Radiobiological evidence suggesting heterogeneous microdistribution of boron compounds in tumors: Its relation to quiescent cell population and tumor cure in neutron capture therapy

Ono, Koji; Masunaga, Shin‐ichiro; Kinashi, Yuko; Takagaki, Masao; Akaboshi, Mitsuhiko; Kobayashi, Takao; Akuta, Keizo

doi:10.1016/0360-3016(95)02180-9

Cited by 93 publications

(80 citation statements)

References 7 publications

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“…Several mechanisms (differing blood supply, proliferating and metabolic activity, and expression of L-amino acid transporter at the cell membrane) might be responsible for this observation. A heterogeneous microdistribution of 10 B has already been postulated by Ono et al (37) from radiobiological experiments.…”

Section: Discussionmentioning

confidence: 59%

“…Due to the almost equal 10 B concentrations in tumor tissues and blood, BSH has not been considered as useful to deliver 10 B to peripheral tumors, at least not until the combined injection of BSH and BPA was proposed (37) to supposedly reach a more homogeneous 10 B distribution. Our results proved that injecting both compounds leads to a more homogenous 10 B distribution in the tumor while maintaining the tumor/ blood and tumor/healthy tissue ratios at an acceptable level.…”

Section: Discussionmentioning

confidence: 99%

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Laser postionization secondary neutral mass spectrometry in tissue: a powerful tool for elemental and molecular imaging in the development of targeted drugs

Wittig¹,

Arlinghaus

Kriegeskotte

et al. 2008

Molecular Cancer Therapeutics

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The exact intracellular localization and distribution of molecules and elements becomes increasingly important for the development of targeted therapies and contrast agents. We show that laser postionization secondary neutral mass spectrometry (laser-SNMS) is well suited to localize particular elements and small molecules with subcellular spatial resolution applying the technique exemplary to Boron Neutron Capture Therapy (BNCT). We showed in a murine sarcoma that the drugs used for clinical BNCT, namely L-para-boronophenylalanine (700 mg/kg body weight i.p.) and sodium mercaptoundecahydrocloso-dodecaborate (200 mg/kg body weight i.p.), transport the therapeutic agent 10 B into the cytoplasm and into the nucleus itself, the most sensitive area of the cell. Sodium mercaptoundecahydro-closo-dodecaborate distributes 10 B homogeneously and L-para-boronophenylalanine heterogeneously. When combining laser-SNMS with prompt ;-ray analysis as a screening technique, strategies for BNCT can be elaborated to develop new drugs or to improve the use of existing drugs on scientifically based evidence. The study shows the power of laser-SNMS in the early stages of drug development, also outside BNCT.

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Section: Discussionmentioning

confidence: 59%

Section: Discussionmentioning

confidence: 99%

Laser postionization secondary neutral mass spectrometry in tissue: a powerful tool for elemental and molecular imaging in the development of targeted drugs

Wittig¹,

Arlinghaus

Kriegeskotte

et al. 2008

Molecular Cancer Therapeutics

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“…Furthermore, it was presumed that, because of different mechanisms of targeting a coadministration of both compounds might lead to a higher amount of 10 Batoms in single tumor cells or to a more homogeneous 10 B-distribution in tumors. [25][26][27] Therefore, an infusion of both drugs together was foreseen in another 3 patients, if BSH and BPA had both a ''favorable'' uptake in the metastases. ''Favorable'' 10 Buptake was defined as follows:…”

Section: Methodsmentioning

confidence: 99%

Uptake of two ¹⁰B‐compounds in liver metastases of colorectal adenocarcinoma for extracorporeal irradiation with boron neutron capture therapy (EORTC Trial 11001)

Wittig

Malagó

Collette

et al. 2007

Intl Journal of Cancer

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Disseminated metastases of colorectal cancer in liver are incurable. The trial EORTC 11001 investigates whether autotransplantation after extracorporeal irradiation of the liver by boron neutron capture therapy (BNCT) might become a curative treatment option because of selective uptake of the compounds sodium mercaptoundecahydro-closo-dodecaborate (BSH) or L-para-boronophenylalanine (BPA). BSH (50 mg/kg bw) or BPA (100 mg/kg bw) were infused into patients who subsequently underwent resection of hepatic metastases. Blood and tissue samples were analyzed for the 10 B-concentration with prompt gamma ray spectroscopy (PGRS). Three patients received BSH and 3 received BPA. Adverse effects from the boron carriers did not occur. For BSH, the highest 10 B-concentration was observed in liver (31.5 6 2.7 lg/ g) followed by blood (24.8 6 4.7 lg/g) and tumor (23.2 6 2.1 lg/g) with a mean 10 B-concentration ratio metastasis/liver of 0.72 6 0.07. For BPA, the highest 10 B-concentration was measured in metastases (12.1 6 2.2 lg/g) followed by liver (8.5 6 0.5 lg/g) and blood (5.8 6 0.8 lg/g). As BPA is transported actively into cells, viable, metabolically active cells accumulate exclusively this compound. Consequently, a model is proposed to adjust the values measured by PGRS for the proportion of viable cells to express the relevant 10 B-concentration in the tumor cells, revealing a 10 Bconcentration ratio metastasis/liver of 6.8 6 1.7. In conclusion, BSH is not suitable as 10 B-carrier in liver metastases as the 10 Bconcentration in liver was higher compared to metastasis. BPA accumulates in hepatic metastases to an extent that allows for extracorporeal irradiation of the liver with BNCT. ' 2007 Wiley-Liss, Inc.

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“…A large body of literature has demonstrated a higher effectiveness of BPA compared with BSH in the BNCT of brain malignances (17,23,24). This might be explained by a different microdistribution and tumor incorporation of the two compounds (25)(26)(27)(28).…”

Section: Introductionmentioning

confidence: 99%

L-DOPA Preloading Increases the Uptake of Borophenylalanine in C6 Glioma Rat Model: A New Strategy to Improve BNCT Efficacy

Capuani

Gili

Bozzali

et al. 2008

International Journal of Radiation Oncology*Biology*Physics

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Purpose: Boron neutron capture therapy (BNCT) is a radiotherapeutic modality based on 10 B(n,a) 7 Li reaction, for the treatment of malignant gliomas. One of the main limitations for BNCT effectiveness is the insufficient intake of 10 B nuclei in the tumor cells. This work was aimed at investigating the use of L-DOPA as a putative enhancer for 10 B-drug 4-dihydroxy-borylphenylalanine (BPA) uptake in the C6-glioma model. The investigation was first performed in vitro and then extended to the animal model. Methods and Materials: BPA accumulation in C6-glioma cells was assessed using radiowave dielectric spectroscopy, with and without L-DOPA preloading. Two L-DOPA incubation times (2 and 4 hours) were investigated, and the corresponding effects on BPA accumulation were quantified. C6-glioma cells were also implanted in the brain of 32 rats, and tumor growth was monitored by magnetic resonance imaging. Rats were assigned to two experimental branches: (1) BPA administration; (2) BPA administration after pretreatment with L-DOPA. All animals were sacrificed, and assessments of BPA concentrations in tumor tissue, normal brain, and blood samples were performed using high-performance liquid chromatography. Results: L-DOPA preloading induced a massive increase of BPA concentration in C6-glioma cells only after a 4-hour incubation. In the animal model, L-DOPA pretreatment produced a significantly higher accumulation of BPA in tumor tissue but not in normal brain and blood samples. Conclusions: This study suggests the potential use of L-DOPA as enhancer for BPA accumulation in malignant gliomas eligible for BNCT. L-DOPA preloading effect is discussed in terms of membrane transport mechanisms. Ó

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Radiobiological evidence suggesting heterogeneous microdistribution of boron compounds in tumors: Its relation to quiescent cell population and tumor cure in neutron capture therapy

Cited by 93 publications

References 7 publications

Laser postionization secondary neutral mass spectrometry in tissue: a powerful tool for elemental and molecular imaging in the development of targeted drugs

Laser postionization secondary neutral mass spectrometry in tissue: a powerful tool for elemental and molecular imaging in the development of targeted drugs

Uptake of two ¹⁰B‐compounds in liver metastases of colorectal adenocarcinoma for extracorporeal irradiation with boron neutron capture therapy (EORTC Trial 11001)

L-DOPA Preloading Increases the Uptake of Borophenylalanine in C6 Glioma Rat Model: A New Strategy to Improve BNCT Efficacy

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Radiobiological evidence suggesting heterogeneous microdistribution of boron compounds in tumors: Its relation to quiescent cell population and tumor cure in neutron capture therapy

Cited by 93 publications

References 7 publications

Laser postionization secondary neutral mass spectrometry in tissue: a powerful tool for elemental and molecular imaging in the development of targeted drugs

Laser postionization secondary neutral mass spectrometry in tissue: a powerful tool for elemental and molecular imaging in the development of targeted drugs

Uptake of two 10B‐compounds in liver metastases of colorectal adenocarcinoma for extracorporeal irradiation with boron neutron capture therapy (EORTC Trial 11001)

L-DOPA Preloading Increases the Uptake of Borophenylalanine in C6 Glioma Rat Model: A New Strategy to Improve BNCT Efficacy

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Uptake of two ¹⁰B‐compounds in liver metastases of colorectal adenocarcinoma for extracorporeal irradiation with boron neutron capture therapy (EORTC Trial 11001)