MECHANISMS OF ACTION OF HAF--KAPOSI'S SARCOMA

在对卡波西肉瘤(KS)发病机制的研究过程中，我们 观察到一种不寻常的现象：恶性[肉瘤]肿瘤的消退 来源于异种移植的人KS肿瘤细胞[KS Y-1和KS SLK]和免疫缺陷小鼠在怀孕早期。这让我们找到了 为确定行动的身份和机制而设计的实验(S) 随后在小鼠尿液和血清中发现的活性因子(S) 以及怀孕早期的女性。这些因素(S)具有以下影响： (1)体外及荷瘤小鼠体内杀伤KS肿瘤细胞 通过诱导细胞程序性死亡；(2)抑制血管生成 不同的检测系统；(3)促进骨髓造血生长 前体；(4)抗浪费；(5)体外抑制HIV-1的表达， 在HIV-1转基因小鼠中，并抑制猴子的SIV感染；和(6) 在这些实验中使用的浓度范围内是无毒的。 这种因子(S)暂称为hCG相关因子。 在一些临床级商品人绒毛膜促性腺激素和一些 人绒毛膜促性腺激素的商业制剂和一些商业制剂 人绒毛膜促性腺激素的β链[betahCG]是一种蛋白质，可以从 HCG和BetahCG[到目前为止，部分纯化的材料保留了所有 生物活性]，可以被某些合成肽模拟 我们称之为萨特林，并利用粗制的活性hCG制剂 在临床试验中表现得非常活跃。我们的怀疑是 HAF可能是BetahCG的内部片段，由特定的 蛋白质分解，这个片段是一些可变包涵体 人绒毛膜促性腺激素和β-绒毛膜促性腺激素商品化制剂。本计划书中的工作将： (1)确认这些观察结果，其中许多是初步的；(2)确定 其中一些涉及到的一般机制不同 生物效应，利用部分纯化的[不含hCG]多聚或寡聚 多肽组分和卫星蛋白；(3)探索 其中几种作用[抗KS，抗血管生成，抗艾滋病毒活性， 甚至是促进造血的作用]可能是由于一种共同的机制， HAF-诱导细胞程序性死亡；(4)进行一些 化学纯化步骤的生物测定[在项目2中]；和，(5) 鉴定纯化的羟基磷灰石的生物学效应。

In the course of studies on the pathogenesis of Kaposi's Sarcoma (KS), we observed an unusual phenomena: regression of malignant [sarcoma] tumors derived from xeno-transplanted neoplastic human KS cells [KS Y-1 and KS SLK] and immunodeficient mice during early pregnancy. This led us to experiments designed to determine the identity and mechanism(s) of action of the active factor(s) subsequent found in both urine and sera of mice and women in early pregnancy. These factor(s) have the following effects: (1) kill KS tumor cells in vitro and in mice with the transplanted tumors by inducing programmed cell death; (2) inhibit angiogenesis in three different test systems; (3) promote growth of bone marrow hematopoietic precursors; (4) are anti-wasting; (5) inhibit HIV-1 expression in vitro, in HIV-1 transgenic mice, and inhibit SIV infection of monkeys; and (6) are not toxic within the concentration range used in these experiments. This factor(s), tentatively called hCG-associated factor [HAF], is present in some clinical grade crude commercial preparations of hCG and some commercial preparations of hCG and some commercial preparations of the beta chain of hCG [betahCG], is protein in nature, can be separated from hCG and betahCG [and to date the partially purified material retains all biological activities], can be mimicked by certain synthetic peptides of betahCG we call Satellins, and utilizing the crude active hCG preparations have been demonstrably active in clinical trials. Our suspicion is that HAF may be an internal fragment of betahCG resulting from a specific proteolysis and that this fragment is a variable containment of some commercial preparations of hCG and betahCG. Work in this proposal will: (1) confirm these observations, many of which are preliminary; (2) define some of the general mechanisms involved for some of these diverse biological effects, utilizing partially purified [hCG-free] poly or oligo peptide fractions and the Satellins; (3) explore the possibility that several of these effects [anti-KS, anti-angiogenic, anti-HIV activities, and even the pro-hematopoietic effect] may be due to a common mechanism, HAF-induction of programmed cell death; (4) carry out some of the bioassays for the chemical purification steps [in Project 2]; and, (5) characterize the biological effects of purified HAF.