title: Chemotherapy Rescues Hypoxic Tumor Cells and Induces Their Reoxygenation and Repopulation-An Effect That Is Inhibited by the Hypoxia-Activated Prodrug TH-302.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  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.
authors: Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
authors: Jasdeep K
authors: JK
authors: Saggar
authors: Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada. Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Toronto, Ontario, Canada. ian.tannock@uhn.ca.
authors: Ian F
authors: IF
authors: Tannock
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015687:Cell Hypoxia / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D000077143:Docetaxel; D004317:Doxorubicin / Q000494:pharmacology; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000473:pathology*; D009593:Nitroimidazoles / Q000494:pharmacology*; D010752:Phosphoramide Mustards / Q000494:pharmacology*; D011355:Prodrugs / Q000494:pharmacology; D043823:Taxoids / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D009593:Nitroimidazoles; D010752:Phosphoramide Mustards; D011355:Prodrugs; C552526:TH 302; D043823:Taxoids; D000077143:Docetaxel; C033815:pimonidazole; D004317:Doxorubicin