th-302 and pimonidazole

Chemotherapy targets rapidly proliferating tumor cells, but spares slowly proliferating hypoxic cells. We hypothesized that nutrition of hypoxic cells would improve in intervals between chemotherapy, and that hypoxic cells destined to die without treatment would survive and proliferate.. We therefore evaluated repopulation and reoxygenation following chemotherapy, and the effects of the hypoxia-activated prodrug TH-302 on these processes. Tumor-bearing mice were treated with doxorubicin or docetaxel ± TH-302. Pimonidazole (given concurrent with chemotherapy) and EF5 (given 24 to 120 hours later) identified hypoxic cells. Proliferation (Ki67) and oxygen status (EF5 uptake) of formerly hypoxic (pimo positive) cells were quantified by immunohistochemistry.. Chronically hypoxic cells had limited proliferation in control tumors. After chemotherapy, we observed reoxygenation and increased proliferation of previously hypoxic cells; these processes were inhibited by TH-302.. Chemotherapy leads to paradoxical sparing of hypoxic cells destined to die in solid tumors in absence of treatment, and their reoxygenation and proliferation: TH-302 inhibits these processes.

Topics: Animals; Antineoplastic Agents; Cell Hypoxia; Cell Line, Tumor; Cell Survival; Docetaxel; Doxorubicin; Female; Humans; Immunohistochemistry; Mice; Mice, Nude; Neoplasms, Experimental; Nitroimidazoles; Phosphoramide Mustards; Prodrugs; Taxoids; Xenograft Model Antitumor Assays