Exp Mol Med.  2006 Oct;38(5):553-564.

Low-dose radiation response of the p21(WAF1/CIP1) gene promoter transduced by adeno-associated virus vector

• Nenoi M
• Daino K
• Ichimura S
• Takahash S
• Akuta T

Abstract

In cancer gene therapy, restriction of antitumor transgene expression in a radiation field by use of ionizing radiation-inducible promoters is one of the promising approaches for tumor-specific gene delivery. Although tumor suppressor protein p53 is induced by low doses (<1 Gy) of radiation, there have been only a few reports indicating potential utilization of a p53-target gene promoter, such as that of the p21 gene. This is mainly because the transiently transfected promoter of p53-target genes is not much sensitive to radiation. We examined the response of the p21 gene promoter to low-dose radiation when transduced into a human breast cancer cell line MCF-7 by use of recombinant adeno-associated virus (rAAV) vectors. It was shown that the p21 gene promoter transduced by rAAV vectors was more highly radiation-responsive than that transiently transfected by electroporation. A significant induction of the p21 gene promoter by radiation of low doses down to 0.2 Gy was observed. When cells were transduced with the p21 gene promoter-driven HSVtk gene by rAAV vector, they were significantly sensitized to repetitive treatment with low dose radiation (1 Gy) in the presence of the prodrug ganciclovir. It was therefore considered that the p21 gene promoter in combination with a rAAV vector is potentially usable for the development of a low-dose radiation-inducible vector for cancer gene therapy.

Keyword

cyclin-dependent kinase inhibitor p21; dependovirus; dTMP kinase; gene therapy; promoter regions (genetic); radiation; simplexvirus

MeSH Terms

X-Rays
Tumor Cells, Cultured
Transgenes/*radiation effects
Transduction, Genetic
Promoter Regions (Genetics)/*radiation effects
Humans
Genetic Vectors/*radiation effects
Gene Therapy/methods
Electroporation/methods
Dose-Response Relationship, Radiation
Cyclin-Dependent Kinase Inhibitor p21/*genetics
Adenoviridae
3' Untranslated Regions/physiology