THE SYNERGISTIC AND ANTAGONISTIC EFFECTS OF CYTOTOXIC AND BIOLOGICAL AGENTS ON THE IN-VITRO ANTITUMOR EFFECTS OF SURAMIN

Suramin has shown antitumour activity in vitro and in vivo. At plasma levels higher than 200 mu M there is, however, excessive toxicity. We have, therefore, attempted to improve the antitumour effects of surami n in vitro by combining it with several other antitumour agents. The M CF-7 mammary carcinoma and PC3 prostate cancer cell lines were exposed continuously to suramin and the other agents for 6 days. The sulphorh odamine B (SRB) assay was used for the assessment of growth inhibition . The dose-response interactions were evaluated using the median-effec t analysis with the Chou and Talalay computer programme. in the MCF-7 cell line, the combination of suramin plus doxorubicin (DXR), cisplati n (CDDP), 5-fluorouracil (5-FU) or tumour necrosis factor (TNF) result ed in synergistic growth inhibition, whilst its combination with milte fosine (HPC) was antagonistic. In the PC-3 cell line, suramin plus CDD P or TNF was synergistic, whilst its combination with DXR, 5-FU and HP C was antagonistic. All tested combinations with interferon-alpha (IFN -alpha), interferon-gamma (IFN-gamma) and with the combination of both IFN-alpha + IFN-gamma were not synergistic. The synergistic effect of suramin with DXR was schedule dependent. Pretreatment (addition of DX R on day 1 and suramin on days 2-5) was additive at the IC50 level, in both cell lines. Addition of DXR at day 5 was more effective than sim ultaneous exposure. We found a synergistic effect for the combination of suramin with CDDP and TNF in both cell lines. In addition the combi nation with DXR and 5-FU was synergistic in MCF-7. Sequential administ ration of DXR-suramin or suramin-DXR increased the growth inhibition.