MONOCLONAL ANTIBODIES TO MAMMARY TUMOR GROWTH FACTORS

该项目的目标是描述 雌激素所需的蛋白质/多肽生长因子- 大鼠和人乳腺癌的反应性和自主性生长 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。 的生长因子 参与可能源于血浆（内分泌因子）或它们 可由肿瘤细胞/基质局部分泌 （自分泌/旁分泌因子）。 我们建议使用多克隆和单克隆的组合 生长因子及其受体的抗体（MAbs），以确定 有丝分裂原最密切相关的雌激素反应， 自主乳腺肿瘤生长。 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， 所分泌的因子具有生物化学特征， 免疫学上和结构上（氨基酸测序）。 雌激素诱导生长因子将从克隆的 MTW 9/PL 2大鼠系和来自人MCF-7、T-47 D和 ZR-75-1细胞;由自主细胞分泌的因子将被 其特征在于使用雌激素受体阴性人MDA- MB-231、BT-20、HBL-100和Hs 578 t线路和自主 MTW 9 B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（ED 50 30-50 pg/ml）促有丝分裂剂 发现了乳腺癌细胞 IGF-1是雌激素诱导的 MCF-7细胞的培养基中。 第二个最有效的因素 碱性成纤维细胞生长因子（b-FGF）。 IGF-1 和FGF样因子被发现在介质中的自主 细胞 我们的计划是继续完成对 重要因素，并使用抗体来抑制雌激素- 促进或自主的文化增长。 单克隆抗体促生长 因子受体将用于确认自分泌作用，或 如有说明，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 定向单克隆抗体试图抑制雌激素反应性， 无胸腺裸鼠中的自主肿瘤形成。 这些研究 将直接测试生长因子作为 体内雌激素应答性和自主性肿瘤生长，和 确定阻止他们的行动是否有可能成为一种新的 治疗方法来控制乳腺癌。

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.