Proliferation-dependent and -independent cytotoxicity by antitumor diarylsulfonylureas: Indication of multiple mechanisms of drug action

摘要: The mechanism(s) by which antitumor diarylsulfonylureas (DSU) cause cytotoxicity has been examined in GC3/c1 human colon adenocarcinoma cells and a subline selected for resistance to N-(5-indanylsulfonyl)-N'-(4-chlorophenyl)urea (ISCU). Resistance was stable the absence of selection pressure. This mutant (designated LYC5) 5.5-fold resistant ISCU compared parental serum containing medium when were exposed 7 days. In contrast, LYC5 not 4-hr exposure ISCU. These data indicated two possible mechanisms action, dependent on concentration time Proliferation-dependent -independent identified wild-type clones. serum-free growth factors, IC50 0.51 microM 7.0 (13.6-fold resistance), whereas without factors both lines 8- 9-fold relative conditions cellular proliferation. Accumulation similar quiescent proliferating cells, reduced only slightly cells. Analysis DNA agarose gel electrophoresis showed that nucleosomal ladders formed No detected during toxic concentrations drug (IC90), or after removal addition stimulate growth. indicate several diarylsulfonylurea agents may cell death. at very high (IC50 approximately 370 microM) short periods (4 hr), proliferation independent, equally sensitive. mechanism relate uncoupling activity However, pharmacological relevant concentrations, primary led formation 0.5 microM). A additional occurred higher associated with degradation.