MECHANISMS OF ACTION OF HAF--KAPOSI'S SARCOMA

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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.