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.

New algorithm to simulate organ movement and deformation for four-dimensional dose calculation based on a three-dimensional CT and fluoroscopy of the thorax.

PURPOSE: The aim of this study was to develop a 4D-modeling algorithm, designated "3D+," to simulate organ movement and deformation for 4D dose calculation without the need for 4D-CT or deformable image registration and to assess the validity of this algorithm. METHODS: This 3D+ algorithm virtually creates 4D-CT images by deforming static 3D-CT data according to a typical motion model and motion data at multiple observation points collected via fluoroscopy. A typical motion model intended for patients with lung tumors immobilized with a vacuum pillow inside a stereotactic body frame was constructed. The geometric accuracy of virtual 4D-CT images created using this 3D+ algorithm was evaluated in eight patients by comparing the simulated results with actual 4D-CT images in terms of visual assessment, landmark analysis, and comparison of the radial distance from the tumor centroid to the body or lung surface. RESULTS: The average accuracy for all patients, as determined via landmark analysis, was 2.8 +/- 1.8 mm, very similar to results obtained through 4D-CT and deformable image registrations. Error in the radial distance from the tumor centroid to the body or lung surface was generally within 1.0 or 2.0 mm, respectively, in virtual versus actual 4D-CT images. Therefore, it is assumed that these geometric errors would have only negligible effects on dose calculation. CONCLUSIONS: 4D modeling of the thorax utilizing the 3D+ algorithm shows acceptable accuracy and is more suited for routine clinical use in terms of processing time than conventional 4D-CT and deformable image registration. The 3D+ algorithm may be useful for simulating dose distribution for advanced beam delivery techniques, such as real-time tumor tracking irradiation and adaptive radiation therapy.

A simple and rapid method for measurement of (10)B-para-boronophenylalanine in the blood for boron neutron capture therapy using fluorescence spectrophotometry.

Background and Purpose; (10)B deriving from (10)B-para-boronophenylalanine (BPA) and (10)B-borocaptate sodium (BSH) have been detected in blood samples of patients undergoing boron neutron capture therapy (BNCT) using prompt gamma ray spectrometer or Inductively Coupled Plasma (ICP) method, respectively. However, the concentration of each compound cannot be ascertained because boron atoms in both molecules are the target in these assays. Here, we propose a simple and rapid method to measure only BPA by detecting fluorescence based on the characteristics of phenylalanine. Material and Methods; (10)B concentrations of blood samples from human or mice were estimated by the fluorescence intensities at 275 nm of a BPA excited by light of wavelength 257 nm using a fluorescence spectrophotometer. Results; The relationship between fluorescence to increased BPA concentration showed a positive linear correlation. Moreover, we established an adequate condition for BPA measurement in blood samples containing BPA, and the estimated (10)B concentrations of blood samples derived from BPA treated mice were similar between the values obtained by our method and those by ICP method. Conclusion; This new assay will be useful to estimate BPA concentration in blood samples obtained from patients undergoing BNCT especially in a combination use of BSH and BPA.

Boron neutron capture therapy for newly diagnosed glioblastoma.

We evaluate the clinical results of a form of tumor selective particle radiation known as boron neutron capture therapy (BNCT) for newly-diagnosed glioblastoma (NDGB) patients, especially in combination with X-ray treatment (XRT). Between 2002 and 2006, we treated 21 patients of NDGB with BNCT utilizing sodium borocaptate and boronophenylalanine simultaneously. The first 10 were treated with only BNCT (protocol 1), and the last 11 were treated with BNCT followed by XRT of 20 to 30 Gy (protocol 2) to reduce the possibility of local tumor recurrence. No chemotherapy was applied until tumor progression was observed. The patients treated with BNCT (protocol 1 plus 2) showed a significant survival prolongation compared with the institutional historical controls. BNCT also showed favorable results in correspondence with the RTOG- and EORTC-RPA subclasses. The median survival time (MST) was 15.6 months for protocols 1 and 2 together. For protocol 2, the MST was 23.5 months. The main causes of death were cerebrospinal fluid dissemination as well as local recurrence. Our modified BNCT protocol showed favorable results of patients with NDGB not only for those with good prognoses but also for those with poor prognoses.

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.

Effect of a change in reactor power on response of murine solid tumors in vivo, referring to impact on quiescent tumor cell population.

PURPOSE: To examine the effect of a change in reactor power on the response of solid tumors, referring to impact on quiescent (Q) tumor cell population. MATERIALS AND METHODS: Tumor-bearing mice received 5-bromo-2'-deoxyuridine (BrdU) to label all proliferating (P) tumor cells, and were treated with boronophenylalanine-10B (BPA) or sodium mercaptododecaborate-10B (BSH). After reactor neutron beam irradiation at a power of 1 or 5 MW with an identical beam spectrum, cells from tumors were isolated and incubated with a cytokinesis blocker. The responses of BrdU-unlabeled Q and total (P + Q) tumor cells were assessed based on the frequencies of micronucleation using immunofluorescence staining for BrdU. RESULTS: After neutron irradiation with or without 10B-carrier, radio-sensitivity was reduced by decreasing reactor power in both cells, especially in Q cells and after irradiation with BPA. The values of relative and compound biological effectiveness were larger at a power of 5 MW and in Q cells than at a power of 1 MW and in total cells, respectively. The sensitivity difference between total and Q cells was widened when combined with 10B-carrier, especially with BPA, and through decreasing reactor power. CONCLUSION: 5 MW is more advantageous than 1 MW for boron neutron capture therapy.

Radiobiologic significance of response of intratumor quiescent cells in vivo to accelerated carbon ion beams compared with gamma-rays and reactor neutron beams.

PURPOSE: To clarify the radiosensitivity of intratumor quiescent cells in vivo to accelerated carbon ion beams and reactor neutron beams. METHODS AND MATERIALS: Squamous cell carcinoma VII tumor-bearing mice were continuously given 5-bromo-2'-deoxyuridine to label all intratumor proliferating cells. Next, they received accelerated carbon ion or gamma-ray high-dose-rate (HDR) or reduced-dose-rate (RDR) irradiation. Other tumor-bearing mice received reactor thermal or epithermal neutrons with RDR irradiation. Immediately after HDR and RDR irradiation or 12 h after HDR irradiation, the response of quiescent cells was assessed in terms of the micronucleus frequency using immunofluorescence staining for 5-bromo-2'-deoxyuridine. The response of the total (proliferating plus quiescent) tumor cells was determined from the 5-bromo-2'-deoxyuridine nontreated tumors. RESULTS: The difference in radiosensitivity between the total and quiescent cell populations after gamma-ray irradiation was markedly reduced with reactor neutron beams or accelerated carbon ion beams, especially with a greater linear energy transfer (LET) value. Clearer repair in quiescent cells than in total cells through delayed assay or a decrease in the dose rate with gamma-ray irradiation was efficiently inhibited with carbon ion beams, especially with a greater LET. With RDR irradiation, the radiosensitivity to accelerated carbon ion beams with a greater LET was almost similar to that to reactor thermal and epithermal neutron beams. CONCLUSION: In terms of tumor cell-killing effect as a whole, including quiescent cells, accelerated carbon ion beams, especially with greater LET values, are very useful for suppressing the dependency on the heterogeneity within solid tumors, as well as depositing the radiation dose precisely.

A novel concept of treatment of diffuse or multiple pleural tumors by boron neutron capture therapy (BNCT).

Two patients, one with malignant pleural mesothelioma and one with a malignant short spindle cell tumor, received boron neutron capture therapy (BNCT). In each case, the tumors regressed or remained stable in size for 3-6 months following BNCT. No acute or late adverse events higher than grade 2 were observed.

Japanese study to organize proper lifestyle modifications for metabolic syndrome (J-STOP-MetS): design and method.

Prevalence of the metabolic syndrome is now a very serious health problem in Japan and a public preventive strategy is essential to reduce morbidity. A systematic interventional strategy for the metabolic syndrome remains to be established. In order to address this issue, a multi-center study; Japanese Study to Organize Proper lifestyle modification for the metabolic syndrome (J-STOP-MetS), has been established by nine preventive medical centers among Rosai hospital groups. This study comprises a cross-sectional study (J-STOP-MetS 1) and a prospective randomized control study (J-STOP-MetS 2). J-STOP-MetS 1 examines the causes of the metabolic syndrome by means of a questionnaire in a large cohort of patients with the metabolic syndrome and control subjects matched for age and sex. J-STOP-MetS 2 examines the hypothesis that guidance on lifestyle modifications will help at risk patients to reduce abdominal fat and cardiovascular risk factors. The metabolic syndrome patients are randomly assigned either to a single visit to a guidance group or multiple visits every two months. The individualized guidance is provided by the coordination of physician, trained nurse, dietician and exercise trainer. Several parameters are measured before and six months after the first guidance session, including, body weight, waist circumference, blood pressure, several blood markers and arterial stiffness. The J-STOP-MetS is the first large-scale clinical study of the metabolic syndrome in Japan and should provide important evidence for the practical management of the metabolic syndrome.

Waveform simulation based on 3D dose distribution for acoustic wave generated by proton beam irradiation.

A pulsed proton beam is capable of generating an acoustic wave when it is absorbed by a medium. This phenomenon suggests that the acoustic waveform produced may well include information on the three-dimensional (3D) dose distribution of the proton beam. We simulated acoustic waveforms by using a transmission model based on the Green function and the 3D dose distribution. There was reasonable agreement between the calculated and measured results. The results obtained confirm that the acoustic waveform includes information on the dose distribution.

Boron neuron capture therapy using epithermal neutrons for recurrent cancer in the oral cavity and cervical lymph node metastasis.

The purpose of this clinical trial was to evaluate the utility of boron neutron capture therapy (BNCT) using epithermal neutrons for cases of recurrent cancer in the oral cavity, which are not indicated for a conventional treatment modality. We enrolled four patients with local recurrence or metastasis to the regional lymph nodes after completion of initial treatments, including surgery, chemotherapy and radiotherapy. Before receiving BNCT, patients underwent 18F-p-bononophenylalanine (BPA) positron emission tomography (PET) examinations to assess the BPA accumulation ratios in tumors and normal tissues. All patients showed at least a tentative partial response, while a marked improvement in quality of life was seen in one patient. Before BNCT, that patient could not be discharged from the hospital because of eating difficulties and malaise; after treatment, he was comfortably discharged. Mild malaise, oral mucositis and alopecia were seen as mild adverse effects; however, no life-threatening systemic symptoms were observed in any of the cases. Our results suggested that BNCT is a useful treatment modality for recurrent or regionally metastasized oral cancer.

Liver disease in hepatitis C virus carriers identified at blood donation and their outcomes with or without interferon treatment: Study on 1019 carriers followed for 5-10 years.

AIM: To portray liver disease and project outcomes in carriers of hepatitis C virus (HCV) in the general population. METHODS: Liver disease was evaluated in 1019 individuals who were found with HCV infection at blood donation, and they were followed for 5-10 years with or without receiving interferon (IFN). RESULTS: At baseline, chronic hepatitis was detected in 529 (51.9%) HCV carriers and more frequently in men than in women (62.6% [299/478]vs 42.5% [230/541], P < 0.01); cirrhosis was diagnosed in five (0.5% [three men included]) and hepatocellular carcinoma (HCC) in one (0.1% [man]). Of the carriers who were followed for 5 years or longer, loss of HCV-RNA from serum was achieved in 61 (31.0%) of the 197 treated with interferon (IFN) and only one of the 211 (0.5%) without IFN (P < 0.0001). HCC developed in 14 carriers including six ofthe 211 (2.8%) without IFN and eight of the 197 (4.1%) with IFN (six non-responders included). Follow ups of the 949 carriers identified age (P < 0.002), male gender (P < 0.01) and cirrhosis at the baseline (P < 0.0001) as factors contributing to the development of HCC. Cumulative incidence rates of HCC during 10 years among carriers found with chronic hepatitis increased in parallel with the age at the baseline. CONCLUSION: Identification of HCV carriers in the general population and treating those indicated with IFN would help decrease the development of HCC and lift its medical, as well as economic, burdens off society.

First attempt of boron neutron capture therapy (BNCT) for hepatocellular carcinoma.

A 60-year-old man with multiple hepatocellular carcinomas (HCCs) was enrolled as the first patient in a pilot study for treating multiple liver tumors with boron neutron capture therapy (BNCT). Because of compromised liver function, the multiple tumors in the right liver lobe were treated with BNCT and those in the left lobe with hepatic arterial chemoembolization. The feasibility and clinical outcome of this first case was assessed. During the treatment and follow-up period, no adverse effect as a result of BNCT was observed except for temporary temperature elevation to 38.3 degrees C, and the AST and ALT being higher than 200 IU/l. For 1 month, the tumors treated with BNCT remained stable in size. The BNCT-treated tumors showed regrowth 3.5 months after BNCT and the patient died of liver dysfunction caused by progression of HCC 10 months after BNCT. The feasibility of BNCT for HCC is confirmed in this first case.

A preliminary experimental study of boron neutron capture therapy for malignant tumors spreading in thoracic cavity.

BACKGROUND: The purpose of the present study is to verify the treatment effects of boron neutron capture therapy (BNCT) in ectopic tumors implanted in the thoracic cavity mimicking malignant pleural mesothelioma (MPM). METHODS: The tumor model was created by implanting murine squamous cell carcinoma cells into the thoracic cavity. Mice were sorted into four groups: group I for non-treatment; group II for neutron irradiation; group III for gamma-ray irradiation; and group IV for BNCT irradiation. The antitumor effect was evaluated on the basis of the change in survival time. To assess the effects of BNCT on normal lung, non-tumor bearing mice were treated using the same method as done to the tumor-burdened mice. RESULTS: The BNCT group had a longer survival time of 31 days (range 5 - 60), which was significantly longer than that of the non-treated control group (P = 0.011), but not significantly different from that of the neutron and gamma-ray groups (P = 0.067 and 0.094, respectively). In the BNCT and neutron groups, incidence of minimal lung fibrosis was significantly higher compared with the non-treated control group (P = 0.003 and 0.04, respectively). CONCLUSIONS: BNCT is a potentially promising treatment for malignant tumors spreading in the thoracic cavity such as MPM.

Effect of Tirapazamine, Metformin or Mild Hyperthermia on Recovery From Radiation-Induced Damage in Pimonidazole-Unlabeled Quiescent Tumor Cells.

BACKGROUND: The aim of the study was to examine the effect of tirapazamine (TPZ) on recovery from radiation-induced damage in pimonidazole-unlabeled quiescent (Q) tumor cells compared with that of metformin (Met) or mild temperature hyperthermia (MTH). METHODS: Proliferating (P) cells in EL4 tumors were labeled by continuous 5-bromo-2'-deoxyuridine (BrdU) administration. Tumors received γ-rays at 1 h after pimonidazole administration followed by Met or TPZ treatment or MTH. Twenty-four hours later, the responses of Q and total (P + Q) cells and those of the pimonidazole-unlabeled cells were assessed with micronucleation and apoptosis frequencies using immunofluorescence staining for BrdU and apoptosis frequency using immunofluorescence staining for pimonidazole, respectively. RESULTS: With γ-rays only, the pimonidazole-unlabeled cell fraction showed significantly enhanced radio-sensitivity compared with the whole cell fraction more remarkably in Q than total cells. However, a significantly greater decrease in radio-sensitivity in the pimonidazole-unlabeled than the whole cell fraction, evaluated using a delayed assay, was more clearly observed in Q than total cells. Post-irradiation MTH or Met treatment more clearly repressed the decrease in radio-sensitivity in the Q than total cells. Post-irradiation TPZ administration produced a large radio-sensitizing effect on both total and Q cells, especially on Q cells. In pimonidazole-unlabeled cell fractions in both total and Q cells, TPZ suppressed the reduction in sensitivity much more efficiently than MTH or Met without any radio-sensitizing effect. CONCLUSION: Post-irradiation TPZ administration has the potential to both suppress recovery from radiation-induced damage and enhance the radio-sensitivity both in total and Q tumor cells. Post-irradiation TPZ administration may be useful for controlling tumors.

Feasibility of boron neutron capture therapy (BNCT) for malignant pleural mesothelioma from a viewpoint of dose distribution analysis.

PURPOSE: To investigate the feasibility of boron neutron capture therapy (BNCT) for malignant pleural mesothelioma (MPM) from a viewpoint of dose distribution analysis using Simulation Environment for Radiotherapy Applications (SERA), a currently available BNCT treatment planning system. METHODS AND MATERIALS: The BNCT treatment plans were constructed for 3 patients with MPM using the SERA system, with 2 opposed anterior-posterior beams. The (10)B concentrations in the tumor and normal lung in this study were assumed to be 84 and 24 ppm, respectively, and were derived from data observed in clinical trials. The maximum, mean, and minimum doses to the tumors and the normal lung were assessed for each plan. The doses delivered to 5% and 95% of the tumor volume, D(05) and D(95), were adopted as the representative dose for the maximum and minimum dose, respectively. RESULTS: When the D(05) to the normal ipsilateral lung was 5 Gy-Eq, the D(95) and mean doses delivered to the normal lung were 2.2-3.6 and 3.5-4.2 Gy-Eq, respectively. The mean doses delivered to the tumors were 22.4-27.2 Gy-Eq. The D(05) and D(95) doses to the tumors were 9.6-15.0 and 31.5-39.5 Gy-Eq, respectively. CONCLUSIONS: From a viewpoint of the dose-distribution analysis, BNCT has the possibility to be a promising treatment for MPM patients who are inoperable because of age and other medical illnesses.

Impact of intra-arterial administration of boron compounds on dose-volume histograms in boron neutron capture therapy for recurrent head-and-neck tumors.

PURPOSE: To analyze the dose-volume histogram (DVH) of head-and-neck tumors treated with boron neutron capture therapy (BNCT) and to determine the advantage of the intra-arterial (IA) route over the intravenous (IV) route as a drug delivery system for BNCT. METHODS AND MATERIALS: Fifteen BNCTs for 12 patients with recurrent head-and-neck tumors were included in the present study. Eight irradiations were done after IV administration of boronophenylalanine and seven after IA administration. The maximal, mean, and minimal doses given to the gross tumor volume were assessed using a BNCT planning system. RESULTS: The results are reported as median values with the interquartile range. In the IA group, the maximal, mean, and minimal dose given to the gross tumor volume was 68.7 Gy-Eq (range, 38.8-79.9), 45.0 Gy-Eq (range, 25.1-51.0), and 13.8 Gy-Eq (range, 4.8-25.3), respectively. In the IV group, the maximal, mean, and minimal dose given to the gross tumor volume was 24.2 Gy-Eq (range, 21.5-29.9), 16.4 Gy-Eq (range, 14.5-20.2), and 7.8 Gy-Eq (range, 6.8-9.5), respectively. Within 1-3 months after BNCT, the responses were assessed. Of the 6 patients in the IV group, 2 had a partial response, 3 no change, and 1 had progressive disease. Of 4 patients in the IA group, 1 achieved a complete response and 3 a partial response. CONCLUSION: Intra-arterial administration of boronophenylalanine is a promising drug delivery system for head-and-neck BNCT.

The potential of transferrin-pendant-type polyethyleneglycol liposomes encapsulating decahydrodecaborate-(10)B (GB-10) as (10)B-carriers for boron neutron capture therapy.

PURPOSE: To evaluate GB-10-encapsulating transferrin (TF)-pendant-type polyethyleneglycol (PEG) liposomes as tumor-targeting (10)B-carriers for boron neutron capture therapy. METHODS AND MATERIALS: A free mercaptoundecahydrododecaborate-(10)B (BSH) or decahydrodecaborate-(10)B (GB-10) solution, bare liposomes, PEG liposomes, or TF-PEG liposomes were injected into SCC VII tumor-bearing mice, and (10)B concentrations in the tumors and normal tissues were measured by gamma-ray spectrometry. Meanwhile, tumor-bearing mice were continuously given 5-bromo-2'-deoxyuridine (BrdU) to label all intratumor proliferating cells, then injected with these (10)B-carriers containing BSH or GB-10 in the same manner. Right after thermal neutron irradiation, the response of quiescent (Q) cells was assessed in terms of the micronucleus frequency using immunofluorescence staining for BrdU. The frequency in the total tumor cells was determined from the BrdU nontreated tumors. RESULTS: Transferrin-PEG liposomes showed a prolonged retention in blood circulation, low uptake by reticuloendothelial system, and the most enhanced accumulation of (10)B in solid tumors. In general, the enhancing effects were significantly greater in total cells than Q cells. In both cells, the enhancing effects of GB-10-containing (10)B-carriers were significantly greater than BSH-containing (10)B-carriers, whether loaded in free solution or liposomes. In both cells, whether BSH or GB-10 was employed, the greatest enhancing effect was observed with TF-PEG liposomes followed in decreasing order by PEG liposomes, bare liposomes, and free BSH or GB-10 solution. In Q cells, the decrease was remarkable between PEG and bare liposomes. CONCLUSIONS: In terms of biodistribution characteristics and tumor cell-killing effect as a whole, including Q cells, GB-10 TF-PEG liposomes were regarded as promising (10)B-carriers.

Improvement effect on the depth-dose distribution by CSF drainage and air infusion of a tumour-removed cavity in boron neutron capture therapy for malignant brain tumours.

Boron neutron capture therapy (BNCT) without craniotomy for malignant brain tumours was started using an epi-thermal neutron beam at the Kyoto University Reactor in June 2002. We have tried some techniques to overcome the treatable-depth limit in BNCT. One of the effective techniques is void formation utilizing a tumour-removed cavity. The tumorous part is removed by craniotomy about 1 week before a BNCT treatment in our protocol. Just before the BNCT irradiation, the cerebro-spinal fluid (CSF) in the tumour-removed cavity is drained out, air is infused to the cavity and then the void is made. This void improves the neutron penetration, and the thermal neutron flux at depth increases. The phantom experiments and survey simulations modelling the CSF drainage and air infusion of the tumour-removed cavity were performed for the size and shape of the void. The advantage of the CSF drainage and air infusion is confirmed for the improvement in the depth-dose distribution. From the parametric surveys, it was confirmed that the cavity volume had good correlation with the improvement effect, and the larger effect was expected as the cavity volume was larger.

Evaluation of hypoxia-specific cytotoxic bioreductive agent-sodium borocaptate-10B conjugates as 10B-carriers in boron neutron capture therapy.

PURPOSE: To evaluate the usefulness of 5 new 10B-compounds (TX-2091, TX-2095, TX-2097, TX-2100, and TX-2110) as 10B-carriers in boron neutron capture therpy (BNCT). They were conjugates that had been synthesized from a hypoxia-specific cytotoxic bioreductive agent, quinoxaline oxide TX-402, and a clinically used 10B-carrier, sodium borocaptate-10B (BSH). MATERIALS AND METHODS: The 5 new compounds were hybrid compounds that have both a hypoxic cytotoxin unit and a thermal neutron-sensitizing unit, BSH. These new compounds and BSH were administered intraperitoneally to SCC VII tumor-bearing mice. Then, the 10B concentrations in the tumors and normal tissues were measured by gamma-ray spectrometry. Subsequently, SCC VII tumor-bearing mice were continuously given 5-bromo-2'-deoxyuridine (BrdU) to label all proliferating (P) cells in the tumors, then treated with TX-2100, which was chosen based on the results of the above-mentioned biodistribution analyses, or BSH in the same manner as in the biodistribution studies. Right after irradiation, during which intratumor 10B concentrations were kept at levels similar to each other, the tumors were excised, minced, and trypsinized. The tumor cell suspensions thus obtained were incubated with cytochalasin-B (a cytokinesis blocker), and the micronucleus (MN) frequency in cells without BrdU labeling [= quiescent (Q) cells] was determined using immunofluorescence staining for BrdU. Meanwhile, the MN frequency in the total (P+Q) tumor cell population was determined from the tumors that were not pretreated with BrdU. Clonogenic cell survival was also determined in mice given no BrdU. RESULTS: 10B biodistribution analyses in tumors, brain, skin, muscles, blood, and liver indicated that TX-2100 has the most favorable characteristics for concentrating a sufficient amount of 10B in tumors and maintaining a high enough 10B concentration during irradiation. In addition, TX-2100 had a significantly stronger radio-sensitizing effect with reactor thermal neutron beams than BSH on both total and Q cells in solid tumors. Further, TX-2100 clearly exhibited a radio-sensitizing effect with gamma-rays not only on total cells but also on Q and hypoxic tumor cells, which was not achieved by BSH. CONCLUSION: A 10B-carrier that acts as a hypoxic cytotoxin on tumor cells as well as having the potential to keep 10B in tumors and sensitize tumor cells more markedly than conventional 10B-carriers, such as TX-2100, is a promising candidate for use in BNCT.