Suramin sodium: pronounced effects on methotrexate transport and anti-folate activity in cultured tumor cells.

Suramin is an experimental anti-neoplastic agent which has shown promising activity against prostatic carcinoma and lymphoma in clinical trials. To elucidate its mechanism of action, suramin was examined for an effect on the transport of folate compounds by tumor cells. Influx of the anti-folate methotrexate via the reduced-folate carrier system of CCRF-CEM cells was found to be highly sensitive to inhibition by suramin but not to various other arylsulfonic acids. Inhibition by suramin was competitive, and the inhibition constant Ki was 1.3 microM, a value 3-fold lower than the Kt for half-maximal influx of methotrexate. Folate binding to the membrane-associated folate-binding protein of KB cells was not affected by suramin. Growth studies revealed that the response of human CCRF-CEM, KB, PC-3 and MCF-7 cells to methotrexate was antagonized from 6- to 17-fold by pharmacological levels (10-200 microM) of suramin. Conversely, growth inhibition was additive or synergistic when suramin was combined with metoprine, a lipophilic anti-folate which enters cells by diffusion. Synergism was observed between metoprine and suramin in CCRF-CEM cells, which take up folate exclusively through the reduced-folate carrier (inhibitable by suramin), whereas additivity was observed for KB cells, which rely largely on the folate-binding protein (unaffected by suramin) for folate import. Our results indicate that inhibition of cellular transport of folate compounds may explain part of the anti-neoplastic effects of suramin on tumor cells.