1. Aboulafia D et al. Intravenous recombinant tumor necrosis factor in the treatment of AIDS-related Kaposi's sarcoma. Journal of Acquired Immunodeficiency Syndromes 2(1): 54-8, 1989. TNF was administered to 5 men once weekly at 100 mcg/m2 for eight weeks. "One patient was removed from the study at week 4 due to the rapid progression of Kaposi's sarcoma." Another patient died, although no pathogenic organism was identified as a cause. "All patients had some progression of their Kaposi's sarcoma on study."

2. Fajardo LF et al. Dual role of tumor necrosis factor-alpha in angiogenesis. American Journal of Pathology 140(3): 539-42, 1992. TNF doses of 0.01-1 ng delivered either by osmotic minipump or by implanted pellet induced angiogenesis. The effect was maximum at 0.1 ng.

3. Aukrust P et al. Serum levels of tumor necrosis factor-alpha (TNF) and soluble TNF receptors in human immunodeficiency virus type 1 infection -- correlations to clinical, immunologic, and virologic parameters. Journal of Infectious Diseases. 169: 420-4, 1994. [published erratum appears in 169(5): 1186-7, 1994] "All clinical groups of HIV-infected patients, regardless of concurrent illness, had significantly elevated levels of both types of soluble TNF receptors (sTNFRs) and immuoreactive TNF-alpha (Medgenix EIA), with the highest concentrations among the AIDS patients." They concluded that levels increase with degree of immunodeficiency and progression of the disease and therefore "may give useful prognostic information."

4. Sunderkotter C et al. Macrophages and angiogenesis. Journal of Leukocyte Biology 55(3): 410-22, 1994. "By release of proteases, growth factors (bFGF, GM-CSF, TGF-a, TGF-1, PDGF, VEGF/VPF, TGF-b), and other monokines (IL-1, IL-6, IL-8, TNF-alpha, substance P, prostaglandins, interferons, thrombospondin 1), activated macrophages have the capability to influence each phase of the angiogenic processm such as alterations in the local extracellular matrix, induction of endothelial cells to migrate or proliferate..."

5. Barillari G et al. Effects of cytokines from activated immune cells on vascular cell growth and HIV-1 gene expression. Journal of Immunology. 149(11): 3727-34, 1992. KS may be one of the earliest signs of developing immunodeficiency. They suggest "products from activated immune cells may affect the development of AIDS-KS" and "conditioned media from activated or dysregulated T-cells contain a variety of cytokines that promote the growth of spindle cells derived from KS lesions of AIDS patients (AIDS-KS cells) and induce normal vascular cells, potential cell progenitors of the AIDS-KS cells, to acquire features of the KS cell phenotype (`spindle' cell morphology and growth responsiveness to the mitogenic effect of extracellular HIV-1 Tat protein). The same conditioned media or cytokines promote HIV-1 gene expression and rescue defective HIV-1 proviruses, interrupting HIV latency, and increasing Tat production. The cellular and viral effects of cytokines are increased in an additive or synergistic manner by picomolar concentration of extracellular Tat."

6. Hofman FM, Wright AD, Dahadwala MM, Wong-Staal F and Walker SM. Exogenous tat protein activates human endothelial cells. Blood 82(9): 2774-80, 1993. This team shows that "Tat does indeed stimulate endothelial cells" and that it "acts synergistically with low concentrations of tumor necrosus factor-alpha to enhance IL-6 secretion."

7. Corbeil J, Evans LA, Uasak E, Cooper DA and Penny R. Culture and properties of cells derived from Kaposi sarcoma. Journal of Immunology 146(9): 2972-6, 1 May 1991. "The KS cells secreted large amounts of cytokines (granulocyte-macrophage-CSF, TNF-alpha, IL-1beta, and expecially IL-6). Conditioned media from the KS cells caused normal capillary EC to proliferate."

8. Moreira AL, Sampaio EP, Zmuidzinas A, Frindt O, Smith KA and Kaplan G. Thalidomide exerts its inhibitory action on tumor necrosis alpha by enhancing mRNA degradation. Journal of Experimental Medicine 177(6): 1675-80, 1 June 1993. "We have examined the mechanism of thalidomide inhibition of lipopolysaccharide (LPS)-induced tumor necrosis factor-alpha (TNF-alpha) production and found that the drug enhances the degradation of TNF-alpha mRNA." The normal half-life of TNF-alpha mRNA was 30 minutes, and this was reduced to 17 minutes by 50 mcg/ml thalidomide.

9. Sampaio EP, Kaplan G, Miranda A et al. The influence of thalidomide on the clinical and immunologic manifestation of erythema nodosum leprosum. The Journal of Infectious Diseases 168: 408-14, 1993. "Patients with systemic ENL demonstrated the highest serum TNF-alpha levels, which decrease significantly during thalidomide treatment. Serum interferon-gamma was also elevated in patients with high TNF levels. Thalidomide therapy reduced not only serum TNF-alpha levels and the clinical symptoms but also the dermal infiltration of polymorphonuclear leukocytes and T-cells."

10. Makonkawkeyoon S, Limson-Pobre RN, Moriera AL, Schauf V and Kaplan G. Thalidomide inhibits the replication of human immunodeficiency virus type 1. Proceedings of the National Academy of Sciences (USA) 90(13): 5974-78, 1 July 1993. "Thalidomide, a selective inhibitor of tumor necrosis factor alpha (TNF-alpha) synthesis, suppresses the activation of latent human immunodeficiency virus type 1 (HIV-I) in a monocytoid (U1) line. The inhibition is dose dependent and occurs after exposure of the cells to recombinant TNF-alpha, phorbol myristate acetate, lipopolysaccharide, and other cytokine combinations. Associated with HIV-I inhibition is a reduction in agonist-induced TNF-alpha protein and mRNA production."

11. Ensoli B, Markham P, Kao U, Barillari G, Fiorelli V, Gendelman R, Raffeld M, Zon G and Gallo RC. Block of AIDS-Kaposi's sarcoma (KS) cell growth, angiogenesis and lesion formation in nude mice by antisense oligonucleotide targeting basic fibroblast growth factor. A novel strategy for the therapy of KS. Journal of Clinical Investigation 94(5): 1736-46, November 1994. "Kaposi's sarcoma (KS) is the most frequent tumor of HIV-1-infected individuals (AIDS-KS). Typical features of KS are proliferating spindle-shaped cells, considered to be the tumor cells of KS, and endothelial cells forming blood vessels. Basic fibroblast growth factor (bFGF), a potent angiogenic factor, is highly expressed by KS spindle cells in vivo and after injection in nude mice it induces vascular lesions closely resembling early KS in humans. Similar lesions are induced by inoculating nude mice with cultured spindle cells from AIDS-KS lesions (AIDS-KS cells) which produce bFGF. Here we show that phosphorothioate antisense (AS) oligonucleotides directed against bFGF mRNA (ASbFGF) inhibit both the growth of AIDS-KS cells derived from different patients and the angiogenic activity associated with these cells, including the induction of KS-like lesions in nude mice. These effects are due to the block of the production of bFGF which is required by AIDS- KS cells to enter the cell cycle and which, after release, mediated angiogenesis." The effects of ASbFGF are reversed by the addition of bFGF to the cells.

12. Ensoli B et al. Synergy between basic fibroblast growth factor and HIV-1 tat protein in induction of Kaposi's sarcoma. Nature 371 (6499): 674-80: 20 October 1994. "Basic fibroblast growth factor (bFGF) and human immunodeficiency virus type 1 (HIV-1) Tat protein synergize in inducing angiogenic Kaposi's sarcoma-like lesions in mice. Synergy is due to Tat, which enhances endothelial cell growth and type-IV collagenase expression in response to bFGF mimicking extracellular matrix proteins. The bFGF, extracellular Tat and Tat receptors are present in HIV-1-associated KS, which may explain the higher frequency and aggressiveness of this form compared to classical Kaposi's sarcoma where only bFGF is present."

13. D'Amato RJ, Loughnan MS, Flynn E and Folkman J. Thalidomide as an inhibitor of angiogenesis. Proceedings of the National Academy of Sciences (USA) 91: 4082-85, 1994. "Thalidomide is a potent teratogen causing dysmelia (stunted limb growth) in humans. We have demonstrated that orally administered thalidomide is an inhibitor of angiogenesis induced by basic fibroblast growth factor in a rabbit cornea micropocket assay." The anti-angiogenic properties of thalidomide analogs correlated positively with their teratogenicity. "Electron microscopic examination of the corneal neovascularization of thalidomide-treated rabbits reveal specific ultrastructural changes similar to those seen in the deformed limb-bud vasculature of thalidomide-treated embryos."

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