Rucaparib significantly potentiated TMZ-induced tumor regrowth delay in a flank tumor model of GBM12. Median time for tumor to exceed a 1000 mm3 size endpoint for placebo, TMZ, and TMZ/rucaparib treatment was 32, 86, and 121 days, p < 0.01, respectively. In contrast, the addition of rucaparib to TMZ therapy in GBM12 orthotopic xenografts was ineffective (median survival: placebo 16 days, TMZ 68 days and TMZ/rucaparib 81 days, p = 0.88. Therefore, subsequent studies focused on evaluating whether exclusion of rucaparib from the brain and orthotopic brain tumors might contribute to the lack of efficacy observed in the orthotopic xenograft models.
| Cell Experiment | |
|---|---|
| Cell lines | GBM12 cell |
| Preparation method | Cells were incubated with 2 −M rucaparib for 60 minutes at 37°C and then transport was quenched with cold PBS prior to lysis in 1% Triton X-100. Cell pellets were stored at −80°C until analysis using high-performance liquid chromatography followed by tandem mass spectrometry (LC-MS/MS). |
| Concentrations | 2 μM |
| Incubation time | 24 h |
| Animal Experiment | |
|---|---|
| Animal models | Mice with established intracranial xenografts |
| Formulation | dissolved in dimethylsulfoxide and diluted in saline |
| Dosages | 1 mg/kg |
| Administration | i.v. |
| Molecular Weight | 555.67 |
| Formula | C10H16O4S.C19H18FN3O |
| CAS Number | 1859053-21-6 |
| Form | Solid |
| Solubility (25°C) | 10 mM in DMSO |
| 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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