Two-step transcriptional amplification-lipid-based nanoparticles using PSMA or midkine promoter for suicide gene therapy in prostate cancer.

A two-step transcriptional amplification system (TSTA) was used to enhance the efficacy of suicide gene therapy for treatment of prostate cancer. We designed a TSTA system and constructed two types of plasmid: one containing GAL4-VP16 fusion protein under the control of a tumor-specific promoter, the other containing luciferase or herpes simplex virus thymidine kinase (HSV-tk) under the control of a synthetic promoter. The TSTA systems using nanoparticles based on lipids were evaluated by measuring the amount of induced luciferase activity as a function of prostate-specific membrane antigen (PSMA) and midkine (Mk) promoters, specific for LNCaP and PC-3 prostate cancer cells, respectively. In LNCaP cells that were PSMA-positive, the TSTA system featuring the PSMA enhancer and promoter exhibited activity that was 640-fold greater than a system consisting of one-step transcription with the PSMA promoter. In contrast, this difference in activity did not occur in PSMA-negative PC-3 cells. In Mk-positive PC-3 cells, the TSTA system with the Mk promoter exhibited a five-fold increase in activity over one-step transcription, but such activity was not induced in Mk-negative LNCaP cells. When using HSV-tk for suicide gene therapy, TSTA systems featuring the PSMA or Mk promoter inhibited in vitro cell growth in the presence of ganciclovir. Furthermore, the TSTA system featuring the Mk promoter suppressed in vivo growth of PC-3 tumor xenografts to a greater extent than one-step transcription. These findings show that TSTA systems can enhance PSMA and Mk promoter activities and selectively inhibit PC-3 cell growth in tumors. This suggests that TSTA systems featuring tumor-specific promoters are suitable for cancer treatment by gene therapy.
AuthorsYoshiyuki Hattori, Yoshie Maitani
JournalCancer science (Cancer Sci) Vol. 97 Issue 8 Pg. 787-98 (Aug 2006) ISSN: 1347-9032 [Print] England
PMID16800821 (Publication Type: Evaluation Studies, Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Antigens, Surface
  • Cytokines
  • Gal-VP16
  • Lipids
  • RNA, Messenger
  • Trans-Activators
  • midkine
  • Luciferases
  • Thymidine Kinase
  • Glutamate Carboxypeptidase II
  • glutamate carboxypeptidase II, human
  • Animals
  • Antigens, Surface (genetics)
  • Cell Line, Tumor
  • Cytokines (genetics)
  • Enhancer Elements, Genetic
  • Gene Amplification
  • Genes, Transgenic, Suicide
  • Genetic Therapy (methods)
  • Glutamate Carboxypeptidase II (genetics)
  • Humans
  • Lipids (chemistry)
  • Luciferases (analysis, genetics)
  • Male
  • Mice
  • Nanostructures (chemistry)
  • Plasmids (genetics)
  • Promoter Regions, Genetic
  • Prostatic Neoplasms (therapy)
  • RNA, Messenger (analysis)
  • Thymidine Kinase (genetics)
  • Trans-Activators (genetics)
  • Transcription, Genetic
  • Xenograft Model Antitumor Assays

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research network!

Choose Username:
Verify Password: