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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

Dose response curves of the net micronucleus frequency for (A) total and (B) quiescent cell populations from B16-BL6 tumors irradiated with reactor neutron beams following the administration of a 10B-carrier in combination with nicotinamide treatment, mild temperature hyperthermia (MTH) or bevacizumab treatment on day 18 following tumor cell inoculation. Open and solid symbols represent irradiation without and with bevacizumab, respectively. 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; BV, bevacizumab.
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f2-etm-08-01-0291: Dose response curves of the net micronucleus frequency for (A) total and (B) quiescent cell populations from B16-BL6 tumors irradiated with reactor neutron beams following the administration of a 10B-carrier in combination with nicotinamide treatment, mild temperature hyperthermia (MTH) or bevacizumab treatment on day 18 following tumor cell inoculation. Open and solid symbols represent irradiation without and with bevacizumab, respectively. 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; BV, bevacizumab.

Mentions: Fig. 1 shows cell survival curves for the total cell population 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. Fig. 2 shows net MN frequencies as a function of irradiated absorbed dose with or without a 10B-carrier, in combination with nicotinamide or MTH, and in the presence or absence of bevacizumab in the total and Q tumor cell populations. The net MN frequency was the MN frequency in tumors that received irradiation minus the MN frequency in tumors that did not. Overall, the net MN frequencies were significantly smaller in Q cells than in the total cell population (P<0.05).


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)

Dose response curves of the net micronucleus frequency for (A) total and (B) quiescent cell populations from B16-BL6 tumors irradiated with reactor neutron beams following the administration of a 10B-carrier in combination with nicotinamide treatment, mild temperature hyperthermia (MTH) or bevacizumab treatment on day 18 following tumor cell inoculation. Open and solid symbols represent irradiation without and with bevacizumab, respectively. 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; BV, bevacizumab.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f2-etm-08-01-0291: Dose response curves of the net micronucleus frequency for (A) total and (B) quiescent cell populations from B16-BL6 tumors irradiated with reactor neutron beams following the administration of a 10B-carrier in combination with nicotinamide treatment, mild temperature hyperthermia (MTH) or bevacizumab treatment on day 18 following tumor cell inoculation. Open and solid symbols represent irradiation without and with bevacizumab, respectively. 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; BV, bevacizumab.
Mentions: Fig. 1 shows cell survival curves for the total cell population 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. Fig. 2 shows net MN frequencies as a function of irradiated absorbed dose with or without a 10B-carrier, in combination with nicotinamide or MTH, and in the presence or absence of bevacizumab in the total and Q tumor cell populations. The net MN frequency was the MN frequency in tumors that received irradiation minus the MN frequency in tumors that did not. Overall, the net MN frequencies were significantly smaller in Q cells than in the total cell population (P<0.05).

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