PATHOGENESIS, IMMUNODIAGNOSIS, AND THERAPY OF CARCINOMA

癌症的发病机制、免疫诊断和治疗

• 批准号: 3173306
• 负责人: Jack R Wands
• 金额: $ 23.4万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1983
• 资助国家: 美国
• 起止时间: 1983-07-01 至 1994-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3173306
• 关键词: alpha fetoprotein; antiantibody; athymic mouse; autoradiography; cell bank /registry; combination cancer therapy; disease /disorder model; epitope mapping; hepatitis B; hepatitis B antigens; hepatitis B virus group; human tissue; immunoconjugates; immunocytochemistry; magnetic resonance imaging; messenger RNA; molecular cloning; molecular oncology; monoclonal antibody; neoplasm /cancer classification /staging; neoplasm /cancer immunodiagnosis; neoplasm /cancer immunotherapy; nucleic acid sequence; polymerase chain reaction; radioimmunoassay; radiotracer; reagent /indicator; serology /serodiagnosis; tissue /cell culture; tumor antigens; viral carcinogenesis

We have been investigating the antigenic characteristics of primary human hepatocellular carcinoma (HCC) cells. Employing monoclonal antibodies (MAbs) important cell surface antigenic changes associated with transformed hepatocytes have been identified. We will pursue investigations that explore antigenic differences displayed on the cell surface during hepatocyte transformation to the malignant phenotype. We have now defined 10 antigens of interest (XF-4, XF-8, AF-5, AF-20, AF-10, SF-25, SF-17, SF-32, SF-90 and FB-50). We plan to: 1) examine antigen expression in various liver diseases such as adenomas, cirrhosis, regenerating nodules, and chronic active hepatitis compared to HCC and other normal tissues. 2) determine some of the biochemical and physical properties of these antigens. 3) perform cDNA cloning in lambda GT10 as well as lambda GT11 and CDM8 expression vectors. 4) obtain primary sequence information on the cDNAs of interest. 5) study gene expression at the protein and mRNA level in HCC and adjacent uninvolved liver, in various liver diseases, other tumors and normal tissues. Since MAbs XF-8, AF-20 and SF-25 may have sufficient sensitivity and tissue specificity to be strongly considered as immunotargeting agents in man, we plan to perform experiments with radiolabeled, drug and toxin antibody conjugates to determine their effects either alone or in combination on the growth rate of HCCs in a new animal model system. These tumors produce both hepatitis B surface antigen (HBsAG) and alphafetoprotein (AFP) which will be used as another independent marker of tumor cell growth and viability. The cDNA of some of these antigens have been cloned. These investigations have led to the development of novel reagents for nuclear imaging and potential immunotherapy. In HCC we have observed the existence of low level hepatitis B virus (HBV) or variant viral infection. These agents need to be characterized at the molecular level. We plan to perform studies on HBsAG negative HCC patients with and without serologic markers of past HBV infection. From serum we will first capture on a solid phase support, HBV or variants with different high affinity monoclonal anti-HBsAG antibodies that recognize all known subtypes of HBV. We will employ the polymerase chain reaction (PCR) to subsequently detect and amplify HBV or variant DNA sequences in serum, lymphocytes, tumor tissue and adjacent uninvolved liver. We expect that the studies outlined in the present application will help to define the molecular events associated with human hepatocyte transformation and will result in novel reagents for immunodiagnosis and therapy.

我们一直在研究原代人的抗原特征 肝细胞癌（HCC）细胞。 采用单克隆抗体 （mAb）重要的细胞表面抗原变化与转化有关 已经鉴定出肝细胞。 我们将进行调查 探索在细胞表面显示的抗原差异 肝细胞转化为恶性表型。 我们现在已经定义了 10抗原（XF-4，XF-8，AF-5，AF-5，AF-20，AF-10，SF-25，SF-25，SF-17，SF-17， SF-32，SF-90和FB-50）。 我们计划：1）检查中的抗原表达 各种肝病，例如腺瘤，肝硬化，再生结节， 与HCC和其他正常组织相比，慢性活性肝炎。 2） 确定这些的某些生化和物理特性 抗原。 3）在Lambda GT10和Lambda GT11中执行cDNA克隆 和CDM8表达向量。 4）获取有关 感兴趣的cDNA。 5）研究蛋白质和mRNA水平的基因表达 在HCC和邻近的未涉及肝脏中，在各种肝病中，其他 肿瘤和正常组织。 由于mABS XF-8，AF-20和SF-25可能具有 足够的敏感性和组织特异性被强烈认为 人类的免疫定位剂，我们计划与 放射性标记，药物和毒素抗体结合物以确定其作用 单独或组合新动物中HCC的增长率 模型系统。 这些肿瘤会产生丙型肝炎表面抗原 （HBSAG）和Alphafetoprotoin（AFP），将用作另一种 肿瘤细胞生长和生存力的独立标记。 某些cDNA 这些抗原已被克隆。 这些调查导致了 开发用于核成像和潜力的新试剂 免疫疗法。 在HCC中，我们观察到了低水平的存在 丙型肝炎病毒（HBV）或变体病毒感染。 这些代理需要 在分子水平上表征。 我们计划对 HBSAG阴性HCC患者有或没有过去HBV的血清学标记 感染。 从血清中，我们将首先在固相支撑上捕获HBV 或具有不同高亲和力单克隆抗HBSAG抗体的变体 识别HBV的所有已知亚型。 我们将采用聚合酶 链反应（PCR）随后检测和扩增HBV或变体DNA 血清，淋巴细胞，肿瘤组织和相邻的未参与的序列 肝。 我们希望本申请中概述的研究将 帮助定义与人肝细胞相关的分子事件 转化，并将导致免疫诊断的新试剂和 治疗。