Use of a modified ornithine decarboxylase promoter to achieve efficient c-MYC- or N-MYC-regulated protein expression

Cancer Res. 2001 Apr 1;61(7):3045-52.


One of the advantages of viral-directed enzyme prodrug therapy (VDEPT) is its potential for tumor-specific cytotoxicity. However, the viruses used to deliver cDNAs encoding prodrug-activating enzymes transduce normal cells as well as tumor cells, and several approaches to achieve tumor-specific expression of the delivered cDNAs are being investigated. One such approach is to regulate transcription of the prodrug-activating enzyme with a promoter that is preferentially activated by tumor cells. Published data suggest that the most promising transcription factor/promoter/enhancer combinations are those activated by a tumor-specific transcription factor to retain tumor cell specificity but that are equal in strength to nonspecific viral promoters in their ability to up-regulate target cDNAs. This report identifies MYC-responsive, modified ornithine decarboxylase (ODC) promoter/enhancer sequences that up-regulate target protein expression in tumor cells overexpressing either N-MYC or c-MYC protein. The most efficient of the four constructs assessed contained six additional CACGTG MYC binding sites 5' to the endogenous ODC promoter (R6ODC). Reporter assays with this chimeric promoter/enhancer regulating expression of chloramphenicol acetyltransferase demonstrated 50-250-fold more activity in MYC-expressing cells compared with similar assays with promoterless plasmids. The R6ODC regulatory sequence was approximately equivalent to the CMV promoter in inducing expression of the neomycin resistance gene in c-MYC-expressing SW480 and HT-29 colon carcinoma cells and in N-MYC-expressing NB-1691 neuroblastoma cells. The modified ODC promoter may, therefore, be useful in achieving tissue-specific expression of target proteins in tumor cells that overexpress c- or N-MYC.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Antineoplastic Agents, Phytogenic / pharmacokinetics
  • Antineoplastic Agents, Phytogenic / pharmacology*
  • Biotransformation
  • Camptothecin / analogs & derivatives*
  • Camptothecin / pharmacokinetics
  • Camptothecin / pharmacology*
  • Carboxylesterase
  • Carboxylic Ester Hydrolases / biosynthesis
  • Carboxylic Ester Hydrolases / genetics
  • Chloramphenicol O-Acetyltransferase / genetics
  • Chloramphenicol O-Acetyltransferase / metabolism
  • Colonic Neoplasms / genetics
  • Colonic Neoplasms / metabolism
  • Gene Expression Regulation, Neoplastic*
  • Genes, Reporter
  • Genes, myc / genetics*
  • Glioblastoma / genetics
  • Glioblastoma / metabolism
  • Humans
  • Immunoblotting
  • Irinotecan
  • MyoD Protein / biosynthesis
  • MyoD Protein / genetics
  • Neuroblastoma / genetics
  • Neuroblastoma / metabolism
  • Ornithine Decarboxylase / genetics*
  • Promoter Regions, Genetic*
  • Proto-Oncogene Proteins c-myc / biosynthesis*
  • Proto-Oncogene Proteins c-myc / genetics
  • Rabbits
  • Rhabdomyosarcoma / genetics
  • Rhabdomyosarcoma / metabolism
  • Transfection
  • Transgenes
  • Tumor Cells, Cultured


  • Antineoplastic Agents, Phytogenic
  • MyoD Protein
  • Proto-Oncogene Proteins c-myc
  • Irinotecan
  • Chloramphenicol O-Acetyltransferase
  • Carboxylic Ester Hydrolases
  • Carboxylesterase
  • Ornithine Decarboxylase
  • Camptothecin