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Effect of bevacizumab combined with boron neutron capture therapy on local tumor response and lung metastasis.

Masunaga SI, Sakurai Y, Tano K, Tanaka H, Suzuki M, Kondo N, Narabayashi M, Watanabe T, Nakagawa Y, Maruhashi A, Ono K - Exp Ther Med (2014)

Bottom Line: In other tumor-bearing mice, 17 days following irradiation, lung metastases were enumerated.Regardless of the presence of a (10)B-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.

View Article: PubMed Central - PubMed

Affiliation: Department of Radiation Life and Medical Science, Research Reactor Institute, Kyoto University, Osaka 590-0494, Japan.

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 a (10)B-carrier [L-para-boronophenylalanine-(10)B (BPA) or sodium mercaptoundecahydrododecaborate-(10)B (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 a (10)B-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.

No MeSH data available.


Related in: MedlinePlus

Counted numbers of macroscopic metastases in the lung on day 35 following tumor cell inoculation as a function of the dose of neutron beam irradiation (A) without and (B) with bevacizumab treatment following the administration of a 10B-carrier in combination with nicotinamide treatment or mild temperature hyperthermia (MTH) on day 18 following tumor cell inoculation. Circle, square, and triangle symbols represent irradiation without nicotinamide or MTH, with nicotinamide, and with MTH, respectively. Bars represent standard errors (n=9). 10B (−), no 10B-carrier; BPA, L-para-boronophenylalanine-10B; BSH, sodium mercaptoundecahydrododecaborate-10B; MTH, mild temperature hyperthermia.
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f3-etm-08-01-0291: Counted numbers of macroscopic metastases in the lung on day 35 following tumor cell inoculation as a function of the dose of neutron beam irradiation (A) without and (B) with bevacizumab treatment following the administration of a 10B-carrier in combination with nicotinamide treatment or mild temperature hyperthermia (MTH) on day 18 following tumor cell inoculation. Circle, square, and triangle symbols represent irradiation without nicotinamide or MTH, with nicotinamide, and with MTH, respectively. Bars represent standard errors (n=9). 10B (−), no 10B-carrier; BPA, L-para-boronophenylalanine-10B; BSH, sodium mercaptoundecahydrododecaborate-10B; MTH, mild temperature hyperthermia.

Mentions: Fig. 3 shows the numbers of lung metastases on day 35 following inoculation as a function of the absorbed dose of neutron beam irradiation with or without a 10B-carrier, in combination with nicotinamide or MTH, and in the presence or absence of bevacizumab treatment. Without bevacizumab or irradiation, irrespective of a 10B-carrier, nicotinamide and MTH decreased and increased the numbers of macroscopic metastases, respectively. With bevacizumab, but under no irradiation, both nicotinamide and MTH decreased the number of metastases. With neutron beam irradiation, as the absorbed dose increased, the number of metastases decreased. Furthermore, the number of metastases decreased markedly with a 10B-carrier, especially BPA, than without. There was a near-parallel shift in the curves and no significant changes in the slopes of the curves for the tumors treated without a 10B-carrier or with BPA or BSH. This indicates that no apparent radio-sensitizing or -protecting effect was observed with or without bevacizumab, nicotinamide or MTH in terms of the numbers of lung metastases. However, with irradiation, nicotinamide reduced the numbers of metastatic nodules from the local tumors treated with the neutron beam only, BPA-BNCT, or BSH-BNCT. The combination with bevacizumab also reduced the number of metastases from the local tumors treated with MTH more than those with nicotinamide and without nicotinamide or MTH.


Effect of bevacizumab combined with boron neutron capture therapy on local tumor response and lung metastasis.

Masunaga SI, Sakurai Y, Tano K, Tanaka H, Suzuki M, Kondo N, Narabayashi M, Watanabe T, Nakagawa Y, Maruhashi A, Ono K - Exp Ther Med (2014)

Counted numbers of macroscopic metastases in the lung on day 35 following tumor cell inoculation as a function of the dose of neutron beam irradiation (A) without and (B) with bevacizumab treatment following the administration of a 10B-carrier in combination with nicotinamide treatment or mild temperature hyperthermia (MTH) on day 18 following tumor cell inoculation. Circle, square, and triangle symbols represent irradiation without nicotinamide or MTH, with nicotinamide, and with MTH, respectively. Bars represent standard errors (n=9). 10B (−), no 10B-carrier; BPA, L-para-boronophenylalanine-10B; BSH, sodium mercaptoundecahydrododecaborate-10B; MTH, mild temperature hyperthermia.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4061189&req=5

f3-etm-08-01-0291: Counted numbers of macroscopic metastases in the lung on day 35 following tumor cell inoculation as a function of the dose of neutron beam irradiation (A) without and (B) with bevacizumab treatment following the administration of a 10B-carrier in combination with nicotinamide treatment or mild temperature hyperthermia (MTH) on day 18 following tumor cell inoculation. Circle, square, and triangle symbols represent irradiation without nicotinamide or MTH, with nicotinamide, and with MTH, respectively. Bars represent standard errors (n=9). 10B (−), no 10B-carrier; BPA, L-para-boronophenylalanine-10B; BSH, sodium mercaptoundecahydrododecaborate-10B; MTH, mild temperature hyperthermia.
Mentions: Fig. 3 shows the numbers of lung metastases on day 35 following inoculation as a function of the absorbed dose of neutron beam irradiation with or without a 10B-carrier, in combination with nicotinamide or MTH, and in the presence or absence of bevacizumab treatment. Without bevacizumab or irradiation, irrespective of a 10B-carrier, nicotinamide and MTH decreased and increased the numbers of macroscopic metastases, respectively. With bevacizumab, but under no irradiation, both nicotinamide and MTH decreased the number of metastases. With neutron beam irradiation, as the absorbed dose increased, the number of metastases decreased. Furthermore, the number of metastases decreased markedly with a 10B-carrier, especially BPA, than without. There was a near-parallel shift in the curves and no significant changes in the slopes of the curves for the tumors treated without a 10B-carrier or with BPA or BSH. This indicates that no apparent radio-sensitizing or -protecting effect was observed with or without bevacizumab, nicotinamide or MTH in terms of the numbers of lung metastases. However, with irradiation, nicotinamide reduced the numbers of metastatic nodules from the local tumors treated with the neutron beam only, BPA-BNCT, or BSH-BNCT. The combination with bevacizumab also reduced the number of metastases from the local tumors treated with MTH more than those with nicotinamide and without nicotinamide or MTH.

Bottom Line: In other tumor-bearing mice, 17 days following irradiation, lung metastases were enumerated.Regardless of the presence of a (10)B-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.

View Article: PubMed Central - PubMed

Affiliation: Department of Radiation Life and Medical Science, Research Reactor Institute, Kyoto University, Osaka 590-0494, Japan.

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 a (10)B-carrier [L-para-boronophenylalanine-(10)B (BPA) or sodium mercaptoundecahydrododecaborate-(10)B (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 a (10)B-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.

No MeSH data available.


Related in: MedlinePlus