Table 1.
Cytotoxicity of Genz-644282 in CPT-resistant human cancer cell lines.
| Compound | Parental Cell Line, IC50 nM | Resistant Subline, IC50 nM | Resistance Ratio | Mechanism of Resistance (ref) |
|---|---|---|---|---|
| DU145 Prostate Cancer | RC0.1 | Mutant Top1 (23, 24) | ||
| CPT | 11.5 +/− 6.4 | >1000 | >87 | |
| Genz-644282 | 4.8 +/− 0.3 | 606.3 +/− 456.7 | 126 | |
| CCRF-CEM Leukemia | CCRF-CEM C2 | Mutant Top1 (25, 26) | ||
| CPT | 5.5 | >1000 | >182 | |
| Genz-644282 | 5.4 +/− 1.8 | 9.3 | 1.7 | |
| MCF7 Breast Cancer | MCF7-siTop1 | siRNA Top1 (22) | ||
| CPT | 13.3 +/− 2.1 | 39.8 | 3 | |
| Genz-644282 | 2.8 +/− 0.1 | 5.9 +/− 0.1 | 2.1 | |
| HCT116 Colon Cancer | HCT116-siTop1 | siRNA Top1 (22) | ||
| CPT | 14.3 +/− 5.0 | 36.8 +/− 0.6 | 2.6 | |
| Genz-644282 | 9 +/− 0.1 | 11.9 +/− 2.7 | 1.3 | |
| H460 NSCLC | H460/Mito | Mitoxantrone-treated (ABCG2 over-expresser) | ||
| Topotecan | 175.5 +/− 139.2 | >767 +/− 403 | >4.4 | |
| Genz-644282 | 15.8+/− 14.7 | >678 +/− 558 | >43 | |
| KB3.1 Cervical Cancer | KB3.1/Vinbl | Vinblastine-treated (ABCB1 over-expresser) | ||
| Doxorubicin | 86.7 +/− 15.7 | >1000 | >11.5 | |
| Genz-644282 | 67.6 +/− 15.1 | 314 +/− 129.6 | 4.6 |
1
IC501 (concentration of drug required for 50% cell growth inhibition) and relative resistances (RR)2 to Genz-644282 and the appropriate positive control [CPT, TPT, or doxorubicin (Dox)] in 6 different pairs of matched cell lines. Individual values correspond to independent experiments.
2
RR (relative resistance) was calculated by dividing the IC50 of the mutant cell line by the IC50 of the corresponding parental cell line.