MITOSIN A NEW PROLIFERATION MARKER FOR CANCER DIAGNOSIS

乳腺癌的诊断给患者和临床医生带来了几个难题，例如是否在手术后使用系统辅助治疗。如果临床医生在诊断时拥有患者肿瘤的分子指纹，从而准确预测复发和治疗反应，这类患者的管理将得到优化。因此，在组织学分级系统中，细胞增殖被用作监测疾病状态的有丝分裂指数；然而，这种方法执行起来很繁琐。新的方法，如DNA流式细胞术，已经被用来将细胞的S期比例与原发性乳腺癌患者的临床结果相关联。流式细胞仪设备的昂贵、技术的普遍标准化以及结果的重复性问题限制了其作为临床标准预后因素的接受程度。最近的研究表明，丝裂蛋白是一种350 kDa的核磷蛋白，它特异性地参与了有丝分裂的进程。初步结果表明，细胞分裂素免疫组织化学染色与S期细胞比例直接相关，与肿瘤早期复发有关。为了研究丝裂素作为预后指标的价值，我们将研制适合于丝裂素免疫组织化学染色的单抗。这些研究将提供对临床样本中有丝分裂素预后意义的基本了解，这将导致人类乳腺癌诊断测试和治疗的发展。建议的商业应用：开发适合于丝裂素免疫组织化学染色的临床有用的单抗，它将取代昂贵而繁琐的流式细胞术分析S期分数作为原发性乳腺癌的预后因素。我们将开发抗体，在各种固定程序和染色技术下发挥作用并产生一致的结果。这将导致一种简单、廉价的诊断测试的开发，这种测试将在较小的非学术治疗中心提供给乳腺癌患者。

Diagnosis of breast cancer presents several dilemmas for patients and clinicians such as whether or not to use systemic adjuvant therapy following surgery. Management of such patients would be optimized if clinicians had a molecular fingerprint of a patient's tumor at the time of diagnosis that would accurately predict recurrence and treatment responses. As such, cell proliferation has been used as a mitotic index to monitor disease status in histologic grading systems; however, this approach is tedious to perform. Newer methods such as DNA flow cytometry have been used to correlate S-phase fraction of cells with clinical outcomes of patients with primary breast cancer. The expense of flow cytometry equipment, universal standardization of techniques and questions about reproducibility of results has limited its acceptance as a standard prognostic factor in the clinic. Recently, it has been shown that mitosin, a 350-kDa nuclear phosphoprotein, is specifically involved in mitotic phase progression. Preliminary results demonstrate that mitosin staining by immunohistochemistry is directly related to S-phase fraction and associated with early disease recurrence. In order to study the value of mitosin as a prognostic indicator we will develop monoclonal antibodies suitable for immunohistochemical staining of mitosin. These studies will provide the basic understanding of the prognostic significance of mitosin, in clinical samples that will lead to development of diagnostic test and treatment of human breast cancer. PROPOSED COMMERCIAL APPLICATIONS: Development of clinically useful monoclonal antibodies suitable for immunohistochemical staining of mitosin which will serve to replace expensive and tedious flow cytometry analysis of S-phase fraction as a prognostic factor for primary breast cancer. We will develop antibodies that will work and give consistent results under a wide variety of fixation procedures and staining techniques. This will lead to development of a simple, inexpensive diagnostic test, which will be available to breast cancer patients in smaller, non-academic treatment centers.