DNA damage and differential cytotoxicity produced in human carcinoma cells by CC-1065 analogues, U-73,975 and U-77,779.
U-73,975 (U-73) and U-77,779 (U-77), two analogues of the cyclopropylpyrroloindole antitumor antibiotic CC-1065, are promising novel chemotherapeutic agents which are known to alkylate the N3 position of adenine in a sequence-selective manner. The concentration of U-73 required to produce a 1 log cell kill in 6 human tumor cell lines varied from 20-60 pM. U-77 was more cytotoxic than U-73, with the concentrations required for a 1 log cell kill ranging from 1-20 pM. The cytotoxicity of U-73 and U-77 was found to be independent of the guanine O6-alkyltransferase phenotype. The sensitivity of the BE and HT-29 human colon carcinoma cells was increased when the time of drug exposure was increased from 2 to 6 h. DNA interstrand cross-links, as measured by the technique of alkaline elution, could only be detected when HT-29 or BE cells were exposed to extremely high concentrations of U-77 for 6 h. No other forms of DNA damage were detected in genomic DNA with either compound. U-77 was also found to induce DNA interstrand cross-links in naked DNA, as measured by an agarose gel method. The rate of interstrand cross-linking was extremely rapid with the "second-arm" of the cross-link being completed within 2 h. The mechanism by which these cyclopropylpyrroloindole compounds elicit their cytotoxicity, however, remains to be elucidated.
Lee
C S
CS
School of Pharmacy and Comprehensive Cancer Center, University of Southern California, Los Angeles 90033.
Gibson
N W
NW
D000903:Antibiotics, Antineoplastic / Q000633:toxicity*; D001572:Benzofurans; D002277:Carcinoma; D016923:Cell Death / Q000187:drug effects*; D003110:Colonic Neoplasms; D003432:Cross-Linking Reagents; D003509:Cyclohexanecarboxylic Acids / Q000633:toxicity*; D053138:Cyclohexenes; D004249:DNA Damage; D004305:Dose-Response Relationship, Drug; D000080890:Duocarmycins; D006801:Humans; D007211:Indoles / Q000633:toxicity*; D007933:Leucomycins; D008175:Lung Neoplasms; D010957:Plasmids; D014407:Tumor Cells, Cultured; D014508:Urea / Q000031:analogs & derivatives* / Q000633:toxicity
D000903:Antibiotics, Antineoplastic; D001572:Benzofurans; D003432:Cross-Linking Reagents; D003509:Cyclohexanecarboxylic Acids; D053138:Cyclohexenes; D000080890:Duocarmycins; D007211:Indoles; D007933:Leucomycins; C018782:CC 1065; C060090:adozelesin; D014508:Urea; C072257:bizelesin