Chemotherapy rescues hypoxic tumor cells and induces their reoxygenation and repopulation - an effect that is inhibited by the hypoxia-activated pro-drug TH-302
Menée à l'aide de modèles murins, cette étude met en évidence des mécanismes par lesquels, de façon paradoxale, la doxorubicine ou le docétaxel induit la survie de cellules tumorales hypoxiques destinées à disparaître en l'absence de traitement, puis montre qu'un composé appelé TH-302 permet d'inhiber ce processus
Purpose: 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. Experimental Design: We therefore evaluated repopulation and reoxygenation following chemotherapy, and the effects of the hypoxia-activated pro-drug TH-302 on these processes. Tumor-bearing mice were treated with doxorubicin or docetaxel +/- TH-302. Pimonidazole (given concurrent with chemotherapy) and EF5 (given 24-120 hours later) identified hypoxic cells. Proliferation (Ki67) and oxygen status (EF5 uptake) of formerly hypoxic (pimo+ve) cells were quantified by immunohistochemistry. Results: 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. Conclusions: 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.