SURAMIN SODIUM - PRONOUNCED EFFECTS ON METHOTREXATE TRANSPORT AND ANTIFOLATE ACTIVITY IN CULTURED TUMOR-CELLS

Suramin is an experimental anti-neoplastic agent which has shown promi sing activity against prostatic carcinoma and lymphoma in clinical tri als. 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 sura min but not to various other arylsulfonic acids. Inhibition by suramin was competitive, and the inhibition constant K-i was 1.3 mu M, a valu e 3-fold lower than the K-t for half-maximal influx of methotrexate. F olate binding to the membrane-associated folate-binding protein of KB cells was not affected by suramin. Growth studies revealed that the re sponse 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 mu M ) of suramin. Conversely, growth inhibition was additive or synergisti c when suramin was combined with metoprine, a lipophilic anti-folate w hich enters cells by diffusion. Synergism was observed between metopri ne and suramin in CCRF-CEM cells, which take up folate exclusively thr ough the reduced-folate carrier (inhibitable by suramin), whereas addi tivity was observed for KB cells, which rely largely on the folate-bin ding protein (unaffected by suramin) for folate import. Our results in dicate that inhibition of cellular transport of folate compounds may e xplain part of the antineoplastic effects of suramin on tumor cells. ( C) 1995 Wiley-Liss, Inc.