Drug | Fractional Inhibition, fa | Parametera | CIb | ||||
---|---|---|---|---|---|---|---|
Paclitaxel | Cisplatin | Topotecan | m | Dm | r | ||
μM | μM | ||||||
(D)1 | |||||||
0.002 | 0.429 | ||||||
0.004 | 0.708 | ||||||
0.005 | 0.761 | ||||||
0.01 | 0.882 | ||||||
0.02 | 0.932 | 1.248 | 0.00217 | 0.990 | |||
(D)2 | |||||||
0.05 | 0.055 | ||||||
0.1 | 0.233 | ||||||
0.2 | 0.301 | ||||||
0.5 | 0.559 | ||||||
1.0 | 0.821 | ||||||
2.0 | 0.953 | 1.458 | 0.320 | 0.986 | |||
(D)3 | |||||||
0.01 | 0.069 | ||||||
0.02 | 0.213 | ||||||
0.05 | 0.373 | ||||||
0.1 | 0.785 | ||||||
0.2 | 0.940 | ||||||
0.5 | 0.991 | 1.855 | 0.0462 | 0.991 | |||
(D)1 + (D)2 (1:100)c | |||||||
0.001 | 0.1 | 0.450 | 0.900 | ||||
0.002 | 0.2 | 0.701 | 0.815 | ||||
0.005 | 0.5 | 0.910 | 0.0001147 | 0.681d | |||
0.01 | 1.0 | 0.968 | 1.572 | + 0.11471 | 0.602 | ||
(D)2 + (D)3 (100:10) | |||||||
0.05 | 0.005 | 0.304 | 0.445 | ||||
0.1 | 0.01 | 0.413 | 0.658 | ||||
0.2 | 0.02 | 0.675 | 0.669 | ||||
0.5 | 0.05 | 0.924 | 0.1053 | 0.561 | |||
1.0 | 1.0 | 0.977 | 1.588 | + 0.01053 | 0.989 | 0.522 | |
(D)1 + (D)3 (1:10) | |||||||
0.001 | 0.01 | 0.274 | 1.373 | ||||
0.002 | 0.02 | 0.579 | 1.078 | ||||
0.005 | 0.05 | 0.901 | 0.00166 | 0.719 | |||
0.01 | 0.1 | 0.965 | 1.891 | + 0.01661 | 0.999 | 0.681 | |
(D)1 + (D)2 + (D)3 (1:100:10) | |||||||
0.001 | 0.1 | 0.01 | 0.456 | 1.121 | |||
0.002 | 0.2 | 0.02 | 0.806 | 0.001162 | 0.729 | ||
0.003 | 0.3 | 0.03 | 0.947 | + 0.11616 | 0.403 | ||
0.005 | 0.5 | 0.05 | 0.995 | 3.363 | + 0.011612 | 0.984 | 0.136 |
↵ a The parameters m, Dm, and r are the slope, antilog of the x-intercept, and the linear correlation coefficient of the median-effect plot, which signifies the shape of the dose-effect curve, the potency (IC50), and the conformity of the data to the mass-action law, respectively. Dm and m values are used for calculating the CI values
↵ b CI < 1, CI = 1, and CI > 1 indicate synergism, additive effect, and antagonism, respectively. As based on the classic isobologram equation, CI can be calculated by eq. 16: CI = [(D)1/(Dx)1] + [(D)2/(Dx)2], where Dx = Dm[fa/(1 — fa)]1/m (eq. 8)
↵ c The drug mixture was serially diluted and added to incubation mixture at 0 h. The combination ratio was approximately equal to the Dm ratio of the component drugs (i.e., close to their equipotency ratio)
↵ d Sample pocket calculator calculation of the CI value of 0.005 μM paclitaxel + 0.5 μM cisplatin that inhibited 833K cell growth by 91.0% (fa = 0.910). On the basis of eq. 8, for paclitaxel alone to inhibit cell growth by 91% would require [D0.91]paclitaxel = (Dm)paclitaxel [0.91/(1 — 0.91)]1/1.248 = 0.00217 μM × 6.385 = 0.01385 μM and for cisplatin alone to inhibit cell growth by 91% would require [D0.91]cisplatin = (Dm)cisplatin [0.91/(1 — 0.91)]1/1.458 = 0.320 μM × 4.888 = 1.564 μM. Therefore, CI = (0.005 μM/0.01385 μM) + (0.5 μM/1.564 μM) = 0.681 at 91% inhibition