Dy (>2n) and hypertriploidy (>3n) still showed sensitive response (HL-60, EM-
Dy (>2n) and hypertriploidy (>3n) still showed sensitive response (HL-60, EM-2, KU-812). In addition to inhibiting Aurora B and C, GSK1070916 also has activity for ABL (Additional File 1, Table S6) which potentially contributes to the sensitivity observed in these cell lines. Comparison of the two response phenotypes for modal chromosome number, using a chromosome count of (3n) as the cutoff, showed a difference in the response between the two cell line populations (p-value = 0.0098, two-tailed Fisher Exact Test; Table 1). Using the in-vitro data as a model for evaluating diploid chromosome number as potential marker for patient selection provided reasonably high sensitivity in predicting response rates (16/18 = 89 ) but a lower specificity in predicting those patients that would not Litronesib chemical information respond to treatment (13/27 = 48 ). Not surprisingly, the negative predictive value for low PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/27488460 chromosome number wasIn addition to the data for the primary chromosome number, as used in Figure 2, karyotype data can be reviewed for percentage of polyploidy in cell subpopulations. For instance, the karyotype data for the TANOUE cell line has a chromosome modal number of 48 for the primary population of cells, but also 12 of the cell population was polyploid (See Additional File 1, Table S2 for karyotype data). To evaluate the effect these subpopulations may have on response, we reviewed the ploidy of cell subpopulations for cell lines with low/ diploid chromosome number (<50) in the primary population (Figure 3). Interestingly, with the limited subset of karyotype data available, we found that the average percentage of polyploid subpopulations was substantially higher for the resistant cell lines compared to sensitive cell lines in the panel. (7.9 vs. 1.2 , n = 28, p-value = 0.00014, Unpaired t-test, 95 , CI 0.0284- 0.1044) (Additional File 1, Table S3).GSK1070916 Treatment Generates Polyploid PhenotypeTreatment of cancer cells with GSK1070916 yielded phenotypes with polyploid DNA content resulting from chromosome replication without nuclear or cell division. A sensitive and diploid T-ALL cell line MOLT16, and a polyploid and resistant T-ALL cell line CTV-1 were treated with increasing concentrations of GSK1070916 for different time periods, and a flow cytometry study was performed. For the sensitive cell line MOLT16, a population of polyploid cells emerged within 24 hrs and maintained their growth with increasing drug concentration. However, over longer period of drug treatment (48 hr and 72 hr), the percentage of polyploid cells were significantly reduced, and there was a simultaneous increase of sub-G1 population representing dead cells, suggesting that the polyploid cells developed earlier were not being tolerated and subsequently died. This is in contrast to CTV-1, which exhibited much higher levels of polyploidy cells and low cell death throughout the study. (Figure 4)Genetics AnalysisFigure 1 Response profile of GSK1070916 for hematological cell lines using cell cycle analysis and cell death measures to determine sensitivity and resistance. Cell lines that are early and moderate responders by cell cycle analysis with a Ymin/T0 ratio 0.5 were considered sensitive (see METHODS).The background genetics of the hematological cell line panel was reviewed in relation to Aurora inhibition by GSK1070916. Expression profiles of Aurora A, B, and C were evaluated in terms of response to Aurora inhibition and no association was observed (p-value = 0.79 and 0.96 res.

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