TH-302 is a 2-nitroimidazole triggered hypoxia-activated prodrug of the cytotoxin bromo-isophosphoramide mustard (Br-IPM). TH-302 inhibits H460 cells and HT29 cells with IC90 of 0.1 μM and 0.2 μM, respectively. TH-302 exhibits potent cytotoxicity to both human and murine MM cells with hypoxic selectivity and dose dependency, and induces G0/G1 cell-cycle arrest under hypoxic conditions. TH-302 treatment resulted in a reduction in the volume of the HF 48 hours after dosing and a corresponding increase in the necrotic fraction. TH-302 is currently in a phase II clinical trial for the treatment of soft tissue sarcoma.
Drug Deliv. 2020 Dec;27(1):1412-1424.
Hypoxic targeting and activating TH-302 loaded transcatheter arterial embolization microsphere
TH-302 (Evofosfamide) purchased from AbMole
Bioorg Chem. 2020 Jun;99:103778.
Development and Biological Investigations of Hypoxia-Sensitive Prodrugs of the Tyrosine Kinase Inhibitor Crizotinib
TH-302 (Evofosfamide) purchased from AbMole
Eur J Med Chem. 2018 Oct 5;158:51-67.
Structure-activity relationship study of hypoxia-activated prodrugs for proteoglycan-targeted chemotherapy in chondrosarcoma
TH-302 (Evofosfamide) purchased from AbMole
PLoS One. 2017 Jul 13;12(7):e0181340.
Development and characterization of a human three-dimensional chondrosarcoma culture for in vitro drug testing
TH-302 (Evofosfamide) purchased from AbMole
 |
Source | Plos One (2017). Figure 6. TH-302 |
| Method | Apoptosis assay | |
| Cell Lines | lymphoma cells | |
| Concentrations | 50 μM | |
| Incubation Time | 24 h | |
| Results | After treatment with 50 μMTH-302 for 24 h under 21% O2, the percentages of apoptotic cells in all the cell types were not significantly different from those of the vehicle-treated cells, and there were negligible morphological abnormalities among the cells |
 |
Source | Plos One (2017). Figure 5. TH-302 |
| Method | Drug sensitivity testing | |
| Cell Lines | lymphoma cells | |
| Concentrations | 1, 10, 100, or 1000 nM | |
| Incubation Time | 24 h | |
| Results | However, after treatment with 50 μMTH-302 for 24 h under 10% O2, there were no significant differences in the viability of any cells |
| Cell Experiment | |
|---|---|
| Cell lines | H460, H82, DU145, A375 and PC3 cells line |
| Preparation method | In vitro cytotoxicity assay Exponentially growing cells were seeded 24 hours before the addition of test compounds. After drug addition, the plates were incubated for 2 hours, or longer if indicated, under defined oxygen concentrations at 37°C in an anaerobic chamber (Bactron II), a hypoxia chamber (Hypoxystation), or a standard tissue-culture incubator. Using this method, cells equilibrated rapidly (<30 minutes) with the gas phase as shown by linearity of time course of cytotoxicity and use of dissolved oxygen probe (OxyLite, Oxford Optronics). Cells were cultured for 72 hours in complete medium after washing under normoxic conditions, and the viable cells were quantified using AlamarBlue. For DPI experiments, cells were pretreated with 100 μmol/L of DPI for 2 hours under air. Drug concentration resulting in growth inhibition of 50% (IC50) relative to untreated control was calculated using Prism software. |
| Concentrations | 0~100µM |
| Incubation time | 2h |
| Animal Experiment | |
|---|---|
| Animal models | PLC/PRF/5, hepatocellular carcoma (HCC) xenograft model with NCI SCID female mice |
| Formulation | saline (0.9% NaCl) |
| Dosages | 50 mg/kg, QD 5/wk*2 wks |
| Administration | intraperitoneally |
| Molecular Weight | 449.04 |
| Formula | C9H16Br2N5O4P |
| CAS Number | 918633-87-1 |
| Solubility (25°C) | DMSO ≥ 60 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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