SELECTIVE-INHIBITION OF CELL-PROLIFERATION AND DNA-SYNTHESIS BY THE POLYSULFATED CARBOHYDRATE IOTA-CARRAGEENAN

iota-Carrageenan is a polysulphated carbohydrate that antagonises some heparin-binding growth factors. We assessed the effect of iota-carrag eenan on the proliferation of a panel of cell lines, some of which req uire heparin-binding growth factors for mitogenesis. The importance of growth factor antagonism for the antiproliferative activity was also determined. Cell proliferation was determined by cell counts and a tet razolium dye (MTT) assay, and DNA synthesis was determined by thymidin e incorporation. The proliferation of the basic fibroblast growth fact or (bFGF)-dependent endothelial cell line FBHE was inhibited by daily administration of iota-carrageenan in a dose-dependent manner [concent ration inhibiting cell growth by 50% (IC50 value), approx. 0.5 mu g/ml ]. However, excess bFGF did not reverse the inhibitory effect. DNA syn thesis was completely inhibited by concentrations of l-carrageenan tha t nonetheless allowed significant protein synthesis to occur. The prol iferation of the androgen-dependent prostate-carcinoma cell line LNCaP was also inhibited by iota-carrageenan (IC50 value, 5.5 mu g/ml) and the cells were arrested at the G1/S boundary. iota-Carrageenan inhibit ed DNA synthesis in MCF-7 cells stimulated by bFGF and transforming gr owth factor alpha (TGF alpha) but not in those stimulated by insulinli ke growth factor 1 (IGF-1). Blocking IGF-1-mediated DNA synthesis with anti-IGF-1 receptor antibody alpha IR3 enhanced the inhibitory activi ty of iota-carrageenan against MCF-7 cells grown in serum. A number of other transformed and non-transformed cell lines were either partiall y inhibited or not inhibited by iota-carrageenan. iota-Carrageenan had low anti-coagulant activity. iota-Carrageenan is a selective anti-pro liferative agent and warrants further investigation for anti-angiogeni c therapy (in view of its activity against endothelial cells) and for the treatment of androgen-dependent prostate cancer.