PMID- 16899626
OWN - NLM
STAT- MEDLINE
DCOM- 20071214
LR  - 20220602
IS  - 1078-0432 (Print)
IS  - 1078-0432 (Linking)
VI  - 12
IP  - 15
DP  - 2006 Aug 1
TI  - Hypoxia-inducible factor-1 inhibition in combination with temozolomide treatment 
      exhibits robust antitumor efficacy in vivo.
PG  - 4747-54
AB  - PURPOSE: 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. EXPERIMENTAL DESIGN: 
      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.
FAU - Li, Leiming
AU  - Li L
AD  - Cancer Research, Global Pharmaceutical Research and Development, Abbott 
      Laboratories, Abbott Park, Illinois 60064, USA.
FAU - Lin, Xiaoyu
AU  - Lin X
FAU - Shoemaker, Alex R
AU  - Shoemaker AR
FAU - Albert, Daniel H
AU  - Albert DH
FAU - Fesik, Stephen W
AU  - Fesik SW
FAU - Shen, Yu
AU  - Shen Y
LA  - eng
PT  - Journal Article
PL  - United States
TA  - Clin Cancer Res
JT  - Clinical cancer research : an official journal of the American Association for 
      Cancer Research
JID - 9502500
RN  - 0 (Angiogenesis Inhibitors)
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Indazoles)
RN  - 0 (Phenylurea Compounds)
RN  - 138391-32-9 (Aryl Hydrocarbon Receptor Nuclear Translocator)
RN  - 7GR28W0FJI (Dacarbazine)
RN  - CO93X137CW (linifanib)
RN  - EC 3.4.22.- (Caspases)
RN  - IY9XDZ35W2 (Glucose)
RN  - YF1K15M17Y (Temozolomide)
SB  - IM
MH  - Administration, Oral
MH  - Angiogenesis Inhibitors/*pharmacology
MH  - Animals
MH  - Antineoplastic Agents/administration & dosage/*pharmacology
MH  - Aryl Hydrocarbon Receptor Nuclear Translocator/*antagonists & inhibitors
MH  - Caspases/drug effects/metabolism
MH  - Cell Death/drug effects
MH  - Cell Line, Tumor
MH  - Cell Proliferation/drug effects
MH  - Dacarbazine/administration & dosage/*analogs & derivatives/pharmacology
MH  - Disease Models, Animal
MH  - Dose-Response Relationship, Drug
MH  - Glucose/pharmacology
MH  - Humans
MH  - Hypoxia/metabolism
MH  - Indazoles/*pharmacology
MH  - Mice
MH  - Mice, SCID
MH  - Phenylurea Compounds/*pharmacology
MH  - Structure-Activity Relationship
MH  - Temozolomide
MH  - Transplantation, Heterologous
MH  - Xenograft Model Antitumor Assays
EDAT- 2006/08/11 09:00
MHDA- 2007/12/15 09:00
CRDT- 2006/08/11 09:00
PHST- 2006/08/11 09:00 [pubmed]
PHST- 2007/12/15 09:00 [medline]
PHST- 2006/08/11 09:00 [entrez]
AID - 12/15/4747 [pii]
AID - 10.1158/1078-0432.CCR-05-2842 [doi]
PST - ppublish
SO  - Clin Cancer Res. 2006 Aug 1;12(15):4747-54. doi: 10.1158/1078-0432.CCR-05-2842.