POTENT INHIBITION OF HUMAN FOLYLPOLYGLUTAMATE SYNTHETASE BY SURAMIN

Suramin, a bis-hexasulfonated napthylurea, was studied as an inhibitor of human folylpolyglutamate synthetase (FPGS), a crucial enzyme in fo late metabolism. Suramin is a more potent (IC50, 0.9 mu M) inhibitor o f FPGS partially purified from CCRF-CEM human leukemia cells than is b romosulfophthalein (IC50, 17 mu M), the first reported nonsubstrate-an alog inhibitor of FPGS (J. J. McGuire et al., Adv. Exptl. Med. Biol. 1 63, 199, 1983). FPGS inhibition by suramin is reversed by bovine serum albumin (which binds suramin). Suramin is a noncompetitive inhibitor with aminopterin (K-ii = 0.9 mu M; K-is = 1.1 mu M) and glutamic acid (K-ii = 1.0 mu M; K-is = 5.2 mu M) as the variable substrates; suramin inhibition tends toward being competitive with respect to the third F PGS substrate, ATP (K-ii = 3.4 mu M; K-is = 0.35 mu M), since the majo r effect is on its K,, Suramin is a much less potent inhibitor of two other folate dependent enzymes, dihydrofolate reductase (IC50, 38 mu M ; methotrexate (MTX), 0.6 nM) and thymidylate synthase (IC50 87 mu M; MTX, 48 mu M). The effects of suramin on growth of CCRF-CEM. cells and a MTX-resistant subline (R30dm) expressing low levels of FPGS activit y were determined, R30dm is slightly collaterally sensitive to suramin consistent with FPGS inhibition contributing to the cytotoxic mechani sm. These data, and those of Rideout et al. (Int. J. Cancer 61, 840, 1 995), demonstrating that the reduced folate carrier system of CCRF-CEM is inhibited, suggest that inhibition of folate metabolism could be i nvolved in the mechanism of action of suramin. (C) 1996 Academic Press , Inc.