌症中检测到更高水平 血清）尿液中的那些。 我们目前正在努力提高抗体，并且 开发更快速的 HPLC 方法来检测血清 BetaCF 复合物。 4. 我们的图书馆有大多数尿液的平行血清样本。 韦 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，无疾病证据和良性疾病n=200-300)，然后 良恶性疾病鉴别诊断的功效，以及 治疗管理和复发检测。 最后，为了 平行目标 1、2 和 3，如上所述，检查血清而不是 比尿液样本并比较血清和尿液的效用 测量。