Table 2.
ABT-888/MMS combination indices (CI) in WT vs PARP SNP rs1805407 carrier cell lines. CI values for three effect levels (ED25, ED50, ED70) representing low, medium, and high toxicity were calculated using median effect analysis by Chou and Talalay. For each cell line, combinations of ABT-888 and MMS were tested at fixed equipotency ratios calculated from single agent ED50 of MMS and ABT-888, as described in Materials and Methods. CI values <1, =1, and >1 are indicative of synergism, additivity and antagonism, respectively. Significant deviation from additivity was determined in Graph Pad Prism by a one sample t-test (two-tailed) using a hypothetical value of CI = 1.
| Cell line | Genotype PARP1/SNP | Ratio ABT: MMS | Effect level | Combination Indexa | Interpretation |
|---|---|---|---|---|---|
| A2780 | C/T | 1:3.8 | ED25 | 0.08 ± 0.04, p < 0.001, 95% CI [−0.02, 0.18] | strong synergy |
| ED50 | 0.22 ± 0.07, p = 0.003, 95% CI [0.04, 0.40] | strong synergy | |||
| ED70 | 0.50 ± 0.09, p = 0.011, 95% CI [0.27, 0.73] | strong synergy | |||
| M14 | C/T | 1:2.3 | ED25 | 0.65 ± 0.18, p = 0.081, 95% CI [0.20, 1.11] | mild synergy |
| ED50 | 0.81 ± 0.10, p = 0.087, 95% CI [0.56, 1.07] | mild synergy | |||
| ED70 | 0.98 ± 0.01, p = 0.093, 95% CI [0.95, 1.01] | additivity | |||
| H522 | T/T | 1:2.0 | ED25 | 0.91 ± 0.33, p = 0.675, 95% CI [0.08, 1.73] | additivity |
| ED50 | 1.21 ± 0.24, p = 0.269, 95% CI [0.61, 1.82] | antagonism | |||
| ED70 | 1.30 ± 0.10, p = 0.011, 95% CI [1.30, 1.80] | antagonism | |||
| SW620 | T/T | 1:1.2 | ED25 | 1.44 ± 0.04, p = 0.002, 95% CI [1.35, 1.52] | antagonism |
| ED50 | 1.42 ± 0.08, p = 0.011, 95% CI [1.23, 1.61] | antagonism | |||
| ED70 | 1.43 ± 0.09, p = 0.016, 95% CI [1.20, 1.66] | antagonism |