MECHANISMS OF ACTION OF HAF--KAPOSI'S SARCOMA

HAF--卡波西肉瘤的作用机制

• 批准号: 6203468
• 负责人: ROBERT C GALLO
• 金额: $ 15.41万
• 依托单位: UNIVERSITY OF MD BIOTECHNOLOGY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-04-01 至 2000-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6203468
• 关键词: AIDS; AIDS related neoplasm /cancer; Kaposi's sarcoma; angiogenesis; angiogenesis inhibitors; animal tissue; antineoplastics; apoptosis; athymic mouse; bioassay; body weight; cachexia; chorionic gonadotropin; corneal endothelium; cysteine endopeptidases; flow cytometry; fluorescence microscopy; gene expression; hematopoiesis; histopathology; neoplasm /cancer remission /regression; protooncogene; synthetic peptide; western blottings

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.

在卡波西肉瘤（KS）发病机制的研究过程中，我们 观察到一个不寻常的现象：恶性[肉瘤]肿瘤消退 源自异种移植的人类 KS 肿瘤细胞 [KS Y-1 和 KS SLK]和妊娠早期免疫缺陷小鼠。这导致我们 旨在确定作用的特性和机制的实验 随后在小鼠尿液和血清中发现的活性因子 以及怀孕初期的女性。这些因素具有以下影响： (1) 杀灭体外和移植肿瘤小鼠体内的KS肿瘤细胞 通过诱导程序性细胞死亡； (2)抑制血管生成三 不同的测试系统； (3)促进骨髓造血生长 前体； (4) 抗浪费； (5)体外抑制HIV-1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没有毒性。 该因子暂时称为 hCG 相关因子 [HAF]，存在 一些临床级的 hCG 商业粗制剂和一些 hCG 的商业制剂和某些商业制剂 hCG 的 β 链 [betahCG]，本质上是蛋白质，可以从 hCG 和 betahCG [迄今为止，部分纯化的材料保留了所有 生物活性]，可以通过某些合成肽来模仿 betahCG，我们称为 Satellins，并利用粗活性 hCG 制剂 在临床试验中表现明显活跃。我们的怀疑是 HAF 可能是 betahCG 的内部片段，由特定的 蛋白水解作用，并且该片段是某些变量的可变包含 hCG 和 betahCG 的商业制剂。该提案的工作将： (1) 确认这些观察结果，其中许多是初步的； (2) 定义 其中一些涉及的一些一般机制 生物效应，利用部分纯化的[不含 hCG] 多聚或寡聚 肽级分和 Satellins； (3) 探讨可能性 其中一些作用[抗 KS、抗血管生成、抗 HIV 活性、 甚至促造血作用]可能是由于一个共同的机制， HAF-诱导程序性细胞死亡； (4) 执行一些 化学纯化步骤的生物测定[项目 2]；并且，(5) 表征纯化 HAF 的生物学效应。