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-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.
Ogasawara
H
H
Pharmacology Division, National Cancer Center Research Institute, Tokyo.
Nishio
K
K
Ishida
T
T
Arioka
H
H
Fukuoka
K
K
Saijo
N
N
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D002110:Caffeine / Q000008:administration & dosage; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D004249:DNA Damage; D004273:DNA, Neoplasm / Q000187:drug effects / Q000378:metabolism; D004357:Drug Synergism; D000080890:Duocarmycins; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy*; D011760:Pyrrolidinones / Q000008:administration & dosage; D012995:Solubility; D014867:Water
D004273:DNA, Neoplasm; D000080890:Duocarmycins; D011760:Pyrrolidinones; D014867:Water; C086920:KW 2189; D002110:Caffeine