Usefulness of combination with both continuous administration of hypoxic cytotoxin and mild temperature hyperthermia in boron neutron capture therapy in terms of local tumor response and lung metastatic potential.

Purpose: To evaluate the usefulness of combined treatment with both continuous administration of a hypoxic cytotoxin, tirapazamine (TPZ) and mild temperature hyperthermia (MTH) in boron neutron capture therapy (BNCT) in terms of local tumor response and lung metastatic potential, referring to the response of intratumor quiescent (Q) 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. The tumors received reactor thermal neutron beam irradiation following the administration of a 10B-carrier (L-para-boronophenylalanine-10B (BPA) or sodium mercaptoundecahydrododecaborate-10B (BSH)) after single intraperitoneal injection of an acute hypoxia-releasing agent (nicotinamide), MTH (40 °C for 60 min), and 24-h continuous subcutaneous infusion of TPZ or combined treatment with both TPZ and MTH. Immediately after irradiation, cells from some tumors were isolated and incubated with a cytokinesis blocker. The responses of the Q and total (=P + Q) tumor 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: 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 a 10B-carrier, combination with continuously administered TPZ with or without MTH enhanced the sensitivity of the both total and Q cells, especially Q cells. Even without irradiation, nicotinamide treatment decreased the number of lung metastases. With irradiation, BPA-BNCT, especially in combination with combined treatment with both TPZ and MTH as well as nicotinamide treatment, showed the potential to reduce the number more than BSH-BNCT.Conclusion: BSH-BNCT combined with TPZ with or without MTH improved local tumor control, while BPA-BNCT in combination with both TPZ and MTH as well as nicotinamide is thought to reduce the number of lung metastases. It was elucidated that control of the chronic hypoxia-rich Q cell population in the primary solid tumor has the potential to impact the control of local tumors as a whole and that control of the acute hypoxia-rich total tumor cell population in the primary solid tumor has the potential to impact the control of lung metastases.

Usefulness of combined treatment with continuous administration of tirapazamine and mild temperature hyperthermia in γ-ray irradiation in terms of local tumour response and lung metastatic potential.

PURPOSE: To evaluate the usefulness of combined treatment with continuous administration of a hypoxic cytotoxin, tirapazamine (TPZ), and mild temperature hyperthermia (MTH) in γ-ray irradiation in terms of local tumour response and lung metastatic potential, referring to the response of intratumour quiescent (Q) cells. MATERIALS AND METHODS: B16-BL6 melanoma tumour-bearing C57BL/6 mice were continuously given 5-bromo-2'-deoxyuridine (BrdU) to label all proliferating (P) cells. The tumour-bearing mice then received γ-ray irradiation after a single intraperitoneal injection or 24 h continuous subcutaneous infusion of TPZ, either with or without MTH. Immediately after the irradiation, cells from some tumours were isolated and incubated with a cytokinesis blocker. The responses of the Q and total (= P + Q) cell populations were assessed based on the frequency of micronuclei using immunofluorescence staining for BrdU. In other tumour-bearing mice, 17 days after irradiation, macroscopic lung metastases were enumerated. RESULTS: Continuous administration elevated the sensitivity of both the total and Q cells, especially the total cells. MTH raised the sensitivity of Q cells more remarkably in both single and continuous administrations, probably because of more exposure to TPZ in intermediately hypoxic areas derived mainly from chronic hypoxia through MTH. With or without irradiation, TPZ, especially administered continuously and combined with MTH, decreased the number of lung metastases. CONCLUSION: The combination of continuous long-term administration of TPZ and MTH in γ-ray irradiation was thought to be promising because of its potential to enhance local tumour response and repress lung metastatic potential.

The usefulness of mild temperature hyperthermia combined with a newly developed hypoxia-oriented 10B conjugate compound, TX-2100, for boron neutron capture therapy.

PURPOSE: To evaluate the usefulness of a new 10B-compound (TX-2100) as a 10B-carrier in boron neutron capture therapy (BNCT), compared with the simultaneous use of its component drugs, sodium borocapate-10B (BSH) and 3-amino-2-quinoxalinecarbonitrile 1,4-dioxide (TX-402). Further, the usefulness of mild temperature hyperthermia (MTH, 40 degrees Celsius, 30 min) combined with TX-2100 was also examined compared with MTH combined with the concurrent administration with its component drugs. MATERIALS AND METHODS: TX-2100 is a hybrid compound that has both a hypoxic cytotoxin unit (TX-402) and a thermal neutron-sensitizing unit (BSH). TX-2100 or both TX-402 plus BSH in combination with MTH or not was administered to SCC VII tumour-bearing mice intra-peritoneally. Then, the 10B concentrations in the tumours and normal tissues were measured by gamma-ray spectrometry. Meanwhile, SCC VII tumour-bearing mice were continuously given 5-bromo-2'-deoxyuridine (BrdU) to label all proliferating (P) cells in the tumours, then treated with TX-2100, TX-402 plus BSH or BSH only, in the same manner as in the biodistribution experiments, either with or without MTH. Right after thermal neutron irradiation during which intra-tumour 10B concentrations remained at similar levels, the tumours were excised, minced and trypsinized. The tumour cell suspensions thus obtained were incubated with cytochalasin-B (a cytokinesis blocker) and the micronucleus (MN) frequency in cells without BrdU labelling (=quiescent (Q) cells) was determined using immunofluorescence staining for BrdU. Meanwhile, the MN frequency in the total (P + Q) tumour cell population was determined from the tumours that were not pre-treated with BrdU. The clonogenic cell survival was also determined in mice given no BrdU. RESULTS: 10B biodistribution analyses in tumours, brain, skin, muscles, blood and liver indicated that the administration of TX-2100 plus MTH is most favourable for concentrating a sufficient amount of 10B in tumours and maintaining a high enough 10B concentration during irradiation. In addition, MTH had a stronger sensitizing effect when combined with TX-2100 than with the concurrent administration of its components TX-402 and BSH on both the total and Q cell populations in solid tumours. CONCLUSION: MTH was very effective in combination with the newly-developed TX-2100. The sensitizing effect in combination with MTH should be examined when new 10B-carriers are designed.

Biodistribution of 10B in a rat liver tumor model following intra-arterial administration of sodium borocaptate (BSH)/degradable starch microspheres (DSM) emulsion.

We reported that intra-arterial administration of borocaptate sodium (BSH)/lipiodol emulsion provided selectively high (10)B concentrations (approximately 200 ppm 6 h after administration) in experimental liver tumors. In the present study, we investigated the pharmacokinetics of BSH following intra-arterial administration of BSH with other embolizing agent, degradable starch microspheres (DSM). The (10)B concentration in the tumor at 1 h after administration of BSH with DSM was 231 ppm. At 6 h, the (10)B concentration in the tumor in BSH with DSM group was 81.5 ppm. The (10)B concentration in the liver at 1 h after administration of BSH with DSM was 184 ppm. At 6 h, the(10)B concentration in the liver in BSH with DSM group was 78 ppm. The tumor/liver (10)B concentration ratios (T/L ratio) in the "BSH+DSM" group were significantly smaller than those in the "BSH+lipiodol" group at 1 h (1.4 vs. 3.6) and 6h (1.1 vs. 14.9). BSH/DSM-boron neutron capture therapy (BNCT) was not suitable for treatment of multiple liver tumors due to the low T/L (10)B concentration ratio. However, the high (10)B accumulation in the liver tumors following intra-arterial administration of BSH/DSM emulsion suggests that BSH/DSM-BNCT has the potential for application to malignant tumors in other sites.

Intra-arterial administration of sodium borocaptate (BSH)/lipiodol emulsion delivers B-10 to liver tumors highly selectively for boron neutron capture therapy: experimental studies in the rat liver model.

PURPOSE: Boron neutron capture therapy (BNCT) is particle radiotherapy with alpha ((4)He) particle and recoiled lithium nucleus ((7)Li) derived from a reaction of boron ((10)B) and thermal neutron. We investigated applying BNCT to malignant liver tumors. The purpose of the present study was to reveal the efficacy for administration of emulsion of a boron compound (sodium borocaptate; BSH) and lipiodol via a hepatic artery using a rat liver tumor model. METHODS AND MATERIALS: Rat liver tumors were developed by direct injection of Walker 256 cells into the liver parenchyma. BSH (75 mg/kg)/lipiodol (0.3 mL/kg) emulsion was administered via the hepatic artery. Boron concentrations in the tumors, liver, and blood were measured at 1, 6, and 12 h after administration. Neutron capture radiography (NCR) was taken to confirm the selective accumulation of (10)B in the liver tumors. RESULTS: Boron concentrations in the liver tumors and the tumor/liver (T/L) boron concentration ratio at 1, 6, and 12 h after administration of BSH/lipiodol emulsion (concentration: T/L ratio) were 479.2 ppm: 4.0, 197.3 ppm: 14.9, and 96.5 ppm: 6.6, respectively. Highly selective irradiation was clearly demonstrated by the NCR images. CONCLUSIONS: Intra-arterial administration of BSH/lipiodol emulsion is effective method for delivering high concentration of (10)B selectively to the liver tumors.