title: Hypoxia-inducible factor-1 inhibition in combination with temozolomide treatment exhibits robust antitumor efficacy in vivo.
abstract: OBJECTIVE
  Inhibiting hypoxia-inducible factor-1 (HIF-1) represents a unique mechanism for cancer therapy. It is conceived that HIF-1 inhibitors may synergize with many classes of cancer therapeutic agents, such as angiogenesis inhibitors and cytotoxic drugs, to achieve a more robust tumor response. However, these hypotheses have not been rigorously tested in tumor models in vivo. The present study was carried out to evaluate the antitumor efficacy of combining HIF-1 inhibition with angiogenesis inhibitors or cytotoxic agents.
  
  
  METHODS
  Using a D54MG-derived tumor model that allows knockdown of HIF-1alpha on doxycycline treatment, we examined the tumor responses to chemotherapeutic agents, including the angiogenesis inhibitor ABT-869 and cytotoxic agents 1,3-bis(2-chloroethyl)-1-nitrosourea and temozolomide, in the presence or absence of an intact HIF-1 pathway.
  
  
  RESULTS
  Surprisingly, inhibiting HIF-1 in tumors treated with the angiogenesis inhibitor ABT-869 did not produce much added benefit compared with ABT-869 treatment alone, suggesting that the combination of an angiogenesis inhibitor with a HIF-1 inhibitor may not be a robust therapeutic regimen. In contrast, the cytotoxic drug temozolomide, when used in combination with HIF-1alpha knockdown, exhibited a superadditive and likely synergistic therapeutic effect compared with the monotherapy of either treatment alone in the D54MG glioma model.
  
  
  CONCLUSIONS
  Our results show that the DNA alkylating agent temozolomide exhibits robust antitumor efficacy when used in combination with HIF-1 inhibition in D54MG-derived tumors, suggesting that the combination of temozolomide with HIF-1 inhibitors might be an effective regimen for cancer therapy. In addition, our results also show that the RNA interference-based inducible knockdown model can be a valuable platform for further evaluation of the combination treatment of other cancer therapeutics with HIF-1 inhibition.
authors.affiliation: Cancer Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, Illinois 60064, USA.
authors.forename: Leiming
authors.initials: L
authors.lastname: Li
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Lin
authors.forename: Alex R
authors.initials: AR
authors.lastname: Shoemaker
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Albert
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Fesik
authors.forename: Yu
authors.initials: Y
authors.lastname: Shen
mesh_terms: D000284:Administration, Oral; D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator / Q000037:antagonists & inhibitors*; D020169:Caspases / Q000187:drug effects / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D000860:Hypoxia / Q000378:metabolism; D007191:Indazoles / Q000494:pharmacology*; D051379:Mice; D016513:Mice, SCID; D010671:Phenylurea Compounds / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D000077204:Temozolomide; D014183:Transplantation, Heterologous; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D007191:Indazoles; D010671:Phenylurea Compounds; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D003606:Dacarbazine; C513486:linifanib; D020169:Caspases; D005947:Glucose; D000077204:Temozolomide