MONOCLONAL ANTIBODIES TO MAMMARY TUMOR GROWTH FACTORS

我们以前曾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的体内生长 暂时命名为雌激素。 这些促有丝分裂多肽是 在一个靶组织中产生的内分泌因子（在 雌激素控制），分泌到血浆中并作用于远处的靶细胞，或 相反，是局部作用的自分泌（自刺激）形式， 在雌激素刺激下释放并作用于靶组织。 在正在进行的内分泌机制的研究中， 三种新的乳腺肿瘤细胞生长因子从绵羊子宫，成熟 绵羊肾和全羊垂体。 这些活动都是醋酸 Mr = 3，900至4，200的酸和热稳定肽， 通过生物化学和生物学分析来区分。 在平行研究中，我们已经表明MTW 9/PL大鼠乳腺肿瘤细胞 在培养物中具有雌二醇诱导、乙酸和热稳定性 自刺激因子（Mr = 4，200），我们已部分纯化，单位为mg W/Fu大鼠中生长的这些肿瘤的量。 完全纯化 这种自分泌活性目前正在使用新的HPLC方法进行研究。 在本申请中，我们提出定义这些生长因子的作用， 雌激素反应性和自主性乳腺肿瘤生长。 具体 目的是（1）确定产生单克隆抗体的条件， 使用体外免疫方法纯化的生长因子，（2） 确定生长因子是否是免疫学上可区分的， (3)以确定是否抗体的内分泌形式， 雌激素能够抑制乳腺雌激素反应性和/或 W/Fu大鼠的自主乳腺肿瘤细胞生长，最后（4） 更好地定义自分泌（自刺激）因子在转化中的作用 对自主性的雌激素反应性增长。 我们的工作假设是雌激素反应性乳腺肿瘤生长 依赖于内分泌和自分泌因素，而自主 肿瘤生长仅需要自分泌因子。 拟议的研究包括 目的是确定抗生长因子单克隆抗体是否 用于乳腺肿瘤的有效治疗剂。

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.