Midkine and cyclooxygenase-2 promoters are promising for adenoviral vector gene delivery of pancreatic carcinoma

Cancer Gene Ther. 2001 Dec;8(12):990-6. doi: 10.1038/sj.cgt.7700403.

Abstract

Midkine (MK), a heparin binding growth factor, and cyclooxygenase-2 (COX-2), a key enzyme in the conversion of arachidonic acid to prostaglandin, are both up-regulated at the mRNA or protein level in many human malignant tumors. Here, we investigated the tumor specificity of both MK and COX-2 promoters in human pancreatic cancer, with the aim to improve the selectivity of therapeutic gene expression. We constructed recombinant adenoviral (Ad) vectors containing either the luciferase (Luc) reporter gene under the control of the COX-2 or MK promoter or the herpes simplex virus thymidine kinase (HSV Tk) gene under the control of the COX-2 promoter and compared the expression with the cytomegalovirus (CMV) promoter. AdMKLuc achieved moderate to relatively high activity upon infection to both primary and established pancreatic carcinoma cells. Of the two COX-2 promoter regions (COX-2M and COX-2L), both revealed a high activity in primary pancreatic carcinoma cells, whereas in the established pancreatic carcinoma cell lines, COX-2L has an approximately equal high activity compared to CMV. In addition, both AdCOX-2M Tk and AdCOX-2L Tk induced marked cell death in response to ganciclovir (GCV) in three of four established pancreatic carcinoma cell lines. From these results, and because it has been reported that AdMKTk and AdCOX-2L Tk in combination with GCV did not reveal significant liver toxicity, we conclude that the MK as well as the COX-2 promoters are promising tumor-specific promoters for Ad vector-based gene therapy of pancreatic cancer.

Publication types

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

MeSH terms

  • Adenoviridae*
  • Angiogenesis Inducing Agents / genetics*
  • Angiogenesis Inducing Agents / therapeutic use
  • Carrier Proteins / genetics*
  • Carrier Proteins / therapeutic use
  • Cyclooxygenase 2
  • Cytokines*
  • Genetic Therapy
  • Genetic Vectors
  • Humans
  • Isoenzymes / genetics*
  • Isoenzymes / therapeutic use
  • Membrane Proteins
  • Midkine
  • Pancreatic Neoplasms / genetics*
  • Pancreatic Neoplasms / therapy*
  • Promoter Regions, Genetic / genetics
  • Prostaglandin-Endoperoxide Synthases / genetics*
  • Prostaglandin-Endoperoxide Synthases / therapeutic use
  • Reassortant Viruses
  • Transfection
  • Tumor Cells, Cultured

Substances

  • Angiogenesis Inducing Agents
  • Carrier Proteins
  • Cytokines
  • Isoenzymes
  • Membrane Proteins
  • Midkine
  • Cyclooxygenase 2
  • PTGS2 protein, human
  • Prostaglandin-Endoperoxide Synthases