▒  HOME > User Guide > Sample date


INPUT SIGNATURES
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.


SINGLE DRUG RESULT
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].


COMBINATORIAL DRUG RESULT
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.

  1. Mukhopadhyay NK et al., Effectiveness of trichostatin A as a potential candidate for anticancer therapy in non-small-cell lung cancer., Ann Thorac Surg 2006 Mar; 81(3) 1042
  2. Nguyen DM et al., Potentiation of paclitaxel cytotoxicity in lung and esophageal cancer cells by pharmacologic inhibition of the phosphoinositide 3-kinase/protein kinase B (Akt)-mediated signaling pathway., J Thorac Cardiovasc Surg. 2004 Feb; 127(2) 365-75.
  3. Kandasamy K et al., Role of the phosphatidylinositol 3'-kinase/PTEN/Akt kinase pathway in tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis in non-small cell lung cancer cells., Cancer Res. 2002 Sep 1; 62(17) 4929-37.
  4. Dong F et al., Downregulation of XIAP and induction of apoptosis by the synthetic cyclin-dependent kinase inhibitor GW8510 in non-small cell lung cancer cells., Cancer Biol Ther. 2006 Feb; 5(2) 165-70
  5. Miyanaga A et al., Antitumor activity of histone deacetylase inhibitors in non-small cell lung cancer cells: development of a molecular predictive model., Mol Cancer Ther. 2008 Jul;7(7):1923-30.
  6. Ramalingam SS et al., Carboplatin and Paclitaxel in combination with either vorinostat or placebo for first-line therapy of advanced non-small-cell lung cancer., J Clin Oncol. 2010 Jan 1; 28(1) 56-62
  7. Athar M et al., Resveratrol: A Review of Pre-clinical Studies for Human Cancer Prevention, Toxicol Appl Pharmacol. 2007 November 1; 224(3) 274–283.
  8. Lebeau B et al., Oral second- and third-line lomustine-etoposide-cyclophosphamide chemotherapy for small cell lung cancer., Lung Cancer. 2010 Feb; 67(2) 188-93
  9. Ettinger et al., Phase III study of CCNU, cyclophosphamide, adriamycin, vincristine, and VP-16 in small-cell carcinoma of the lung., Cancer. 1982 Apr 15; 49(8) 1544-54.
  10. Lebeau B et al., Six vs twelve cycles for complete responders to chemotherapy in small cell lung cancer: definitive results of a randomized clinical trial. The "Petites Cellules" Group., Eur Respir J. 1992 Mar; 5(3) 286-90.
  11. Koster DA et al., Antitumour drugs impede DNA uncoiling by topoisomerase I., Nature. 2007 Jul 12;448(7150):213-7. Epub 2007 Jun 24.