Structure activity analysis of the formation of DNA damage induced in human tumor cells by the cyclodisone class of anti-tumor agent.
1,5,2,4-dioxadithiocane-2,2,4,4-tetraoxide (compound II) and 1,5,2,4-dioxadithionane-2,2,4,4-tetraoxide (compound III) are two structural analogues of the anticancer agent cyclodisone. Compound III was found to be more toxic to human colon carcinoma cells of the Mer- phenotype (BE) than the Mer+ phenotype (HT-29). In contrast, compound II showed little preferential toxicity with both cell lines being equally sensitive to this agent. DNA interstrand crosslinks were induced in the sensitive cell line by compound III but only at concentrations which were extremely cytotoxic. No DNA interstrand crosslinks were detected in the resistant cell line by compound III nor in either cell line by compound II. Total crosslinks which reflects both DNA interstrand and DNA-protein crosslinks, were observed in both cell lines after exposure to each agent although the kinetics of formation and repair of these lesions differed between both the compounds and each cell line. DNA strand breaks were also induced in both cell lines by each compound and were found to be totally 'protein associated' with compound III and to a lesser extend with compound II. The mechanism of action of this class of compound is thus different from other bifunctional alkylating agents and has still to be identified.
Berardini
M D
MD
Laboratory of Pharmacology, AMC Cancer Research Center, Denver, CO 80214.
Pacheco
D Y
DY
Gibson
N W
NW
D000468:Alkalies; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D003432:Cross-Linking Reagents; D004249:DNA Damage; D006801:Humans; D013329:Structure-Activity Relationship; D013846:Thiepins / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000468:Alkalies; D000970:Antineoplastic Agents; D003432:Cross-Linking Reagents; D013846:Thiepins; C048244:cyclodisone