| RRC ID |
39768
|
| Author |
Braiden V, Ohtsuru A, Kawashita Y, Miki F, Sawada T, Ito M, Cao Y, Kaneda Y, Koji T, Yamashita S.
|
| Title |
Eradication of breast cancer xenografts by hyperthermic suicide gene therapy under the control of the heat shock protein promoter.
|
| Journal |
Hum Gene Ther
|
| Abstract |
To investigate the usefulness of heat shock protein (HSP) promoter for breast cancer gene therapy, hyperthermia and HSV thymidine kinase (tk) suicide gene combination therapy was examined with mouse mammary cancer cell line FM3A. HSP promoter activity was markedly increased after heat shock (41-45 degrees C), with maximum activation (about 400-fold) at 3 hr. An in vitro cytotoxic assay showed that HSP-tk-transduced FM3A cells became more sensitive (more than 50,000 times) to ganciclovir (GCV) with heat shock, but untreated cells showed no increased cytotoxic sensitivity to GCV compared with control FM3A cells. In addition to promoter-oriented selective cell killing, a "chemosensitization effect" as a bystander effect was demonstrated by hyperthermia and suicide gene combination therapy, using a non-heat-inducible promoter. Immunohistochemical analysis revealed that this synergistic killing effect was dependent on apoptotic cell death with upregulation of both Fas and FasL (Fas ligand) expression. We also examined the efficacy of HSP-tk gene therapy in vivo by implanting breast cancer in subcutaneous and intraperitoneal models of BALB/c nude mice targeted by the HVJ-anionic liposome method. Significant tumor regression was observed in HSP-tk-transduced tumors followed by hyperthermia therapy, but no such inhibition was noted in either the mock vector transfection or hyperthermia group compared with control tumor-bearing mice. Our results demonstrate that this combination system is synergistically effective in mediating Fas-dependent apoptosis for a specific gene therapy targeting HSP-expressing mammary carcinomas, even in advanced and heat-resistant breast cancer.
|
| Volume |
11(18)
|
| Pages |
2453-63
|
| Published |
2000-12-10
|
| DOI |
10.1089/10430340050207948
|
| PMID |
11119417
|
| MeSH |
Animals
Antiviral Agents / pharmacology
Apoptosis
Breast Neoplasms / genetics*
Breast Neoplasms / therapy*
Dose-Response Relationship, Drug
Fas Ligand Protein
Female
Ganciclovir / pharmacology
Genetic Therapy / methods*
Heat-Shock Proteins / genetics*
Hot Temperature
Immunohistochemistry
In Situ Nick-End Labeling
Liposomes / metabolism
Mammary Neoplasms, Animal / metabolism
Membrane Glycoproteins / metabolism
Mice
Mice, Inbred BALB C
Mice, Nude
Neoplasm Transplantation
Plasmids / metabolism
Promoter Regions, Genetic*
Retroviridae / metabolism
Temperature
Thymidine Kinase / metabolism
Time Factors
Tissue Distribution
Transduction, Genetic
Transfection
Tumor Cells, Cultured
Up-Regulation
fas Receptor / metabolism
|
| IF |
4.51
|
| Times Cited |
45
|
|
WOS Category
|
MEDICINE, RESEARCH & EXPERIMENTAL
BIOTECHNOLOGY & APPLIED MICROBIOLOGY
GENETICS & HEREDITY
|
| Resource |
| Human and Animal Cells |
FM3A(RCB0086)
FM3A FT-101(RCB0032) |
