2001 Fiscal Year Final Research Report Summary
Enhancement of antitumor effect of internal radiotherapy by inhibition of DNA repair and improvement of intratumoral oxygenation
| Project/Area Number |
12670859
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Radiation science
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| Research Institution | Kanazawa University Graduate School of Medical Sciences |
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Principal Investigator |
KINUYA Seigo Kanazawa University, Biotracer Medicine, Instructor, 医学系研究科, 助手 (20281024)
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| Project Period (FY) |
2000 – 2001
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| Keywords | radiopharmaceutical / internal radiotherapy / methyxanthine delivative / radioscnsitization / monoclonal antibody / cell cycle arrest / intratumoral oxygenation |
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| Research Abstract |
1. Tumor cells lacking functional p53 suppressor gene may arrest at G2 phase of the cell cycle after exposure to ionizing radiation, resulting in increased radioresistance. Methylxanthines (MTX), pentoxifylline (PTX) or caffeine (CAP), can inhibit the G2 phase checkpoint arrest of damaged cells and, thus, radiosensitize them. LSI80 human colon cancer cells lacking functional p53 were irradiated with ^<186>Re-MAG3-A7 monoclonal antibody against colorectal cancer in the presence or absence of PTX or CAP. Both PTX and CAP dose-dependently enhanced the cytotoxicity of ^<186>Re-MAG3-A7. Flow cytometer showed cell cycle arrest of irradiated cells in G2/M phase, which was inhibited by the presence of PTX or CAP.
2. Balb/c mice with xenografts of LS180 cells were treated with ^<131>I-A7 anti-colorectal monoclonal antibody. A dose of 50 mg/kg/day of PTX was administered I.p. immediately after the ^<131>I-A7 injection and daily thereafter for 7 days. The administration of PTX alone did not suppress tumor growth, but the efficacy of RIT with ^<131>I-A7 was significantly improved by PTX. PTX administration did not alter the biodistribution or intratumoral distribution of ^<131>I-A7. However, intratumoral pO2 was significantly improved by PTX administration. PTX-induced radiosensitization of tumor cells due to better oxygenation is responsible for the better RIT outcomes, because the net radiation absorbed dose to the tumors did not appear to be changed.
These results indicate that MTXs can enhance the efficacy of infernal radiation therapy through multiple effects such as increase of tumor oxygenation and inhibition of the G2 cell cycle arrest of irradiated cells.
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