Methylxanthine sensitization of human colon cancer cells to 186Re-labeled monoclonal antibody.
Tumor cells lacking the functional p53 suppressor gene may arrest at the G2 phase of the cell cycle after exposure to ionizing radiation, resulting in increased radioresistance. Methylxanthines (MTXs), such as pentoxifylline (PTX) or caffeine (CAF), can inhibit the G2-phase checkpoint arrest of damaged cells and thus radiosensitize them. However, the effect of MTX in cells irradiated with low-dose-rate beta-emission is not well understood.


METHODS
A clonogenic assay was performed with LS180 human colon cancer cells lacking the functional p53 suppressor gene. Cells were irradiated with increasing concentrations of 186Re-mercaptoacetyltriglycine (186Re-MAG3)-labeled A7 monoclonal antibody against colorectal cancer (0-925 kBq/mL) at 37 degrees C in 5% CO2 for 24 h in the presence or absence of PTX (0-2 mmol/L) or CAF (0-5 mmol/L). The enhancement ratio (ER) with MTX was calculated as a ratio of 50% cell-killing concentration of 186Re-MAG3-A7 in control cells to that in cells treated with PTX or CAF. The cell cycle distribution was analyzed with a flow cytometer.


RESULTS
The concentration of 50% cell kill was 474 kBq/mL 186Re-MAG3-A7. Both PTX and CAF dose dependently enhanced the cytotoxicity of 186Re-MAG3-A7: ERs of 0.5 mmol/L PTX, 2 mmol/L PTX, 1 mmol/L CAF, and 5 mmol/L CAF were 1.50, 2.18, 1.54, and 2.63, respectively. Flow cytometry showed that the percentage nonirradiated cells in the G2/M phase of the cell cycle was 11.3% +/- 1.66%. On the other hand, cells exposed to 186Re-MAG3-A7 accumulated in the G2/M phase of the cell cycle (40.2% +/- 1.46%), which was inhibited by the presence of 1 mmol/L PTX (19.8% +/- 8.12%) or 2 mmol/L CAF (26.9% +/- 6.21%).


CONCLUSIONS
Cellular modulation of the cell cycle with PTX and CAF radiosensitized LS180 colon cancer cells exposed to 186Re radiation.
Kinuya
S
S
Departments of Nuclear Medicine and Pediatrics, Kanazawa University School of Medicine, Kanazawa, Japan.
Yokoyama
K
K
Kudo
M
M
Kasahara
Y
Y
Kobayashi
K
K
Motoishi
S
S
Onoma
K
K
Bunko
H
H
Michigishi
T
T
Tonami
N
N
D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D002453:Cell Cycle / Q000528:radiation effects; D002470:Cell Survival / Q000528:radiation effects; D003110:Colonic Neoplasms / Q000235:genetics / Q000473:pathology*; D016158:Genes, p53; D006801:Humans; D007399:Interphase / Q000528:radiation effects; D009842:Oligopeptides / Q000494:pharmacology*; D009942:Organometallic Compounds / Q000494:pharmacology*; D011836:Radiation Tolerance; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D019275:Radiopharmaceuticals / Q000494:pharmacology*; D012211:Rhenium / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000473:pathology / Q000528:radiation effects*; D014410:Tumor Stem Cell Assay; D014970:Xanthines / Q000494:pharmacology*
D000911:Antibodies, Monoclonal; D009842:Oligopeptides; D009942:Organometallic Compounds; D011838:Radiation-Sensitizing Agents; D019275:Radiopharmaceuticals; D014970:Xanthines; C114893:rhenium-mercaptoacetyltriglycine; C008514:methylxanthine; D012211:Rhenium