MONOCLONALS ANTIBODIES TO MAMMARY TUMOR GROWTH FACTORS

这个项目的目标是描述 雌激素所需的蛋白质/多肽生长因子- 反应性和自主性的大鼠和人乳腺癌生长 并将这些信息应用于开发新的治疗方法 控制这种疾病的方法。增长因素 受累可能源于血浆(内分泌因子)或它们 可能由肿瘤细胞/间质局部分泌 (自分泌/旁分泌因子)。 我们建议使用多克隆和单克隆的组合 抗生长因子及其受体的抗体(MAb)用于确定 有丝分裂原与雌激素反应和 乳腺肿瘤自主生长。自分泌/旁分泌因子 将在无血清确定的培养条件下进行研究 分泌的因子具有生化特征， 在免疫学和结构上(氨基酸序列)。 雌激素诱导的生长因子将从克隆的 MTW9/PL2大鼠株系及人MCF-7、T-47D和 ZR-75-1细胞；自主细胞分泌的因子将是 用雌激素受体阴性的人丙二醛 MB-231、BT-20、HBL-100和Hs578T线及自主式 MTW9B大鼠细胞克隆。我们的实验显示胰岛素样生长 因子1(IGF-1)是最有效的(ED50为30-50 pg/ml)有丝分裂原 对乳腺癌细胞进行鉴定。IGF-1是雌激素诱导的 进入MCF-7细胞的培养液中。第二大最具影响力的因素 经鉴定为碱性成纤维细胞生长因子(b-FGF)。两者都是IGF-1 而成纤维细胞生长因子样因子存在于自主性中。 细胞。我们的计划是继续对大多数 重要因素，并使用抗体抑制雌激素- 在文化中促进或自主发展。单抗促进生长 因子受体将用于确认自分泌作用，或 在指示的情况下，作为血液传播活动的内分泌作用。 当细胞培养研究完成后，我们将使用受体 定向单抗试图抑制雌激素反应和 裸鼠体内自主性肿瘤的形成。这些研究 将直接检验生长因子作为调节因子的作用 体内雌激素反应和肿瘤自主生长，以及 确定阻止他们的行动是否具有作为新的 控制乳腺癌的治疗方法。

The goals of this project are to characterize the protein/polypeptide growth factors required for estrogen- responsive and autonomous rat and human breast cancer growth and to apply this information to development of new therapeutic approaches to control of this disease. The growth factors involved may originate from the plasma (endocrine factors) or they may be secreted locally by tumor cells/stromal (autocrine/paracrine factors). We propose to use a combination of polyclonal and monoclonal antibodies (MAbs) to growth factors and their receptors to define the mitogens most closely related to estrogen-responsive and autonomous breast tumor growth. Autocrine/paracrine factors will be studied under serum-free defined culture conditions and the factors secreted characterized biochemically, immunologically and structurally (amino acid sequencing). Estrogen-inducible growth factors will be sought from clones of the MTW9/PL2 rat line and from the human MCF-7, T-47D and ZR-75-1 cells; factors secreted by autonomous cells will be characterized using the estrogen receptor negative human MDA- MB-231, BT-20, HBL-100 and Hs578t lines and autonomous MTW9B rat cell clones. Our experiments show insulin-like growth factor 1 (IGF-1) is the most potent (ED50 30-50 pg/ml) mitogen identified for breast cancer cells. IGF-1 is estrogen-inducible into the medium of MCF-7 cells. The second most potent factor identified is basic fibroblast growth factor (b-FGF). Both IGF-1 and FGF-like factors are found in the medium of autonomous cells. Our plan is to continue complete identification of the most important factors, and to use antibodies to inhibit estrogen- promoted or autonomous growth in culture. MAbs to growth factor receptors will be used to confirm an autocrine role, or where indicated, as endocrine role of blood borne activities. When the cell culture studies are complete, we will use receptor directed MAbs to attempt inhibition of estrogen-responsive and autonomous tumor formation in athymic nude mice. These studies will directly test of the role in growth factors as mediators of estrogen-responsive and autonomous tumor growth in vivo, and establish whether blocking their action has potential as a new therapeutic approach to control of breast cancer.