HOMEPRODUCTSCOMPANYCONTACTFAQResearchDictionaryPharmaSign Up FREE or Login

Secretion of thymidine kinase to increase the effectivity of suicide gene therapy results in the loss of enzymatic activity.

Abstract
Low efficiency of gene transfer is one of the major limitations of gene therapy. A solution to this problem may be transmission; by modification of the transgene, the gene product can be secreted and internalized by the surrounding cells. Cancer gene therapy using the herpes simplex thymidine kinase (HSV-TK) suicide gene is a promising treatment, and TK has been used in clinical trials with some success. However, this kind of therapy has limited efficacy due to the low level of gene transfer reached. A modified TK protein, capable of migrating from the producing cell to neighboring cells, would result in a greater proportion of cells affected by the treatment. As a first step towards transmission, we constructed a secretory form of HSV-TK by including the Igkappa leader peptide in the gene. An endoplasmatic reticulum export signal was added to the construct to further improve its secretion. Secretion and protein production in cancer cells, the enzymatic activity of the modified proteins and the ability of the modified TK to sensitize cancer cells to ganciclovir were tested. Addition of the Igkappa leader resulted in high levels of secretion of HSV-TK, with up to 70% of the total amount of protein secreted. Inclusion of an ER export signal did not further improve secretion. The enzyme activity of the secreted TK however, was decreased when compared to native TK. This study is the first to report on secretion of TK, and provides a first step in a novel strategy to improve the efficiency of cancer gene therapy. The loss of function in secreted TK however, may present a major hurdle in the development of a transmitted form of TK.
AuthorsA M J Beerens, M G Rots, B Bermúdez, E F J de Vries, H J Haisma
JournalJournal of drug targeting (J Drug Target) Vol. 16 Issue 1 Pg. 26-35 (Jan 2008) ISSN: 1061-186X [Print] England
PMID18172817 (Publication Type: Journal Article)
Chemical References
  • I-kappa B Proteins
  • Thymidine Kinase
  • Ganciclovir
Topics
  • Adenoviridae (genetics)
  • Animals
  • Blotting, Western
  • COS Cells
  • Cell Survival (drug effects)
  • Cells, Cultured
  • Chlorocebus aethiops
  • Ganciclovir (pharmacology)
  • Genes, Transgenic, Suicide
  • Genetic Therapy
  • Genetic Vectors
  • Herpesvirus 1, Human (enzymology, genetics)
  • I-kappa B Proteins (metabolism)
  • Thymidine Kinase (genetics, metabolism)

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 graph!


Choose Username:
Email:
Password:
Verify Password:
Enter Code Shown: