Revealing the Origin and Nature of Drug Resistance of Dynamic Tumour Systems

Revealing the Origin and Nature of Drug Resistance of Dynamic Tumour Systems

Ricardo Santiago-Mozos, Imtiaz A. Khan, Michael G. Madden
Copyright: © 2010 |Pages: 28
DOI: 10.4018/jkdb.2010100102
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In this paper, the authors identify the strategies that resistant subpopulations of cancer cells undertake to overcome the effect of the anticancer drug Topotecan. For the analyses of cell lineage data encoded from timelapse microscopy, data mining tools are chosen that generate interpretable models of the data, addressing their statistical significance. By interpreting the short-term and long-term cytotoxic effect of Topotecan through these data models, the authors reveal the strategies that resistant subpopulations of cells undertake to maximize their clonal expansion potential. In this context, this paper identifies a pattern of cell death independent of cytotoxic effect. Finally, it is observed that cells exposed to Topotecan have higher movement over time, indicating a putative relationship between cytotoxic effect and cell motility.
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Biological Sample Preparation

The human osteosarcoma cell line [U-2 OS (ATCC HTB 96)23], derived from a 15-year-old Caucasian female and transfected with a fluorescent reporter cyclin B1 GFP, is selected. The cells are maintained at 37 ºC and 5% CO2 using standard tissue culture techniques. Media used is McCoys 5A modified (Sigma) supplemented with 2 mM glutamine, 100 units/ml penicillin, 100 mg/ml streptomycin, 10% fetal calf serum and 1000 mg/ml geneticin.

Cells are treated with 1 µM and 10 µM bolus dose of anticancer agent Topotecan (TPT) (Bailly, 2000). TPT is a water soluble derivative of the alkaloid Camptothecin and act as a topoisomerase I, a nuclear enzyme involved in DNA replication and repair, inhibitor (Wang, 1996). TPT is used for the treatment of a wide range of cancers, including lung (Ichinose et al., 2010), breast (Cheung et al., 2008), ovarian (Lorusso et al., 2010) and bone (Seibel et al., 2007), both in experimental and clinical contexts.

An hour post treatment, the cultured dishes are placed onto a time lapse instrument designed to capture transmission phase images from multi well plates. Image sequences are taken for 115 hours at 15-minute time intervals. The cell lineage data is encoded by ProgeniTRAK (Khan et al., 2006) and is retrieved from a cell lineage database ProgeniDB (Khan et al., 2007).

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