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Expression data: GDS3257 - Lung adenocarcinoma (forty nine normal lung tissues vs. fifty eight lung tumor tissues) The expression data was analyzed using a method called empirical Bayes in limma. To extract statistically differentially expressed genes, 2-fold change and p-value < 0.05 were set as default. As we are looking combinatorial drugs which could reverse the action of lung adenocarcinoma, phenotype of signature genes was reversed. So up-regulated genes became down-regulated genes, and down-regulated genes became up-regulated genes.

Potential anticancer molecules and FDA approved anticancer agent were successfully included in top 10 molecules such as Trichostatin A [1], LY-294002 [2] [3], GW-8510 [4], Vorinostat [5] [6], Resveratrol [7], and Lomustine [8] [9] [10].

We tested top 20 combinatorial drugs on A549 cells. Among them, two cases, alsterpaullone and scriptaid, irinotecan and semustine, showed synergistic effects. In these two cases, the effect of the combination is greater than the summed effects of the partner drugs. Irinotecan vs Alsterpaiullone
Isobologram analyses of A549 cell proliferation inhibition by combinatorial drugs.
The IC50 values of each drug are plotted on the axes (rectangle); the dotted line represents the addictive effects, whereas triangles representing the concentrations of combinatorial drugs resulting in 50% proliferation inhibition of the combination are positioned on the left of the dotted line, indicating synergism.

The combination of irinotecan and semustine can be described as an example of actions on different targets. Irinotecan inhibits topoisomerase 1. By interacting with DNA, it stabilizes covalent topoisomerase-DNA complexes to block DNA replication fork [11]. Semustine is a classical alkylating agent. It damages DNA by binding of alkyl group to the specific sites in DNA. However these alkyl group-caused anticancer effect often be reduced because of the counteractive activity of mutagenic translesional bypass replication. And since irinotecan reduces such counteractive effect, the combination of irinotecan and semustine results in synergism.

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