Does the antitumor cyclopropylpyrroloindole antibiotic CC-1065 cross-link DNA in tumor cells?

We have found that a cyclopropylpyrroloindole antibiotic, compound CC-1065 (benzo[1,2-b:4,3-b']dipyrrole-3(2H)-carboxamide, 7-[[1,6-dihydro-4-hydroxy- 5-methoxy-7-[(4,5,8,8a-tetrahydro-7-methyl-4-oxocyclopropan[c]pyrrolo[3,2-e ]indol-2(1H)-yl)carbonyl]benzo[1,2-b: 4,3-b']dipyrrol-3(2H)-yl]-carbonyl]-1 ,6-dihydro-4-hydroxy-5-methoxy, (7bR,8aS)), forms interstrand DNA cross-lin ks of an apparently covalent nature in HeLa S-3 cells. This compound induce d interstrand cross-links at concentrations ranging from 0.1 to 1 nM/3 hr i n whole cells, but these cross-links were absent or marginally low when the drug was added to cell lysates with inactivated cellular enzymes or isolat ed nuclei, which suggests that metabolic activation of the drug is a necess ary step for DNA cross-linking to occur. In contrast, an analog of CC-1065, Bizelesin, which forms DNA-DNA cross-links by direct alkylation, induced i nterstrand DNA cross-links in both whole cells and in cell lysates. Interes tingly, a demethoxy analog of CC-1065. Adozelesin, did not induce DNA cross -links under the same conditions. CC-1065 was found to be extremely potent in terms of concentrations required to cross-link DNA of tumor cells, and t his may be related to its remarkable cytotoxic activity. (C) 2000 Elsevier Science Inc. All lights reserved.