Abstract 744: Determining the mechanism of action of novel bisintercalating agents using the cDNA microarray technology
Authors: Malek A. Zihlif, Laurence P.G. Wakelin, Daniel Catchpoole, Bernard Stewart
Journal: Cancer Research (2010)

Abstract DNA-intercalating agents inhibit cell growth by two well-established mechanisms: poisoning topoisomerases and inhibiting transcription. The ability to form slowly dissociating DNA complexes with half lives of hundreds of sec, distinguishes the transcription elongation inhibitors from the topoisomerase poisons, which generally dissociate from DNA rapidly in the ms to sec time range (White and Phillips, 1989; Fox and Waring, 1985). We used the microarray technology to elucidate the possible differential effects of bisintercalating agents on transcription and also to answer an important question, whether the bisintercalating agents inhibit transcription, or whether they are topoisomerase poisons. To do this, we compared the resulting expression profiles of the bisintercalators with those derived from the established agents. The novel agents are dimmers of 9-aminoacridine carboxamide in which the linker is attached at the 9 position and bearing different 4-carboxamide threading side chains (Wakelin LPG et al, J Med Chem 46:5790-5802, 2003). The established agents are adriamycin and DACA as a representative for topoisomerase II poisons, and echinomycin, and nogalamycin as a representative for transcription inhibitor. The cultured human CEM cells were the model system and the 5 x IC50 for 24h were the concentration and the time of exposure. The expression of 6000 human genes printed on cDNA microarray was the target. All of the drugs perturb transcription, resulting in both up- and down-regulation of many hundreds of genes; however the cluster analysis has segregated the examined compounds into two distinguished groups. The first represents the transcription inhibitors and charatcterised by higher inhibitory impact and markedly lower up-regulation effect. This group include echinomycin, nogalamycin, and 5 bisinterclating dimmers that compromise different linker and sidechains. The second distinguished group represents the topoisomerase II poisons and incorporate adraimycin and DACA, and another 6 bisintercalting dimmers, which have also different linkers and sidechains. Significantly, the ontological responses follow the above classification by yielding two biological responses profiles. The first characterized by the domination of the regulation of transcription ontological genes, and the second biological responses profile dominated by the protein modification process genes set. Assuming the cells are trying to up-regulate these functions to offset drug inhibition: a kind of biological Le Chatelier's Principal, will imply that the member of the first group engage apoptosis through the inhibition of transcription, while the second involve topoisomerase poisoning in their mode of action. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 744.