Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The boron-containing melanin precursor analogue p-boronophenylalanine (BPA) has previously been shown to selectively deliver boron to pigmented murine melanomas when administered in a single intragastric dose. If boron neutron capture therapy is to become a clinically useful method of radiation therapy for human malignant melanoma, the boron carrier must be capable of delivering useful amounts of boron to remote tumor sites (metastases) and to poorly pigmented melanomas. We have now determined the ability of BPA to accumulate in several nonpigmented melanoma models including human melanoma xenografts in nude mice. The absolute amount of boron in the nonpigmented melanomas was about 50% of that observed in the pigmented counterparts but was still selectively concentrated in the tumor relative to normal tissues in amounts sufficient for effective neutron capture therapy. Single intragastric doses of BPA resulted in selective localization of boron in the amelanotic Greene melanoma carried in the anterior chamber of the rabbit eye and in a pigmented murine melanoma growing in the lungs. The ratio of the boron concentration in these tumors to the boron concentration in the immediately adjacent normal tissue was in the range of 3:1 to 4:1. These distribution studies support the proposal that boron neutron capture therapy may be useful as a regional therapy for malignant melanoma.
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PMID:Experimental boron neutron capture therapy for melanoma: systemic delivery of boron to melanotic and amelanotic melanoma. 210 31

The effective treatment depth in boron neutron capture therapy with thermal neutrons depends on the beam aperture, heavy water concentration, boron concentrations in the tumor, normal tissue and blood, tolerance dose to normal tissue and the capillary dose modification factor. In this study a 15 cm aperture is used and the tolerance dose to normal tissue is evaluated to be 15 Gy. Human pharmacokinetic data are evaluated for BSH and D, L-BPA, the two compounds currently used in thermal BNCT. Results show that the average measured tumor to blood boron ratios and standard deviations are 1.4 (0.4) for BSH and 4.3 (1.8) for subcutaneous melanoma. Experimental dose-depth phantom results for the Musashi Institute of Technology reactor are used with expected boron concentrations to calculate the maximum therapeutic depth in the brain for a thermal neutron beam. For BPA, the subcutaneous melanoma boron concentrations are assumed for intracranial metastases, and no allowance is made for possible enhanced uptake in the dopamine and noradrenaline tracts. Results for BSH are enhanced by inclusion of the capillary dose reduction factor. Calculations show that for expected boron tumor to blood ratios, the modified advantage depth is about 4 cm and the maximum therapeutic depth is about 1.5 cm for both BSH and BPA. Typical heavy water ratios of 15% increase the treatment depth by 0.5 cm, but this is offset by the use of smaller beam aperture in practice.
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PMID:Maximum therapeutic depth in thermal neutron capture therapy. 843 38

Fast neutron radiotherapy has proven to be an effective form of treatment in a selected subset of tumors (salivary gland tumors, sarcomas, and locally-advanced prostate cancer), but has not proven to be more beneficial than conventional photon irradiation for the majority of tumor types upon which it has been tested. Normal tissue tolerance limits preclude simply further escalating the neutron dose. Boron neutron capture (BNC) provides a way of selectively augmenting the radiation dose to the tumor. This process is described, and cell culture and animal model data reviewed. An irradiation configuration was developed where an enhancement of 2.10(-3) for 1 microgram of 10B per gram of tissue was achieved. This is similar to the enhancement achievable in the center of a 20 x 20 cm field envisioned for future applications such as metastases in the brain. A boron concentration of 50 micrograms per gram of tumor tissue leads to a 10% increase in the delivered physical dose in this scenario. The first human test of BNC enhancement of a fast neutron radiotherapy beam using pharmacologically-acceptable doses of orally-administered, 10B-enriched, L-paraboronophenylalanine is reported. An enhancement of tumor response was demonstrated for a melanoma skin nodule test system. Boron levels achieved in blood, skin, and tumors are presented. Future research plans are discussed.
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PMID:Fast neutron radiotherapy and boron neutron capture therapy: application to a human melanoma test system. 894 78

Centers in Japan and the United States are extending boron neutron capture therapy (BNCT) to the treatment of malignant melanoma (MM). Positron emission tomography (PET) has been used to image glioblastoma multiforme with 18F-boronophenylalanine (18F-BPA) for the purpose of generating 10B distribution maps. These distribution maps can be used to improve the BNCT treatment planning. 18F-BPA was given to a patient with widely metastatic MM involving the thorax and brain. 18F-BPA PET scans of the chest and the head were obtained and compared to the computed tomograms (CT) and magnetic resonance (MR) images. The lung metastases seen on the chest CT images and intracranial metastases seen on CT and MR images were correlated with the PET images. The PET images clearly identified a brain lesion that was difficult to identify on MR and CT images. The 18F-BPA lung and peri-oral mucous gland activity was intense indicating a relatively high concentration of BPA. The intensity seen in the peri-oral mucous glands is consistent with the experiences in the BNCT clinical trials. These results have implications in the use of BNCT outside of the cranium. The PET images allow the generation of treatment plans that are consistent with the clinical findings. PET imaging with 18F-BPA can be used to identify potential tumors that may be amenable to BNCT and to improve treatment plans prior to BNCT.
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PMID:The use of positron emission tomography to develop boron neutron capture therapy treatment plans for metastatic malignant melanoma. 1274 13

Bim is a BH3-only protein belonging to the Bcl-2 family of apoptotic regulators. Upon activation, Bim can antagonize all the prosurvival Bcl-2 proteins, leading to apoptosis. To investigate whether Bim plays a role in melanoma progression, we used tissue microarray and immunohistochemistry to measure Bim expression in 52 cases of dysplastic nevi, 159 cases of primary melanomas and 52 cases of melanoma metastases, and evaluated the prognostic value of Bim expression. Our results showed that Bim expression is reduced as melanoma progresses. Significant differences for Bim staining pattern were observed between dysplastic nevi and metastatic melanomas (P<0.001, chi2 test), and between primary melanomas and metastatic melanomas (P<0.001, chi2 test). Moreover, reduced Bim expression is significantly correlated with poor 5-year survival of melanoma patients but failed to be an independent prognostic factor by Cox regression analysis. Our data suggest that Bim loss may play an important role in melanoma progression.
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PMID:Bim expression is reduced in human cutaneous melanomas. 1763 19

In this review, we summarize current knowledge of the biological functions of the atypical BH3-only proteins BNIP3 and BNIP3L, focusing on the role of these proteins in cancer. Hypoxia increases the expression of BNIP3 through the transcription factor HIF-1, but despite a considerable number of investigations, it has proven difficult to establish a clear role for BNIP3 in the cellular hypoxic response. BNIP3 can induce a form of cell death that shows features of both necrosis and apoptosis, but unusually for a BH3-only protein, death occurs independently of the BH3 domain and is critically dependent on a C-terminal transmembrane domain, which also localizes the protein to the mitochondria. BNIP3 expression does not always result in cell death, suggesting that additional factors may suppress BNIP3 or cooperate with it to induce death. BNIP3 is highly expressed in some tumors, including those of the breast, lung and cervix. However, in colorectal and pancreatic cancers BNIP3 is frequently epigenetically silenced, possibly reflecting different functions for BNIP3 in different tissues. Recent reports have shown that BNIP3 can induce autophagy and there is some evidence to suggest this may represent an emerging role for BH3-only proteins in general. However, the mechanism through which BNIP3 induces autophagy and the cellular consequences of this are yet to be established.
Cancer Metastasis Rev 2007 Dec
PMID:The role of the hypoxia-inducible BH3-only proteins BNIP3 and BNIP3L in cancer. 1780 42

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 forthe (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 +/- 2.7 microg/g) followed by blood (24.8 +/- 4.7 microg/g) and tumor (23.2 +/- 2.1 microg/g) with a mean (10)B-concentration ratio metastasis/liver of 0.72 +/- 0.07. For BPA, the highest (10)B-concentration was measured in metastases (12.1 +/- 2.2 microg/g) followed by liver (8.5 +/- 0.5 microg/g) and blood (5.8 +/- 0.8 microg/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)B-concentration ratio metastasis/liver of 6.8 +/- 1.7. In conclusion, BSH is not suitable as (10)B-carrier in liver metastases as the (10)B-concentration 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.
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PMID:Uptake of two 10B-compounds in liver metastases of colorectal adenocarcinoma for extracorporeal irradiation with boron neutron capture therapy (EORTC Trial 11001). 1798 41

The selective uptake of boron by tumors compared to that by healthy tissue makes boron neutron capture therapy (BNCT) an extremely advantageous technique for the treatment of tumors that affect a whole vital organ. An example is represented by colon adenocarcinoma metastases invading the liver, often resulting in a fatal outcome, even if surgical resection of the primary tumor is successful. BNCT can be performed by irradiating the explanted organ in a suitable neutron field. In the thermal column of the Triga Mark II reactor at Pavia University, a facility was created for this purpose and used for the irradiation of explanted human livers. The neutron field distribution inside the organ was studied both experimentally and by means of the Monte Carlo N-particle transport code (MCNP). The liver was modeled as a spherical segment in MCNP and a hepatic-equivalent solution was used as an experimental phantom. In the as-built facility, the ratio between maximum and minimum flux values inside the phantom ((phi(max)/phi(min)) was 3.8; this value can be lowered to 2.3 by rotating the liver during the irradiation. In this study, the authors proposed a new facility configuration to achieve a uniform thermal neutron flux distribution in the liver. They showed that a phi(max)/phi(min) ratio of 1.4 could be obtained without the need for organ rotation. Flux distributions and dose volume histograms were reported for different graphite configurations.
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PMID:Thermal neutron irradiation field design for boron neutron capture therapy of human explanted liver. 1819 97

The ability to selectively hit the tumour cells is an essential characteristic of an anti-tumour therapy. In boron neutron capture therapy (BNCT) this characteristic is based on the selective uptake of (10)B in the tumour cells with respect to normal tissues. An important step in the BNCT planning is the measurement of the boron concentration in the tissue samples, both tumour and healthy. When the tumour is spread through the healthy tissue, as in the case of metastases, the knowledge of the different kinds of tissues in the sample being analysed is crucial. If the percentage of tumour and normal tissues cannot be evaluated, the obtained concentration is a mean value depending on the composition of the different samples being measured. In this case an imaging method that could give information both on the morphology and on the spatial distribution of boron concentration in the sample would be a fundamental support. In this paper, the results of the boron uptake analysis in the tumour and in the healthy samples taken from human livers after boron phenylalanine (BPA) infusion are shown; boron imaging was performed using neutron autoradiography.
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PMID:Neutron autoradiography imaging of selective boron uptake in human metastatic tumours. 1859

Ex-situ BNCT for multifocal unresectable liver metastases employing whole or partial autograft techniques requires knowledge of boron concentrations in healthy liver and metastases following perfusion and immersion in Wisconsin solution (W), the procedure employed for organ preservation during ex-situ irradiation. Measurements of boron concentration in blood, liver and metastases following an intravenous infusion of BPA-F in five colorectal liver metastases patients scheduled for surgery were performed. Tissue samples were evaluated for boron content pre and post perfusion and immersion in W. Complementary histological studies were performed. The data showed a dose-dependent BPA uptake in liver, a boron concentration ratio liver/blood close to 1 and a wide spread in the metastases/liver concentration ratios in the range 0.8-3.6, partially attributable to histological variations between samples. Based on the boron concentrations and dose considerations (liver < or =15 Gy-Eq and tumor> or =40 Gy-Eq) at the RA-3 thermal neutron facility (mean flux of about (6+/-1) x 10(9) n cm(-2)s(-1)), ex-situ treatment of liver metastases at RA-3 would be feasible.
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PMID:Boron biodistribution study in colorectal liver metastases patients in Argentina. 1937 31


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