MECHANISMS OF ACTION OF HAF--KAPOSI'S SARCOMA

HAF--卡波西肉瘤的作用机制

• 批准号: 6311551
• 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: 2000
• 资助国家: 美国
• 起止时间: 2000-04-01 至 2001-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6311551
• 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.

在有关卡波西肉瘤（KS）发病机理的研究过程中，我们 观察到异常现象：恶性[肉瘤]肿瘤的消退 源自Xeno移植的肿瘤人KS细胞[KS Y-1和KS 妊娠早期的SLK]和免疫缺陷的小鼠。这导致了我们 旨在确定动作的身份和机制的实验 随后在小鼠的尿液和血清中发现的活性因子 和妇女在怀孕初期。这些因素具有以下效果： （1）在体外杀死KS肿瘤细胞，并在具有移植肿瘤的小鼠中杀死KS肿瘤细胞 通过诱导程序性细胞死亡； （2）抑制三个 不同的测试系统； （3）促进骨髓造血的生长 前体； （4）是反浪费的； （5）在体外抑制HIV-1表达， 在HIV-1转基因小鼠中，并抑制猴子的SIV感染； （6） 在这些实验中使用的浓度范围内无毒。 暂定称为HCG相关因子[HAF]的因素存在 在某些临床级别的HCG和一些 HCG的商业准备和一些商业准备 HCG [betahcg]的β链本质上是蛋白质，可以与 HCG和BETAHCG [至今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模仿 betahcg我们称卫星，并利用原油活跃的HCG准备 在临床试验中显然是活跃的。我们的怀疑是 HAF可能是由特定的betahcg的内部碎片 蛋白水解，该片段是某些的可变遏制 HCG和BETAHCG的商业准备。该提案中的工作将： （1）确认这些观察结果，其中许多是初步的； （2）定义 其中一些多样的一些一般机制 生物学效应，利用部分纯化的[无HCG] Poly或Oligo 肽分数和卫星； （3）探索可能性 其中几种影响[反KS，抗血管生成，抗HIV活性， 甚至亲毛的效应]也可能是由于一种共同的机制而引起的 诱导程序性细胞死亡的诱导； （4）执行一些 化学纯化步骤的生物测定[项目2中]；和（5） 表征纯化的HAF的生物学作用。