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TH-302 is a 2-nitroimidazole triggered hypoxia-activated prodrug of bromo-isophosphoramide mustard [1].

Hypoxia is a prevailing feature of tumors due to the abnormal aspects and structure of tumor vasculatures. It is found that hypoxic tumors usually show resistance to the traditional chemo- and radiation therapies and hypoxic tumors are more metastatic and invasive. Since the hypoxic tumors are not hyperproliferative, the traditional anti-proliferation drugs are not suitable. As a hypoxia-activated prodrug, TH-302 can release the cytotoxic agent Br-IPM and selectively deliver it the to the tumor cells under the anoxic condition [1 and 2].

The activity of TH-302 is dependent on the degree of anoxia and the exposure time of the drug under hypoxia. Higher activity requires lower oxygen concentration. Different with tirapazamine (another HAP), TH-302 needed much severer hypoxia (about 0.1%) to keep high potency. When treated in a panel of 32 kinds of tumor cells, TH-302 showed modest cytotoxicity with IC50 values all above 40 μM under the normal air condition. In contrast, TH-302 exerted elevated anti-tumor potency under the hypoxic condition. The IC50 values of it were in a range from 0.1 to 90 μM. Among these tumor cells, the non-small cell lung cancer H460 cells were most sensitive against TH-302 treatment with IC50 value of 0.1±0.03 μM. Besides that, TH-302 also showed potent efficacies in many other tumor cells, including Caki-1 (renal), SK-MEL-5 (melanoma), DU145 (prostate) and HCT116 (colon), with IC50 values of 0.4, 0.7, 0.7 and 0.8 μM, respectively [1].

In mice bearing H460 xenografts, administration of TH-302 at doses of 6.25 to 50 mg/kg dose-dependently caused tumor growth inhibition (TGI) with 43% to 89% and 50 mg/kg TH-302 administration showed no hematologic toxicity. Apart from this, TH-302 was found to induce DNA damage. TH-302 at dose of 100 mg/kg for 6 hours resulted in notable increase of γH2AX-positive cells [2].

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