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  • Title: 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.
    Author: Ogasawara H, Nishio K, Ishida T, Arioka H, Fukuoka K, Saijo N.
    Journal: Jpn J Cancer Res; 1997 Nov; 88(11):1033-7. PubMed ID: 9439677.
    Abstract:
    Duocarmycins, including KW-2189, bind in the minor groove of double-stranded DNA at A-T-rich sequences, followed by covalent bonding with N-3 of adenine in preferred sequences. We examined the effect of DNA-repair 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 duocarmycin-induced DNA strand breaks, which are potentially lethal to cells, are repaired through a caffeine-sensitive pathway.
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