title: Effect of bevacizumab combined with boron neutron capture therapy on local tumor response and lung metastasis.
abstract: The aim of the present study was to evaluate the effect of bevacizumab on local tumor response and lung metastatic potential during boron neutron capture therapy (BNCT) and in particular, the response of intratumor quiescent (Q) cells. B16-BL6 melanoma tumor-bearing C57BL/6 mice were continuously administered bromodeoxyuridine (BrdU) to label all proliferating (P) tumor cells. The tumors were irradiated with thermal neutron beams following the administration of a10B-carrier [L-para-boronophenylalanine-10B (BPA) or sodium mercaptoundecahydrododecaborate-10B (BSH)], with or without the administration of bevacizumab. This was further combined with an acute hypoxia-releasing agent (nicotinamide) or mild temperature hyperthermia (MTH, 40°C for 60 min). Immediately following the irradiation, cells from certain tumors were isolated and incubated with a cytokinesis blocker. The responses of the Q cells and the 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 following irradiation, lung metastases were enumerated. Three days following bevacizumab administration, the sensitivity of the total tumor cell population following BPA-BNCT had increased more than that following BSH-BNCT. The combination with MTH, but not with nicotinamide, further enhanced total tumor cell population sensitivity. Regardless of the presence of a10B-carrier, MTH enhanced the sensitivity of the Q cell population. Regardless of irradiation, the administration of bevacizumab, as well as nicotinamide treatment, demonstrated certain potential in reducing the number of lung metastases especially in BPA-BNCT compared with BSH-BNCT. Thus, the current study revealed that BNCT combined with bevacizumab has the potential to sensitize total tumor cells and cause a reduction in the number of lung metastases to a similar level as nicotinamide.
authors.affiliation: Department of Radiation Life and Medical Science, Research Reactor Institute, Kyoto University, Osaka 590-0494, Japan.
authors.forename: Shin-Ichiro
authors.initials: SI
authors.lastname: Masunaga
authors.affiliation: Department of Radiation Life and Medical Science, Research Reactor Institute, Kyoto University, Osaka 590-0494, Japan.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Sakurai
authors.affiliation: Department of Radiation Life and Medical Science, Research Reactor Institute, Kyoto University, Osaka 590-0494, Japan.
authors.forename: Keizo
authors.initials: K
authors.lastname: Tano
authors.affiliation: Department of Radiation Life and Medical Science, Research Reactor Institute, Kyoto University, Osaka 590-0494, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Tanaka
authors.affiliation: Department of Radiation Life and Medical Science, Research Reactor Institute, Kyoto University, Osaka 590-0494, Japan.
authors.forename: Minoru
authors.initials: M
authors.lastname: Suzuki
authors.affiliation: Department of Radiation Life and Medical Science, Research Reactor Institute, Kyoto University, Osaka 590-0494, Japan.
authors.forename: Natsuko
authors.initials: N
authors.lastname: Kondo
authors.affiliation: Department of Radiation Life and Medical Science, Research Reactor Institute, Kyoto University, Osaka 590-0494, Japan.
authors.forename: Masaru
authors.initials: M
authors.lastname: Narabayashi
authors.affiliation: Department of Radiation Life and Medical Science, Research Reactor Institute, Kyoto University, Osaka 590-0494, Japan.
authors.forename: Tsubasa
authors.initials: T
authors.lastname: Watanabe
authors.affiliation: Department of Radiation Life and Medical Science, Research Reactor Institute, Kyoto University, Osaka 590-0494, Japan.
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Nakagawa
authors.affiliation: Department of Radiation Life and Medical Science, Research Reactor Institute, Kyoto University, Osaka 590-0494, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Maruhashi
authors.affiliation: Department of Radiation Life and Medical Science, Research Reactor Institute, Kyoto University, Osaka 590-0494, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Ono
keywords: 10B-carrier; bevacizumab; boron neutron capture therapy; mild temperature hyperthermia; nicotinamide; quiescent cell