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Methylxanthine Sensitization of Human Colon Cancer Cells to ¹⁸⁶Re-Labeled Monoclonal Antibody

Departments of Nuclear Medicine and Pediatrics, Kanazawa University School of Medicine, Kanazawa; Radioisotope Laboratory, Department of Research Reactor, Japan Atomic Energy Research Institute, Tokaimura; and Medical Informatics, Kanazawa University Hospital, Kanazawa, Japan

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 ß-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°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%). Conclusion: Cellular modulation of the cell cycle with PTX and CAF radiosensitized LS180 colon cancer cells exposed to ¹⁸⁶Re radiation.

Key Words: radiosensitization • methylxanthine • ¹⁸⁶Re • ß-irradiation • cell cycle