AG14361 is a novel poly (ADP-ribose) polymerase-1 inhibitor with a GI50 of 10.9 µM. AG14361 enhances temozolomide activity in all MMR-proficient cells (1.5–3.3-fold) but is more effective in MMR-deficient cells (3.7–5.2-fold potentiation), overcoming temozolomide resistance. AG14361 significantly potentiated camptothecin-mediated cytotoxicity in all cells, except the base excision repair–deficient EM9 cells. In the breast cancer cell lines, AG14361 had no effect on IR-induced degradation of IkappaBalpha or nuclear translocation of p50 or p65. However, AG14361 inhibited IR-induced NF-kappaB-dependent transcription of a luciferase reporter gene.
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Source | Breast Cancer Res (2014). Figure 4. AG14361 |
| Method | i.p. | |
| Cell Lines | mice | |
| Concentrations | 30 mg/kg | |
| Incubation Time | 20 days | |
| Results | There was an increase in TUNEL-positive cells in tumors with an increasing order from no treatment, AG14361, lestaurtinib, to AG14361/lestaurtinib |
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Source | Breast Cancer Res (2014). Figure 3. AG14361 |
| Method | i.p. | |
| Cell Lines | mice | |
| Concentrations | 30 mg/kg | |
| Incubation Time | 20 days | |
| Results | For tumors derived from both types of cells, monotreatment of AG14361 slightly delayed tumor growth compared with the vehicle group, and lestaurtinib treatment significantly delayed tumor growth, that took tumors 30 more days, on average, to reach a similar size compared with the tumors in the vehicle-treated group |
| Cell Experiment | |
|---|---|
| Cell lines | LoVo, A549, and SW620 cells |
| Preparation method | Cell growth inhibition was estimated in exponentially growing LoVo, A549, and SW620 cells in 96-well plates. Cells were exposed to temozolomide (0–1000 μM, see Fig. 4, A) or topotecan (0–30 nM, see Fig. 4, B) in the presence or absence of 0.4 μM AG14361. Cells were also exposed to AG14361 (0–20 μM, see Fig. 4, C) alone or in the presence of 400 μM temozolomide. After 5 days of culture, these cells were fixed with 10% trichloroacetic acid and stained with sulforhodamine B (28). The concentration of temozolomide, topotecan, and AG14361 alone or in combination that inhibited growth by 50% (GI50) was calculated from computer-generated curves. |
| Concentrations | 0–20 μM |
| Incubation time | 5 days |
| Animal Experiment | |
|---|---|
| Animal models | CD-1 nude mice bearing palpable, subcutaneous SW620 or LoVo xenografts |
| Formulation | saline |
| Dosages | 5 or 15 mg/kg daily for 5 days |
| Administration | intraperitoneally |
| Molecular Weight | 320.39 |
| Formula | C19H20N4O |
| CAS Number | 328543-09-5 |
| Solubility (25°C) | DMSO ≥12 mg/mL |
| Storage |
Powder -20°C 3 years ; 4°C 2 years In solvent -80°C 6 months ; -20°C 1 month |
| Species | Mouse | Rat | Rabbit | Guinea pig | Hamster | Dog |
| Weight (kg) | 0.02 | 0.15 | 1.8 | 0.4 | 0.08 | 10 |
| Body Surface Area (m2) | 0.007 | 0.025 | 0.15 | 0.05 | 0.02 | 0.5 |
| Km factor | 3 | 6 | 12 | 8 | 5 | 20 |
| Animal A (mg/kg) = Animal B (mg/kg) multiplied by | Animal B Km |
| Animal A Km |
For example, to modify the dose of Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for Compound A of 10 mg/kg.
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