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-links of an apparently covalent nature in HeLa S(3) cells. This compound induced interstrand cross-links at concentrations ranging from 0.1 to 1 nM/3 hr in whole cells, but these cross-links were absent or marginally low when the drug was added to cell lysates with inactivated cellular enzymes or isolated nuclei, which suggests that metabolic activation of the drug is a necessary 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 interstrand DNA cross-links in both whole cells and in cell lysates. Interestingly, 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 this may be related to its remarkable cytotoxic activity.
Skladanowski
A
A
Department of Pharmaceutical Technology and Biochemistry, Technical University of Gdañsk, Narutowicza St 11, 80-952, Gdañsk, Poland.
Koba
M
M
Konopa
J
J
D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D001572:Benzofurans; D002455:Cell Division / Q000187:drug effects; D003432:Cross-Linking Reagents / Q000494:pharmacology*; D003509:Cyclohexanecarboxylic Acids / Q000494:pharmacology; D053138:Cyclohexenes; D004247:DNA / Q000187:drug effects* / Q000378:metabolism; D004273:DNA, Neoplasm / Q000187:drug effects / Q000378:metabolism; D000080890:Duocarmycins; D006367:HeLa Cells; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D007933:Leucomycins / Q000494:pharmacology*; D014508:Urea / Q000031:analogs & derivatives* / Q000494:pharmacology
D000903:Antibiotics, Antineoplastic; D001572:Benzofurans; D003432:Cross-Linking Reagents; D003509:Cyclohexanecarboxylic Acids; D053138:Cyclohexenes; D004273:DNA, Neoplasm; D000080890:Duocarmycins; D007211:Indoles; D007933:Leucomycins; C018782:CC 1065; C060090:adozelesin; D014508:Urea; D004247:DNA; C072257:bizelesin