Showdomycin and its reactive moiety,maleimide: A comparison in selective toxicity and mechanism of action in vitro

Showdomycin, a C-nucleoside antibiotic, was twice as toxic to L1210 murine leukemia cells as to murine bone narrow progenitor cells of the granulocyte-macrophage series. Its aglycone, maleimide, was equally toxic to both cell lines. Cysteine, adenosine and the potent nucleoside transport inhibitor 6-(2-hydroxy-5-nitrobenzyl)thio]-9-β-d-ribofuranosylpurine (HNBMPR) reversed the early stages of toxicity of showdomycin to L1210 cells, but did not reduce the toxicity of maleimide. At cytotoxic concentrations, showdomycin progressively inactivated the nucleoside uptake system to completion. This inhibition of nucleoside uptake was reversed by cysteine under conditions where it reversed cytotoxicity. The binding of 6-(4-nitrobenzyl)thio]-9-β-d-ribofuranosylpurine (NBMPR) by L1210 cells was also inhibited by showdomycin, indicating that the antibiotic inactivated the nucleoside transport site. The data suggest that the C-nucleoside structure confers some selectivity to the cytotoxic action of maleimide, directing it toward the nucleoside transport system of the tumor cell.