ANTIHELICASE ACTION OF DNA-BINDING ANTICANCER AGENTS - RELATIONSHIP TO GUANOSINE-CYTIDINE INTERCALATOR BINDING

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.