Significance of manipulating intratumor hypoxia in the effect on lung metastases in radiotherapy, with reference to its effect on the sensitivity of intratumor quiescent cells.

摘要

PURPOSE: To evaluate the effect of manipulating intratumor hypoxia during radiotherapy on lung metastasis, referring to its effect on the sensitivity of quiescent tumor cells. MATERIALS AND METHODS: B16-BL6 melanoma tumor-bearing C57BL/6 mice were continuously given 5-bromo-2'-deoxyuridine (BrdU) to label all proliferating (P) cells. They received gamma-ray irradiation following loading with the acute hypoxia-releasing agent nicotinamide or local hyperthermia at mild temperatures (MTH). Immediately after the irradiation, cells from some tumors were isolated and incubated with a cytokinesis blocker. The sensitivity of quiescent (Q) cells was assessed in terms of the micronucleus frequency using immunofluorescence staining for BrdU. That of the total (=P + Q) tumor cell population was determined from BrdU non-treated tumors. In other tumor-bearing mice, 17 days after irradiation, macroscopic lung metastases were enumerated. RESULTS: In the total cells, a more marked enhancement in sensitivity was observed with nicotinamide than MTH. In Q cells, MTH combination induced a more marked enhancement than nicotinamide. Both nicotinamide and MTH reduced the size of the hypoxic fraction in the two cell populations, especially nicotinamide in the total cells and MTH in Q cells. Without gamma-ray irradiation, nicotinamide loading tended to decrease the number of lung metastases. With gamma-ray irradiation, nicotinamide loading and MTH, especially the former, reduced the number of metastases more than gamma-ray irradiation only. CONCLUSION: Hypoxia manipulation in solid tumors has the potential to influence lung metastases. Notably, acute hypoxia-releasing nicotinamide may be promising for reducing the number of lung metastases.