IN-VITRO ENHANCEMENT OF ANTITUMOR-ACTIVITY OF A WATER-SOLUBLE DUOCARMYCIN DERIVATIVE, KW-2189, BY CAFFEINE-MEDIATED DNA-REPAIR INHIBITION IN HUMAN LUNG-CANCER CELLS

Duocarmycins, including KW-2189, bind in the minor groove of double-st randed DNA at A-T-rich sequences, followed by covalent bonding with N- 3 of adenine in preferred sequences. We examined the effect of DNA-rep air modulators, such as caffeine and aphidicolin, on the cytotoxicity of duocarmycins towards human lung cancer cells, as determined by dye formation assay. Caffeine (0.5 or 1 mM), but not aphidicolin, enhanced the growth-inhibitory activity of KW-2189, DU-86, and duocarmycin SA. Caffeine inhibited repair of DNA strand breaks induced by KW-2189, as assayed by the alkaline elution technique. This suggests that duocarm ycin-induced DNA strand breaks, which are potentially lethal to cells, are repaired through a caffeine-sensitive pathway.