| RRC ID |
18986
|
| 著者 |
Cody JJ, Rivera AA, Lyons GR, Yang SW, Wang M, Sarver DB, Wang D, Selander KS, Kuo HC, Meleth S, Feng X, Siegal GP, Douglas JT.
|
| タイトル |
Arming a replicating adenovirus with osteoprotegerin reduces the tumor burden in a murine model of osteolytic bone metastases of breast cancer.
|
| ジャーナル |
Cancer Gene Ther
|
| Abstract |
Most patients with advanced breast cancer develop osteolytic bone metastases, which have numerous complications. Because current therapies are not curative, new treatments are needed. Conditionally replicating adenoviruses (CRAds) are anticancer agents designed to infect and lyse tumor cells. However, in spite of their promise as selective cancer therapeutics, replicating adenoviruses have shown limited efficacy in the clinical setting. We hypothesized that a CRAd armed with osteoprotegerin (OPG) would eradicate bone metastases of breast cancer both directly, by oncolysis, and indirectly, by inhibiting osteoclastic bone resorption, and thus reducing the tumor burden. We constructed an armed CRAd (Ad5-Δ24-sOPG-Fc-RGD) by replacing viral E3B genes with a fusion of the ligand-binding domains of OPG and the Fc portion of human IgG1. Conditional replication was conferred by a 24-base pair deletion within E1A (Δ24), which prevents the binding of E1A to the retinoblastoma tumor suppressor/cell cycle regulator protein and limits replication in normal cells. Enhanced infection of cells expressing low levels of the primary Ad5 receptor was conferred by incorporating an arginine-glycine-aspartic acid (RGD) peptide sequence into the fiber knob to mediate binding to α(v) integrins. After characterization of the armed CRAd, we demonstrated that infection of breast cancer cells by Ad5-Δ24-sOPG-Fc-RGD both killed the infected cells by oncolysis and inhibited the formation of osteoclasts in an in vitro co-culture model. In a murine model of osteolytic bone metastases of breast cancer, the CRAd armed with shortened OPG (sOPG)-Fc reduced tumor burden in the bone and inhibited osteoclast formation more effectively than an unarmed CRAd.
|
| 巻・号 |
17(12)
|
| ページ |
893-905
|
| 公開日 |
2010-12-1
|
| DOI |
10.1038/cgt.2010.47
|
| PII |
cgt201047
|
| PMID |
20798695
|
| PMC |
PMC3842170
|
| MeSH |
Adenoviridae / genetics*
Animals
Bone Neoplasms / pathology
Bone Neoplasms / secondary*
Breast Neoplasms / genetics
Breast Neoplasms / pathology
Breast Neoplasms / therapy*
Carrier Proteins / genetics
Carrier Proteins / metabolism
Cell Line, Tumor
Female
Humans
Mice
Osteoprotegerin / genetics*
Osteoprotegerin / metabolism
Tumor Burden / genetics
Virus Replication
|
| IF |
4.534
|
| 引用数 |
14
|
|
WOS 分野
|
MEDICINE, RESEARCH & EXPERIMENTAL
BIOTECHNOLOGY & APPLIED MICROBIOLOGY
ONCOLOGY
GENETICS & HEREDITY
|
| リソース情報 |
| ヒト・動物細胞 |
ST2(RCB0224) |
