Abstract
Purpose:
To evaluate the effect manipulating intratumor hypoxia on local tumor response and lung metastatic potential in radiotherapy including boron neutron capture therapy (BNCT).
Methods and Materials:
B16-BL6 melanoma tumor-bearing C57BL/6 mice were continuously given 5-bromo-2'-deoxyuridine (BrdU) to label all proliferating (P) cells. The tumors received γ-ray irradiation or reactor thermal neutron beam irradiation following the administration of a 10B-carrier (L-para-boronophenylalanine-10B (BPA) or sodium mercaptoundecahydrododecaborate-10B (BSH)) in combination with an acute hypoxia-releasing agent (nicotinamide) or mild temperature hyperthermia (MTH). Immediately after the irradiation, cells from some tumors were isolated and incubated with a cytokinesis blocker. The responses of the quiescent (Q) and total (= P + Q) cell populations were assessed based on the frequency of micronuclei using immunofluorescence staining for BrdU. 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. BPA-BNCT increased the sensitivity of the total tumor cell population more than BSH-BNCT. However, the sensitivity of Q cells treated with BPA was lower than that of BSH-treated Q cells. With or without irradiation, nicotinamide treatment decreased the number of lung metastases. With irradiation, BPA-BNCT, especially in combination with nicotinamide treatment, showed the potential to reduce the number more than BSH-BNCT.
Conclusion:
Acute hypoxia-releasing nicotinamide may be promising for reducing the number of lung metastases. BSH-BNCT in combination with MTH improves local tumor control, while BPA-BNCT in combination with nicotinamide may reduce the number of lung metastases.
