We have studied the effect of suramin and highly sulfated glycosaminoglycans in the biology of human sarcoma, glioblastoma and prostate cancer cells. With regard to sarcoma cells, we have determined an enhanced inhibition of colony formation and cell proliferation in the presence of suramin, as compared to other tumor types. In all, five different sarcoma cell lines have been tested (four osteogenic and one rhabdomyosarcoma). 144 hour exposure to suramin concentrations below the LD50 (in the range of 75-150 micrograms/ml) result in marked alterations in the degree of heparin-binding growth factor MRNA expression. In particular, c-sis message (which possesses marked homology to the B chain of PDGF) diminishes, while transforming growth factor b message increases compared to control. The degree of both c-myc or c-fos MRNA expression did not change significantly in these cell lines upon exposure to suramin. Brief exposure (i.e., 48 hours) of the G-292 osteogenic sarcoma cell line to a sublethal dose of suramin (50 microgram/ml), results in marked morphologic changes with assumption of a more polar fusiform cell shape. Change in the concentration of alkaline phosphatase, a possible marker of osteogenic differentiation, is equivocal in these cells. However, because it is a lysosomal enzyme, alkaline phosphatase may be directly effected by suramin. We have now confirmed that glioblastoma cell lines are variably sensitive to suramin in a manner which correlates to the level of c-sis message expression. In addition, significant morphologic changes appear to occur only in the glioblastoma lines containing detectable amounts of c-sis upon exposure to suramin. These cells appear to assume a less differentiated phenotype. The va-n*able sensitivity among human prostate cell lines is independent of a cell line's sensitivity to androgen, bFGF, PDGF or EGF. However, suramin is capable of reverting the stimulatory effect of exogenously administered growth factor, and to a lesser degree, androgen administration on DNA synthesis and cell proliferation. The cellular accumulation of drug determined after 144 hours exposure does appear to correlate with sensitivity. In addition, PSA and acid phosphatase concentrations in the conditioned media of prostate cancer cells exposed to suramin decreases out of proportion to the resulting decline in cell number. The clinical trials with suramin in refractory cancer are ongoing.
