MONOCLONAL ANTIBODIES TO MAMMARY TUMOR GROWTH FACTORS

我们以前已经提出雌激素促进乳腺肿瘤细胞 通过诱导一组新的介质生长因子在体内生长 暂定为雌激素类。这些有丝分裂多肽是 在一个靶组织中产生的内分泌因子(在 雌激素控制)，分泌到血浆并作用于远处的靶细胞，或 取而代之的是局部作用的自分泌(自刺激)形式 在雌激素刺激下释放并在靶组织中起作用。 在正在进行的内分泌机制研究中，我们提纯了大量的镁 绵羊子宫中三种新的乳腺肿瘤细胞生长因子的成熟 母羊的肾和全羊的脑下垂体。这些活动都是乙酸乙酯的 MR=3,900~4,200的酸性和热稳定性多肽 在生化和生物分析方面有所不同。 在平行研究中，我们发现MTW9/PL大鼠乳腺肿瘤细胞 在培养中具有雌二醇诱导性、醋酸性和热稳定性。 我们以镁为单位部分纯化的自激因子(mR=4,200) 在W/FU大鼠体内生长的这些肿瘤的数量。完全提纯 这种自分泌活动现在正在使用新的高效液相方法进行。 在本申请中，我们建议定义这些增长因素的作用 参与雌激素反应和乳腺肿瘤的自主生长。具体的 目的是(1)确定产生单抗的条件 对纯化的生长因子采用体外免疫方法，(2) 确定生长因子在免疫上是否可区分， (3)确定抗内分泌抗体是否存在于 雌激素能够抑制乳腺雌激素反应和/或 W/FU大鼠乳腺肿瘤细胞的自主生长，最终(4) 更好地定义自分泌(自刺激)因子在转化中的作用 从雌激素敏感型生长到自主性。 我们的工作假设是雌激素反应性乳腺肿瘤的生长 依赖于内分泌和自分泌因素，而自主的 肿瘤的生长只需要自分泌因子。建议进行的研究包括 旨在确定抗生长因子单抗是否 治疗乳腺肿瘤的有效药物。

We have proposed previously that estrogens promote mammary tumor cell growth in vivo via induction of a new group of mediator growth factors tentatively designated estromedins. These mitogenic polypeptides are either endocrine factors that are produced in one target tissue (under estrogen control), secreted into plasma and act on distant target cells, or instead, are locally acting autocrine (autostimulatory) forms that are released and act in the target tissue in response to estrogen stimulation. In ongoing studies of the endocrine mechanism, we have purified mg amounts of three new mammary tumor cell growth factors from sheep uterus, mature ewe kidney and whole sheep pituitaries. These activities are all acetic acid and heat stable peptides of Mr = 3,900 to 4,200 and are shown to be distinct by biochemical and biological analyses. In parallel studies, we have shown that the MTW9/PL rat mammary tumor cells in culture possess an estradiol inducible, acetic acid and heat stable autostimulatory factor (Mr = 4,200) that we have partially purified in mg amounts from these tumors growing in W/Fu rats. Complete purification of this autocrine activity is now in progress using new HPLC methods. In this application we propose to define the role of these growth factors in estrogen responsive and autonomous mammary tumor growth. The specific aims are (1) to determine the conditions for raising monoclonal antibodies to the purified growth factors using in vitro immunization methods, (2) to determine whether the growth factors are immunologically distinguishable, (3) to determine whether the antibodies to the endocrine forms of estromedins are able to inhibit mammary estrogen responsive and/or autonomous mammary tumor cell growth in W/Fu rats, and finally (4) to better define the role of autocrine (autostimulatory) factors in conversion of estrogen-responsive growth to autonomy. It is our working hypothesis that estrogen-responsive mammary tumor growth is dependent upon endocrine and autocrine factors, whereas, autonomous tumor growth requires only autocrine factors. The studies proposed are aimed at establishing whether antigrowth factor monoclonal antibodies are effective therapeutic agents for mammary tumors.