Recombinant human platelet factor-4 (rhPF4), purified from Escherichia coli, inhibited blood vessel proliferation in the chicken chorioallantoic membrane in a dose-dependent manner. Treatment of several cell types with rhPF4 in vitro suggested that the angiostatic effect was due to specific inhibition of growth factor-stimulated endothelial cell proliferation. The inhibitory activities were associated with the carboxyl-terminal, heparin-binding region of the molecule and could be abrogated by including heparin in the test samples, an indication that sulfated polysaccharides might modulate the angiostatic activity of platelet factor-4 in vivo. Understanding of the mechanisms of control of angiogenesis by endogenous proteins should facilitate the development of effective treatments for diseases of pathogenic neovascularization such as Kaposi's sarcoma, diabetic retinopathy, and malignant tumor growth.
Although it is well established that angiogenesis is essential to tumor development, no human protein with high specificity and efficacy for prevention of angiogenesis has been characterized. In a previous study, we demonstrated that recombinant platelet factor 4 (rPF 4) inhibited angiogenesis in the chicken chorioallantoic membrane. In the present study, we have extended that finding to the use of recombinant human platelet factor 4 (rHuPF 4) to inhibit solid tumor growth in the mouse. rHuPF 4 effectively suppressed the growth of the B16-F10 murine melanoma in syngeneic C57BL/6J hosts and prevented the growth of primary tumors of both B16-F10 murine melanoma and HCT 116 human colon carcinoma in semisyngeneic CByB6F1/J female athymic nude mice. These two transformed cell lines were completely insensitive to rHuPF 4 in vitro at levels (50 micrograms/mL) that extensively inhibit normal endothelial cell proliferation. The migration of human endothelial cells was also inhibited at these concentrations of rHuPF 4, suggesting a second mechanism by which rHuPF 4 may modulate capillary development. The observed antitumor effects of rHuPF 4 might be due to the inhibition of angiogenesis. This finding could have implications for the development of novel therapeutic approaches to angiogenic diseases. Alternative, and possibly concurrent, mechanisms of the rHuPF 4 antitumor effect include lymphokine-activated killer cell activation and the induction of other cytokines.
Keratinocytes and endothelial cells produce basic fibroblast growth factor (b-FGF), and this cytokine is mitogenic for both cell types. Additionally, b-FGF is stored in the vicinity of keratinocytes and endothelial cells in basement membrane and extracellular matrix, and can be displaced from these "buffers" by various stimuli. Displacement of b-FGF by physical stimuli, such as scratching or rubbing, could explain koebnerization in diseases such as psoriasis. It has been shown that the fungal metabolite cyclosporine A will inhibit the proliferation of keratinocytes in vitro when their proliferation is driven by epidermal growth factor (EGF) and/or bovine pituitary extract. Since b-FGF may be both a positive autocrine and paracrine signal involved in the proliferation of both keratinocytes and endothelial cells, we evaluated the effects of cyclosporine on the b-FGF-driven proliferation of these cell types in vitro. We have shown that normal human keratinocyte and endothelial cell proliferation driven by b-FGF alone can be inhibited by cyclosporine A. Concentrations of cyclosporine A achievable in skin after oral administration can significantly inhibit the b-FGF-driven proliferation of both of these cell types. Basic fibroblast growth factor may be an important signal driving both keratinocyte proliferation and angiogenesis in certain disease states, such as psoriasis, as well as aberrant endothelial cell proliferation as is seen in Kaposi's sarcoma. The efficacy of cyclosporine A in treating these disease states may be due, at least in part, to the ability of cyclosporine A to interrupt b-FGF-mediated autocrine and paracrine feedback loops acting on and between endothelial cells and keratinocytes.
We have observed that 8–4-[4–2-pyrimidyl)-1-piperazinyl]butyl]-8-azaspiro [4.5]decane-7.9-dione, an agent commonly known as buspirone HCl, possesses immunosuppressive activity when administered either topically or systemically, as assessed in a mouse model of contact hypersensitivity. Topical or systemic administration of buspirone significantly reduced the tissue swelling and leukocyte infiltration associated with the elicitation phase of contact hypersensitivity. Buspirone is a safe, widely used drug which has a history of use in humans throughout the world. These data demonstrate a previously unknown pharmacologic activity of buspirone.
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