Nr. Bachur et al., ANTIHELICASE ACTION OF DNA-BINDING ANTICANCER AGENTS - RELATIONSHIP TO GUANOSINE-CYTIDINE INTERCALATOR BINDING, Molecular pharmacology, 44(5), 1993, pp. 1064-1069
DNA-binding antibiotics such as intercalators, narrow groove binders,
and other substances modify duplex DNA, making it an altered substrate
for DNA helicases. The intercalators daunorubicin, actinomycin D, ech
inomycin, and elsamicin, the narrow groove binders distamycin and mith
ramycin, and the plant toxin teniposide, each representing a different
chemical class, block SV40 large T antigen DNA helicase action with I
C50 values ranging from 4 x 10(-8) to 2 x 10(-6) m. A partially purifi
ed human HeLa cell DNA helicase is also potently blocked by daunorubic
in, distamycin, and teniposide. Because eukaryotic cells contain helic
ases of varying abundance, specificity, and type, this site of action
for DNA-binding antibiotics may help explain antibiotic potency and sp
ecificity for DNA or RNA inhibition. The antihelicase effect of the an
tibiotic-double-stranded DNA complex may be central to the anticancer
activities of these substances. An additional interesting correlation
is the antihelicase action of DNA-intercalating antibiotics and their
DNA-binding preference for G-C base pair sites. The G-C base pair bind
ing preference of the intercalating antibiotics may result from evolut
ionary selection because of the higher G-C binding stability, compared
with A-T binding stability. The combination of the higher base pair s
tability at G-C regions and increased duplex DNA stability induced by
intercalating antibiotic yields a total additive stability of the inte
rcalator-G-C base pair complex that resists helicase action.