Suramin prevents neovascularisation and tumour growth through blocking of basic fibroblast growth factor activity

Abstract

Summary Inhibition of angiogenesis through blocking of growth factors involved in this process could be a novel therapeutic approach in several important pathologies, neoplasia among them. Suramin has recently been described to possess antineoplastic activity in animals and humans, and it has been proposed that an important role in this activity is played by antagonism of growth factors and especially bFGF. To investigate this hypothesis in vivo, we used gelatin sponges loaded with bFGF and implanted subcutaneously in mice. Suramin showed an inhibitory activity on bFGF-induced angiogenesis, whereas it was inactive in the case of heparin-complexed bFGF. Suramin was also studied in an in vivo model of tumour-induced angiogenesis using the murine M5076 reticulosarcoma, a tumour producing significant levels of bFGF. Suramin was able to reduce tumour growth and tumour induced angiogenesis, and exogenous administration of bFGF countered suramin effects.Physiologically, angiogenesis (i.e. the formation of new capillary vessels), is an important event in embryonic development and in the adult female reproductive cycle (Gospodarowicz & Thakral, 1978). Under pathological conditions neovascularisation occurs during the wound healing process (Knighton, 1981) and in a variety of diseases ranging from diabetic retinopathy to psoriasis and several types of chronic inflammations (Goldie, 1969). It has also been shown that the process of solid tumours growth is angiogenesisdependent (Gullino, 1978;Folkman, 1990). Several substances of different chemical nature and cellular origin, including growth factors produced by the neoplastic cells themselves, have been described to be involved in tumourinduced neoangiogenesis (Shing et al., 1985;Folkman & Klagsbrun, 1987) by directly and/or indirectly stimulating endothelial cells proliferation and/or migration (Ausprunk & Folkman, 1977). One of the better characterised among such angiogenic factors is basic Fibroblast Growth Factor (bFGF) (Rifkin & Moscatelli, 1989), whose presence in a large number of normal and malignant cells is well established, and that has been implicated as a major contributing factor in both physiological and pathological neovessel formation (Folkman et al., 1988;Klagsbrun et al., 1986;Thompson et al., 1988;Hayek et al., 1987). Since solid tumour growth and progression are strictly dependent from neovessel formation (Folkman et al., 1989;Brem et al., 1977) interfering with this process by counteracting the effect of angiogenic growth factors could represent a novel and selective therapeutic approach to malignancy.Suramin, a polysulphonated trypan red derivative used in the past as antitrypanosomic agent (Hawking et al., 1987), has recently generated interest as an antinoplastic agent (Stein et al., 1989;Myers et al., 1990; Richard, 1990;Hosang, 1985;Mills et al., 1990) to their cell surface receptors through direct complexation of the growth factors and/or via a modification of the cell receptor (Coffey et al., 1987). This activity could explain suramin inhibitio...

A structure-activity analysis of antagonism of the growth factor and angiogenic activity of basic fibroblast growth factor by suramin and related polyanions

“…The study of Pesenti et al (1992) has shown that i.v. suramin is able to block bFGF-induced vascularisation of a gelatin sponge implanted subcutaneously in rats.…”

“…We have employed a similar model to examine the antiangiogenic activity of the related polyanions. A polyether sponge was employed rather than the gelatin sponge of Pesenti et al (1992), which unlike the gelatin sponge spontaneously vascularises slowly as a result of an inflammatory response.…”

“…Other steps include endothelial cell migration, tube formation and anastomoses (for more detail see D'Amore & Thompson, 1987;Bicknell & Harris, 1992). In view of the recent report that suramin can exert an antiangiogenic effect (Pesenti et al, 1992), it was of interest to us to examine some structurally related polyanions for their ability to inhibit bFGF-stimulated capillary endothelial cell proliferation and subsequently angiogenesis in vivo. Sixteen polysulphonated naphthylureas were examined, and we have identified structural features of the suramin molecule that endow growth factor-blocking activity and, further, show that some of the polyanions have at least equivalent antiangiogenic activity to suramin but are 5-to 10-fold less toxic to mice.…”

Leads for Development of New Naphthalenesulfonate Derivatives with Enhanced Antiangiogenic Activity

“…The antiangiogenic activity of suramins is based, at least in part, on their ability to disrupt the interaction of many growth factors with their membrane receptors, such as in the case of FGFs and their tyrosine kinase receptors (19, 24 -26). Because it has been shown that heparin disrupts aFGF⅐suramin complexes (27) and counteracts the antiangiogenic effect of these polysulfonated ureas (25,26), suramins are considered to act by blocking the heparin-binding sites of FGFs (28). Another group of antiangiogenic and antitumoral compounds is comprised by suradistas, a type of noncytotoxic synthetic binaphthalene sulfonic distamycin-A derivatives.…”

Inhibition of angiogenesis and murine tumour growth by laminarin sulphate

“…This assay, initially developed by Folkman (1975) to study tumour-induced angiogenesis, is now widely used as an resulted in inhibition of angiogenesis on all the eggs tested, but this concentration of LAM S5 was associated with increased toxicity to the chick embryos (Table I). Suramin, which has anti-angiogenic activity (Pesenti et al, 1992) and was used as a positive control in our studies, had less antiangiogenic activity than LAM S5 (Table I). Several polysulphated carbohydrates with anti-angiogenic activity have also been shown to inhibit tumour growth in animal models (see introduction).…”