engleski

Computational analysis of in vitro screening data highlights an atypical cytostatic mechanism of a cytosine derivative

Previously, pyrimidine nucleic base derivatives with a sulfonamide pharmacophore have been indicated as potential antitumor agents. We have shown that N-1-sulfonylpyrimidine derivatives have strong antiproliferative activity on human tumor cell lines, where 1-(p-toluenesulfonyl)cytosine (TsC) in specific was shown to have a selective effect with regard to normal cells and was easily synthesized on a large scale. Past experiments using radio-assays of enzyme activity have indicated that TsC induces a general shutdown in the cellular DNA, RNA and protein biosynthesis. In the present work we have used an interdisciplinary approach to further elucidate the compounds’ mechanistic class. Primarily, we have employed an augmented number of cell lines (eleven), of which eight overlapped with the DTP-NCI screening panel, and one non-transformed human fibroblast cell line. This has allowed us to computationally search for compounds with similar activity profiles and/or mechanistic class by integrating our data with the comprehensive DTP-NCI database ; a permutation testing procedure was used to estimate statistical significance of the matches. We have applied supervised data mining methodology (a Random Forest classifier), allowing us to get a prediction of mechanism of action, along with estimates of predictive reliability. When using only a subset of the full DTP-NCI 60 cell line panel, this approach may complement the information obtained from self organizing maps (SOM), a method commonly used in examinations of cytostatic activity profiles. Finally, we have performed cell cycle perturbation and apoptosis analysis of the most sensitive cell line (MCF-7), which has shown marked G1 phase arrest accompanied with the reduction of the number of cells in S phase. As expected, TsC did not alter the cell cycle of normal cells. Our results point to an unusual mechanism of cytostatic action, possibly a combination of nucleic acid antimetabolite activity and a novel molecular mechanism. We hypothesize that the novel mechanism might be similar to the activity of benzothiazoles, previously described as involving the aryl hydrocarbon receptor, activation of CYP1A1 and CYP1B1 genes and a subsequent DNA damage response. Our work has been published in the “ Investigational New Drugs” journal, Volume 26 (April 2008), pages 97-110, available from http://dx.doi.org/10.1007/s10637-007-9084-1

nucleobase; antitumor compound; cell line screen; random forest

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