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.