title: Effects of DNA minor groove binding agents on global gene expression.
abstract: The capacity of two minor groove binding agents that differ in their DNA sequence selectivity to modulate gene expression in human leukaemia cells was investigated. The chosen compounds were the chromomycin A3, a GC selective minor groove binder, and alkamin, an AT selective minor groove binder. As revealed by DNA microarray analysis of 6000 genes, at equitoxic doses, 5×IC(50) values for growth inhibition, the two drugs disturbed transcription, resulting in both up- and down-regulation of many hundreds of genes, 24 h after drug exposure. Direct comparisons between the most affected genes and also the cluster analysis indicated a relatively low degree of similarity between the tow expression profiles. Moreover, the ontological and the pathway responses also indicated a distinguished biological responses. Chromomycin treatment was characterized by many negative impacts on the important cellular functions and by the activation for those functions that usually take the cells towards apoptosis. In the second biological profile, the domination of many positive functions might indicate that the cells were attempting to overcome and repair the alkamin assault. Examples of these functions are positive regulation of gene expression, positive regulation of macromolecule biosynthetic processes, the cell cycle pathway and DNA repair.
authors.affiliation: Department of Pharmacology, Faculty of Medicine, University of Jordan, Amman, Jordan. M.zihlif@ju.edu.jo
authors.forename: Malek
authors.initials: M
authors.lastname: Zihlif
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Catchpoole
authors.forename: Bernard W
authors.initials: BW
authors.lastname: Stewart
authors.forename: Laurence P G
authors.initials: LP
authors.lastname: Wakelin
mesh_terms: D000813:Anilides / Q000494:pharmacology*; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects*; D014128:Chromomycin A3 / Q000494:pharmacology*; D004273:DNA, Neoplasm / Q000378:metabolism*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D015458:Leukemia, T-Cell / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D009588:Nitrogen Mustard Compounds / Q000494:pharmacology*; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured
chemical_list: D000813:Anilides; D014408:Biomarkers, Tumor; D004273:DNA, Neoplasm; D009588:Nitrogen Mustard Compounds; D019384:Nucleic Acid Synthesis Inhibitors; D012333:RNA, Messenger; C539372:alkamin; D014128:Chromomycin A3