Effect of FTase inhibitors in animal models
| Compound . | Model/tumor . | RASmutation/activation . | Dose (mg/kg/d) . | Growth inhibition . | Reference nos. . |
|---|---|---|---|---|---|
| Manumycin | Nude mice/K-Ras fibrosarcoma | K-RAS/+ | 70% | 154 | |
| Balb/c nude mice/pancreas (MIAPaCa-2) carcinoma | K-RAS/+ | 1, 2, 5 | 191 | ||
| L-739,749 | Nude Harlan mice/Rat-1 cell tumors | H-RAS/+ | 20 | 51%-66% | 129 |
| N-RAS/+ | |||||
| K-RAS/+ | |||||
| B956, B1086 | Nude mice/bladder (EJ-1) | H-RAS/+ | 100 | 144 | |
| fibrosarcoma (HT1080) | N-RAS/+ | ||||
| colon (HCT 116) | K-RAS/+ | ||||
| L-744,832 | MMTV-v-H-RAS transgenic mice/ | v-H-RAS/+ | 10-40 | −5.4 vs 16.7 | 135 |
| mammary, salivary | 40 | −7.7 vs 11.8 | 134 | ||
| carcinoma | −9.9 vs 33.3 | ||||
| −12.3 vs 26.3 | |||||
| −10.2 vs 43.6 | |||||
| FTI-276 | Nude Harlan Sprague-Dawley | K-RAS/+ | 10, 50, 100 | 75% | 140 |
| FTI-277 | mice/lung (A-549, Calu-1) tumors NIH3T3 cells | H-RAS-F/+ | 50 | 80% | |
| FTI-276 | A/J mice lung adenomas | 50 | 58% | 200 | |
| FTI-276 | Nude Harlan Sprague-Dawley | K-RAS/+ | 70 | 70%-94% | 168 |
| GGTI-2973-150 | mice/lung (A-549, Calu-1) tumors | 56%-70%3-150 | |||
| Compound no. 46 | Athymic Balb/c | H-RAS/+ | 45 | T/C3-151 = 154% | 187 |
| Compound no. 51 | Rat-1 cells | 45 | T/C3-151 = 142% | ||
| Compound 83b, 85b | Nude mice/colon (DLD-1, SW-260) | K-RAS/+ | 10, 50 | 72% | 148 |
| H-Ras-CVLS fibroblasts | 95% | ||||
| H-Ras-CVLL fibroblasts | 50% | ||||
| SCH66336 | Nude mice/colon (DLD-1, HCT 116) | K-RAS/+ | 2.5, 10, 40 | 76% | 147 |
| pancreas (MIA PaCa-2) | K-RAS/+ | 75% | |||
| NIH3T3 | H-RAS/+ | 100% | |||
| Compound no. 4 | Nude mice/colon (DLD-1) | K-RAS/+ | 10, 50 | 70% | 146 |
| SCH66336 | Nude mice/lung (A549, HTB177) | K-RAS/+ | 40 | 70%, 83% | 192 |
| pancreas (AsPC-1, HPAF-II | K-RAS/+ | 72%, 67% | |||
| Hs 700T, MIA PaCa-2) | 67%, 78% | ||||
| colon (HCT116, DLD-1) | K-RAS/+ | 84%, 76% | |||
| prostate (DU-145) | no mutation | 86% | |||
| urinary bladder (EJ) | H-RAS/+ | 100% | |||
| wap-H-RAS transgenic mice/mammary, salivary tumors | H-RAS/+ | 2.5, 10, 40 | 67%-86% | ||
| SCH59228 | Athymic mice/colon (DLD-1) | K-RAS/+ | 10, 50 | >90% | 149 |
| H-Ras and K-Ras | H-RAS/+ | ||||
| fibroblast tumors | K-RAS/+ | ||||
| L-744,832 | MMTV-N-RASNtransgenic mice/lymphoid and mammary tumors | N-RAS/+ | 40 | −0.7 vs 28.3 | 137 |
| L-744,832 | MMTV-TGFα/neu transgenic mice/mammary tumors | −/+ | 40 | −7.4 vs 19 | 183 |
| Compound 5m | Nude mice/NIH3T3 | H-RAS-F | 150 | 88 | 186 |
| FTS3-150 | SCID mice/melanoma (518A2, 607B) | N-RAS | 53-150 | 82-90 | 188 |
| Compound . | Model/tumor . | RASmutation/activation . | Dose (mg/kg/d) . | Growth inhibition . | Reference nos. . |
|---|---|---|---|---|---|
| Manumycin | Nude mice/K-Ras fibrosarcoma | K-RAS/+ | 70% | 154 | |
| Balb/c nude mice/pancreas (MIAPaCa-2) carcinoma | K-RAS/+ | 1, 2, 5 | 191 | ||
| L-739,749 | Nude Harlan mice/Rat-1 cell tumors | H-RAS/+ | 20 | 51%-66% | 129 |
| N-RAS/+ | |||||
| K-RAS/+ | |||||
| B956, B1086 | Nude mice/bladder (EJ-1) | H-RAS/+ | 100 | 144 | |
| fibrosarcoma (HT1080) | N-RAS/+ | ||||
| colon (HCT 116) | K-RAS/+ | ||||
| L-744,832 | MMTV-v-H-RAS transgenic mice/ | v-H-RAS/+ | 10-40 | −5.4 vs 16.7 | 135 |
| mammary, salivary | 40 | −7.7 vs 11.8 | 134 | ||
| carcinoma | −9.9 vs 33.3 | ||||
| −12.3 vs 26.3 | |||||
| −10.2 vs 43.6 | |||||
| FTI-276 | Nude Harlan Sprague-Dawley | K-RAS/+ | 10, 50, 100 | 75% | 140 |
| FTI-277 | mice/lung (A-549, Calu-1) tumors NIH3T3 cells | H-RAS-F/+ | 50 | 80% | |
| FTI-276 | A/J mice lung adenomas | 50 | 58% | 200 | |
| FTI-276 | Nude Harlan Sprague-Dawley | K-RAS/+ | 70 | 70%-94% | 168 |
| GGTI-2973-150 | mice/lung (A-549, Calu-1) tumors | 56%-70%3-150 | |||
| Compound no. 46 | Athymic Balb/c | H-RAS/+ | 45 | T/C3-151 = 154% | 187 |
| Compound no. 51 | Rat-1 cells | 45 | T/C3-151 = 142% | ||
| Compound 83b, 85b | Nude mice/colon (DLD-1, SW-260) | K-RAS/+ | 10, 50 | 72% | 148 |
| H-Ras-CVLS fibroblasts | 95% | ||||
| H-Ras-CVLL fibroblasts | 50% | ||||
| SCH66336 | Nude mice/colon (DLD-1, HCT 116) | K-RAS/+ | 2.5, 10, 40 | 76% | 147 |
| pancreas (MIA PaCa-2) | K-RAS/+ | 75% | |||
| NIH3T3 | H-RAS/+ | 100% | |||
| Compound no. 4 | Nude mice/colon (DLD-1) | K-RAS/+ | 10, 50 | 70% | 146 |
| SCH66336 | Nude mice/lung (A549, HTB177) | K-RAS/+ | 40 | 70%, 83% | 192 |
| pancreas (AsPC-1, HPAF-II | K-RAS/+ | 72%, 67% | |||
| Hs 700T, MIA PaCa-2) | 67%, 78% | ||||
| colon (HCT116, DLD-1) | K-RAS/+ | 84%, 76% | |||
| prostate (DU-145) | no mutation | 86% | |||
| urinary bladder (EJ) | H-RAS/+ | 100% | |||
| wap-H-RAS transgenic mice/mammary, salivary tumors | H-RAS/+ | 2.5, 10, 40 | 67%-86% | ||
| SCH59228 | Athymic mice/colon (DLD-1) | K-RAS/+ | 10, 50 | >90% | 149 |
| H-Ras and K-Ras | H-RAS/+ | ||||
| fibroblast tumors | K-RAS/+ | ||||
| L-744,832 | MMTV-N-RASNtransgenic mice/lymphoid and mammary tumors | N-RAS/+ | 40 | −0.7 vs 28.3 | 137 |
| L-744,832 | MMTV-TGFα/neu transgenic mice/mammary tumors | −/+ | 40 | −7.4 vs 19 | 183 |
| Compound 5m | Nude mice/NIH3T3 | H-RAS-F | 150 | 88 | 186 |
| FTS3-150 | SCID mice/melanoma (518A2, 607B) | N-RAS | 53-150 | 82-90 | 188 |
Several FTase inhibitors have shown in vivo antitumor activity in mice. These inhibitors have been demonstrated to cause regression of tumors that depend on activated Ras in mouse xenograft and transgenic mouse models. The growth inhibition is given in percent of controls or as the comparison of the tumor mean growth rate (in mm3/day) in the presence or absence of the FTase inhibitor. Cell growth inhibition may be a result of induction of apoptosis or arrest in the G1 phase of the cell cycle.
FTS, S-farnesylthiosalicyclic acid, is an inhibitor of PPMTase.
T/C indicates relative median survival time of treated (T) versus control (C) groups (% T/C values). The activity criterion for increased lifespan was a T/C of ≥125%.