PMID- 17184154
OWN - NLM
STAT- MEDLINE
DCOM- 20070222
LR  - 20161124
IS  - 1043-0342 (Print)
IS  - 1043-0342 (Linking)
VI  - 18
IP  - 1
DP  - 2007 Jan
TI  - Hypoxia-induced cytosine deaminase gene expression for cancer therapy.
PG  - 27-38
AB  - Hypoxia, a hallmark of many solid tumors, is associated with angiogenesis and 
      tumor progression. It activates a signal cascade that culminates in the 
      stabilization of hypoxia-inducible factor-1 (HIF-1) transcription factor and 
      activation of genes that possess hypoxia response elements. The loss of tumor 
      suppressors such as p53 has been shown to stabilize HIF-1alpha, which is 
      overexpressed in the majority of human cancers, and its over-expression 
      correlates with poor prognosis and treatment failure. Here we constructed 
      hypoxia-inducible promoters and examined their activities in murine and human 
      cancer cells with variable p53 status. Loss of p53 function in cancer cells 
      resulted in increased HIF-1-dependent transcriptional activity. To investigate 
      the feasibility of exploiting the hypoxic tumor microenvironment for targeted 
      gene therapy of cancer, we constructed retroviral vectors harboring luciferase or 
      Escherichia coli cytosine deaminase (CD) genes under the control of the 
      hypoxia-inducible promoter. Murine Lewis lung carcinoma (LL2) cells carrying 
      defective p53, when retrovirally transduced with the hypoxia-inducible 
      promoter-driven luciferase gene under hypoxic conditions, increased luciferase 
      reporter gene expression in vitro and in vivo. Significant antitumor effects were 
      achieved in mice bearing LL2 tumors that expressed CD driven by a 
      hypoxia-inducible promoter after treatment with 5-fluorocytosine. These results 
      suggest the potential applications of suicide genes, such as the CD gene, under 
      the control of hypoxia-inducible promoters for cancer gene therapy, which may 
      target efficiently to hypoxic regions of tumors with p53 mutations.
FAU - Lee, Che-Hsin
AU  - Lee CH
AD  - Department of Microbiology and Immunology, National Cheng Kung University Medical 
      College, Taiwan.
FAU - Wu, Chao-Liang
AU  - Wu CL
FAU - Shiau, Ai-Li
AU  - Shiau AL
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Hum Gene Ther
JT  - Human gene therapy
JID - 9008950
RN  - 0 (Antimetabolites, Antineoplastic)
RN  - 0 (Escherichia coli Proteins)
RN  - 0 (Hypoxia-Inducible Factor 1)
RN  - 0 (Tumor Suppressor Protein p53)
RN  - EC 3.5.4.1 (Cytosine Deaminase)
RN  - U3P01618RT (Fluorouracil)
SB  - IM
MH  - Animals
MH  - Antimetabolites, Antineoplastic/pharmacology
MH  - Carcinoma, Lewis Lung/genetics/metabolism/pathology/*therapy
MH  - Cell Line, Tumor
MH  - Cytosine Deaminase/*biosynthesis/genetics
MH  - Escherichia coli Proteins/biosynthesis/genetics
MH  - Fluorouracil/pharmacology
MH  - *Genes, Transgenic, Suicide
MH  - *Genetic Therapy
MH  - Humans
MH  - Hypoxia/genetics/*metabolism
MH  - Hypoxia-Inducible Factor 1/*biosynthesis/genetics
MH  - Male
MH  - Mice
MH  - Neovascularization, Pathologic/genetics/metabolism/pathology/therapy
MH  - Response Elements/genetics
MH  - Retroviridae
MH  - Transduction, Genetic
MH  - Tumor Suppressor Protein p53/genetics
EDAT- 2006/12/23 09:00
MHDA- 2007/02/23 09:00
CRDT- 2006/12/23 09:00
PHST- 2006/12/23 09:00 [pubmed]
PHST- 2007/02/23 09:00 [medline]
PHST- 2006/12/23 09:00 [entrez]
AID - 10.1089/hum.2005.239 [doi]
PST - ppublish
SO  - Hum Gene Ther. 2007 Jan;18(1):27-38. doi: 10.1089/hum.2005.239.