Growth inhibitory effects of selected antifolates against human CCRF-CEM and MOLT-4 leukemia cells with acquired resistance to MTX and 7-OHMTX
Cell line . | MTX, nM*†¶ . | 7-OHMTX, μM . | TMQ, nM† . | ZD1694, mM*‡¶ . | ZD93331, nM*‡ . | AG2037, nM*§¶ . |
|---|---|---|---|---|---|---|
| CCRF-CEM/WT | 12.6 ± 0.2 | 17.7 ± 5.5 | 1 ± 4.6 | 3.9 ± 0.4 | 10.4 ± 2.6 | 13.1 ± 1.6 |
| CCRF-CEM/MTX | 1175 ± 36 | > 250 (> 14) | 9.1 ± 1.0 (0.4) | 176 ± 5 (45) | 601 ± 195 (58) | 83.5 ± 24.2 (6.3) |
| CCRF-CEM/7-OHMTX | 15.9 ± 2.1 | > 250 (> 14) | 6.5 ± 2.1 (0.3) | 106 ± 64 (27) | 11.5 ± 2.9 (1.1) | 37.3 ± 9.2 (2.8) |
| Molt-4/WT | 13.5 ± 2.1 | 3.5 ± 1.4 | 19.1 ± 2.1 | 4.5 ± 0.3 | 15.4 ± 1.6 | 41.6 ± 2.6 |
| Molt-4/MTX | 962 ± 42 | > 250 (> 71) | 3.9 ± 0.7 (0.2) | 667 ± 38 (148) | 1304 ± 182 (85) | 842 ± 204 (20) |
| Molt-4/7-OHMTX | 15.6 ± 3.6 | > 250 (> 71) | 8.3 ± 2.9 (0.4) | 111 ± 56 (25) | 10.7 ± 2.3 (0.7) | 36.1 ± 1.5 (0.9) |
Cell line . | MTX, nM*†¶ . | 7-OHMTX, μM . | TMQ, nM† . | ZD1694, mM*‡¶ . | ZD93331, nM*‡ . | AG2037, nM*§¶ . |
|---|---|---|---|---|---|---|
| CCRF-CEM/WT | 12.6 ± 0.2 | 17.7 ± 5.5 | 1 ± 4.6 | 3.9 ± 0.4 | 10.4 ± 2.6 | 13.1 ± 1.6 |
| CCRF-CEM/MTX | 1175 ± 36 | > 250 (> 14) | 9.1 ± 1.0 (0.4) | 176 ± 5 (45) | 601 ± 195 (58) | 83.5 ± 24.2 (6.3) |
| CCRF-CEM/7-OHMTX | 15.9 ± 2.1 | > 250 (> 14) | 6.5 ± 2.1 (0.3) | 106 ± 64 (27) | 11.5 ± 2.9 (1.1) | 37.3 ± 9.2 (2.8) |
| Molt-4/WT | 13.5 ± 2.1 | 3.5 ± 1.4 | 19.1 ± 2.1 | 4.5 ± 0.3 | 15.4 ± 1.6 | 41.6 ± 2.6 |
| Molt-4/MTX | 962 ± 42 | > 250 (> 71) | 3.9 ± 0.7 (0.2) | 667 ± 38 (148) | 1304 ± 182 (85) | 842 ± 204 (20) |
| Molt-4/7-OHMTX | 15.6 ± 3.6 | > 250 (> 71) | 8.3 ± 2.9 (0.4) | 111 ± 56 (25) | 10.7 ± 2.3 (0.7) | 36.1 ± 1.5 (0.9) |
Growth inhibitory effects were analyzed after 72 hours of drug exposure and expressed as IC50 concentration, drug concentration required to inhibit cell growth by 50%. Results are presented as the mean ± SD of 3 to 5 separate experiments. Values in parentheses depict resistance factor; ratio IC50 value resistant cell line versus parental cell line.
RFC-dependent antifolate
Primary target, DHFR
Primary target, TS
Primary target, GARFT
Polyglutamylation-dependent antifolate