Abstract
The ability of a series of polysulphonated naphthylureas structurally related to suramin to inhibit basic fibroblast growth factor (bFGF) or serum-stimulated growth of endothelial cells [either large vessel, human umbilical vein endothelial cells (HUVEC) or microvascular, bovine adrenal capillary endothelial (BACE) cells] and angiogenesis in vivo has been examined. The polyanions encompassed two main structural variations, namely the number of aromatic amide groups intervening between two terminal naphthyl rings and/or variation in the substitution pattern of the naphthyl rings. The polyanions were either inactive (group I) or inhibited (group II) bFGF-stimulated uptake of [3H]methylthymidine by BACE cells. Group I compounds shared a common structural feature in that they were simple binaphthyl-substituted ureas. In contrast, group II compounds all had an extended multiple ring structure with at least two aromatic groups intervening between the two terminal naphthyl rings. Compounds with either two or four intervening groups were equipotent in blocking bFGF in vitro. However, compounds with two bridging aromatic groups were 5- to 10-fold less toxic than suramin in mice, suggesting a potential for an improved therapeutic ratio. The ability of the polyanions to block bFGF-driven endothelial cell proliferation in vitro correlated with antiangiogenic activity in vivo as shown by use of the rat sponge angiogenesis model. These observations could substantially widen the anti-tumour therapeutic opportunities for this class of compound.
Highlights
Suramin is a polysulphonated naphthylurea that has been employed in the treatment of onchocerciasis and trypanosomiasis for over 50 years
Suramin has been employed in the treatment of cancers that are unresponsive to convential chemotherapy, including prostate carcinomas (Myers et al, 1990) and lymphomas (La Rocca et al, 1990c)
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
Summary
Suramin is a polysulphonated naphthylurea that has been employed in the treatment of onchocerciasis and trypanosomiasis for over 50 years. In the light of selective toxicity of suramin for the adrenal cortex, it was examined as a potentially novel anti-cancer agent in the treatment of metastatic adrenocortical carcinoma and shown to have some activity (La Rocca et al, 1990a, b). Suramin has been employed in the treatment of cancers that are unresponsive to convential chemotherapy, including prostate carcinomas (Myers et al, 1990) and lymphomas (La Rocca et al, 1990c). Suramin administered i.p. has in addition been shown to inhibit growth of human osteosarcoma xenografts in Balb/cA-nu/nu mice for periods of up to 9 weeks (Walz et al, 1991)
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