| Project/Area Number |
11671464
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (C)
|
| Allocation Type | Single-year Grants |
|---|
| Section | 一般 |
|---|
| Research Field |
Orthopaedic surgery
|
|---|
| Research Institution | Kagoshima University |
|---|
Principal Investigator |
KOMIYA Setsuro Kagoshima University, Faculty of Medicine, Professor, 医学部, 教授 (30178371)
|
|---|
| Co-Investigator(Kenkyū-buntansha) |
TANIGUCHI Noboru Kagoshima University, Faculty of Medicine, Staff, 医学部, 医員
ISHIDOU Yasuhiro Kagoshima University, University Hospital, Faculty of Medicine Staff, 医学部附属病院, 医員
ITO Hiroshi Kagoshima University, Faculty of Medicine, Research Associate, 医学部, 助手 (40223177)
KOZAI Kenichiro Kurume University, Faculty of Medicine, Research Associate, 医学部, 助手 (90258418)
|
|---|
| Project Period (FY) |
1999 – 2000
|
| Project Status |
Completed (Fiscal Year 2000)
|
| Budget Amount *help |
¥3,700,000 (Direct Cost: ¥3,700,000)
Fiscal Year 2000: ¥1,600,000 (Direct Cost: ¥1,600,000)
Fiscal Year 1999: ¥2,100,000 (Direct Cost: ¥2,100,000)
|
|---|
| Keywords | osteosarcoma / Chimera vector / Gene therapy / Interleukin 2 / Cytokine / adenovirus / Pulmonary metastasis / 自殺遺伝子 / アデノウイルスベクター |
|---|
| Research Abstract |
Here we show that a single injection of adenoviral vector (Ad) encoding the IL-2 gene only into a primary tumor can eradicate disseminated micro-metastases of osteosarcoma. Mice received injections of murine osteosarcoma LM8 cells subcutaneously and intravenously via the tail vein at days 0 and 6, respectively, leading to 100% incidence of both the primary tumor and metastasis in the lung and 60-80% incidence of metastases in the liver and kidney. At day 7, a single injection of each Ad at various dosages was given only into the subcutaneous tumor. Not only was the growth of the subcutaneous tumor suppressed, but also metastases in this lung, liver and kidney were dramatically inhibited by Ad.IL-2. We noted that maximal therapeutic effects for both primary and metastatic tumors were seen only when the optimal dose (3x10^7 plaque-forming units (pfu))(I.e., not the highest dose) of Ad.IL-2 (1x10^8 pfu) than this optimal dose was used, revealing over 2ng/ml of serum IL-2 level. On the other hand, gene transduction in connective tissues adjacent to the tumor was sufficient to confer systemic antitumoral immunity in vivo, as adenoviral gene transduction efficiency (AGTE) in LM8 cells is extremely low. Thus, this approach does not require high AGTE in tumor cell, which currently limits the clinical utility of some of the gene therapy approaches. In conclusion, Ad.IL-2 gene therapy, which is just a single injection of the optimal dose of Ad.IL-2 only into a primary tumor, may be clinically useful for osteosarcoma patents in terms of feasibility, low invasiveness, cost effectiveness as well as therapeutic potential, especially for lung metastasis, for which current therapies are less effective. The most critical factor is the use of the optimal therapeutic expression level of IL-2, but the high AGTE in tumor cells is not necessary.
|
