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.
|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.
|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|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 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 resveratrol of 11.2 mg/kg.
Selective tumor hypoxia targeting by hypoxia-activated prodrug TH-302 inhibits tumor growth in preclinical models of cancer.
Sun JD, et al. Clin Cancer Res. 2012 Feb 1;18(3):758-70. PMID: 22184053.
Molecular and cellular pharmacology of the hypoxia-activated prodrug TH-302.
Meng F, et al. Mol Cancer Ther. 2012 Mar;11(3):740-51. PMID: 22147748.
Targeting the multiple myeloma hypoxic niche with TH-302, a hypoxia-activated prodrug.
Hu J, et al. Blood. 2010 Sep 2;116(9):1524-7. PMID: 20530289.
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