Quantitative subcellular imaging of boron compounds in individual mitotic and interphase human glioblastoma cells with imaging secondary ion mass spectrometry (SIMS)

Chandra, Subhash; Tjarks, Werner; Lorey, Daniel R.; Barth, Rolf F.

doi:10.1111/j.1365-2818.2007.01869.x

Cited by 44 publications

(36 citation statements)

References 48 publications

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“…On the other hand, the subcellular localization of 3 CTAs after in vivo administration may prove to be a significant advantage in their future development as boron delivery agents. Using the technique of secondary ion mass spectrometry (SIMS), it has been demonstrated that another 3CTA, designated N4 (14,15), was distributed throughout interphase and mitotic T9 glioma cells, including their chromosomes (23). The latter observation suggests that it possibly was incorporated into DNA.…”

Section: Discussionmentioning

confidence: 99%

Thymidine kinase 1 as a molecular target for boron neutron capture therapy of brain tumors

Barth¹,

Yang²,

Wu³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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The purpose of the present study was to evaluate the effectiveness of a 3-carboranyl thymidine analogue (3CTA), 3-[5-{2-(2,3-dihydroxyprop-1-yl)-o-carboran-1-yl}pentan-1-yl] thymidine, designated N5-2OH, for boron neutron capture therapy (BNCT) of brain tumors using the RG2 rat glioma model. Target validation was established using the thymidine kinase (TK) 1(؉) wild-type, murine L929 cell line and its TK1(؊) mutant counterpart, which were implanted s.c. (s.c.) into nude mice. Two intratumoral (i.t.) injections of 10 B-enriched N5-2OH were administered to tumor-bearing mice at 2-hour intervals, after which BNCT was carried out at the Massachusetts Institute of Technology (MIT) Research Reactor. Thirty days after BNCT, mice bearing TK1(؉) L929 tumors had a 15؋ reduction in tumor volume compared with TK1(؊) controls. Based on these favorable results, BNCT studies were then initiated in rats bearing intracerebral (i.c.) RG2 gliomas, after i.c. administration of N5-2OH by Alzet osmotic pumps, either alone or in combination with i.v. (i.v.) boronophenylalanine (BPA), a drug that has been used clinically. The mean survival times (MSTs) of RG2 glioma bearing rats were 45.6 ؎ 7.2 days, 35.0 ؎ 3.3days, and 52.9 ؎ 8.9 days, respectively, for animals that received N5-2OH, BPA, or both. The differences between the survival plots of rats that received N5-2OH and BPA alone were highly significant (P ‫؍‬ 0.0003). These data provide proof-of-principle that a 3CTA can function as a boron delivery agent for NCT. Further studies are planned to design and synthesize 3CTAs with enhanced chemical and biological properties, and increased therapeutic efficacy. 3-carboranyl thymidine analogues Boron neutron capture therapy (BNCT) is one of many experimental approaches that has been used to treat patients with glioblastoma multiforme (GBM), the most malignant of all human brain tumors (1, 2). It is a radiotherapeutic modality that is based on the selective delivery of nonradioactive boron-10 ( 10 B), followed by irradiation with either low energy thermal or intermediate energy epithermal neutrons to the site of the tumor. Besides GBMs, BNCT has been used to treat patients with recurrent malignant meningiomas (3), either cutaneous primaries or cerebral metastases of melanoma (1), and most recently, patients with recurrent carcinomas of the head and neck (4), and hepatic metastases of colon cancer (5). Interested readers are referred to several recent reviews (1) and monographs relating to various aspects of BNCT (6, 7).A prerequisite for successful BNCT is the selective accumulation of 10 B within tumor cells. To accomplish this, a wide variety of low and high molecular weight boron delivery agents have been designed and synthesized to specifically target malignant cells (8). However, only two agents have been used clinically, a dihydroxyboryl derivative of phenylalanine, referred to as boronphenylalanine (BPA), and an anionic polyhedral boron cluster, sodium borocaptate (BSH). Our most recent studies have focused on two specific molecular...

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Section: Discussionmentioning

confidence: 99%

Thymidine kinase 1 as a molecular target for boron neutron capture therapy of brain tumors

Barth¹,

Yang²,

Wu³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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“…For example, De Wolde and colleagues (30), in an attempt to correlate the protein synthesis rate of human brain tumors with histologic parameters of proliferation (Ki-67 and AGNOR counts), found no correlation between L-tyrosine positron emission tomography and Ki-67 in human brain tumors. Similarly, Sasajima and colleagues (31), in exploring the relationship between proliferative activity, amino acid transport, and glucose metabolism in glioma cell lines, found an inverse relationship between the influx of a nonmetabolizable system L-specific amino acid (aminocylopentane carboxylic acid; also known as cycloleucine) and proliferation index and TdR accumulation, and a recent in vitro study on the localization of 10 B (BPA) in metaphase and interphase T98G human glioblastoma cells using secondary ion mass spectrometry (SIMS) reported reduced levels of 10 B in the cytoplasm of mitotic cells compared with interphase cells (32). Our data also seem to support a lack of an association between amino acid uptake and proliferative activity.…”

Section: Discussionmentioning

confidence: 99%

l-Amino Acid Transporter-1 and Boronophenylalanine-Based Boron Neutron Capture Therapy of Human Brain Tumors

2009

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The system L-amino acid transporter-1 (LAT-1) imports pboronophenylalanine (BPA) into cells and may play a major role in the effectiveness of BPA-based boron neutron capture therapy. The functional status of LAT-1 and its relationship to cell proliferation were simultaneously examined in the same section of human tumor material using a dual-labeling technique. The uptake of BPA (boron inductively coupled plasma mass spectrometry) was profiled in the presence of agonists and antagonists in fresh tumor explants. The number of LAT-1-expressing cells (mean F SD) was three times higher than that of proliferating cell nuclear antigen (PCNA)-expressing cells (71.5 F 17.02% versus 23.8 F 16.5%; P < 0.0001; n = 38 glioblastoma and metastatic tumors). There was no correlation between PCNA cells and the number of LAT-1/ PCNA double-stained cells, and not all PCNA-expressing cells coexpressed LAT-1. Boron uptake reached 30 F 15 Mg/g of wet weight of tissue by 4 hours both in tumor and brain around tumor tissue containing tumor cells compared with time 0 (P < 0.005; n = 4 glioblastoma tumors). This uptake was inhibited by both phenylalanine and 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid. These LAT-1 data indicate that BPA-based boron neutron capture therapy might affect up to 70% of tumor cells, representing a three times higher proportion of tumor cells than their cell cycle status might suggest. Cells expressing PCNA, but not LAT-1, will require a different therapeutic strategy. [Cancer Res 2009;69(5):2126-32]

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“…2 illustrates one study by Chandra and colleagues to image 12 C, 39 K, 23 Na, 40 Ca, and 10 B distribution in human glioblastoma T98G cells treated with a BNCT agent, p-boronophenylalanine (BPA). 31 One particular sample preparation (i.e., cryogenic sandwich-fracture method) is also elegantly described in this article. This method has great potential to apply for the sample preparation with other metallomics techniques.…”

Section: Bioimaging Of Metals At the Single-cell Levelmentioning

confidence: 99%

Trace metal imaging with high spatial resolution: Applications in biomedicine

et al. 2011

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New generations of analytical techniques for imaging of metals are pushing hitherto boundaries of spatial resolution and quantitative analysis in biology. Because of this, the application of these imaging techniques described herein to the study of the organization and dynamics of metal cations and metal-containing biomolecules in biological cell and tissue is becoming an important issue in biomedical research. In the current review, three common metal imaging techniques in biomedical research are introduced, including synchrotron X-ray fluorescence (SXRF) microscopy, secondary ion mass spectrometry (SIMS), and laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS). These are exemplified by a demonstration of the dopamine-Fe complexes, by assessment of boron distribution in a boron neutron capture therapy cell model, by mapping Cu and Zn in human brain cancer and a rat brain tumor model, and by the analysis Metallomics, 2011, 3, 28-37 29 of metal topography within neuromelanin. These studies have provided solid evidence that demonstrates that the sensitivity, spatial resolution, specificity, and quantification ability of metal imaging techniques is suitable and highly desirable for biomedical research. Moreover, these novel studies on the nanometre scale (e.g., of individual single cells or cell organelles) will lead to a better understanding of metal processes in cells and tissues.

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Quantitative subcellular imaging of boron compounds in individual mitotic and interphase human glioblastoma cells with imaging secondary ion mass spectrometry (SIMS)

Cited by 44 publications

References 48 publications

Thymidine kinase 1 as a molecular target for boron neutron capture therapy of brain tumors

Thymidine kinase 1 as a molecular target for boron neutron capture therapy of brain tumors

l-Amino Acid Transporter-1 and Boronophenylalanine-Based Boron Neutron Capture Therapy of Human Brain Tumors

Trace metal imaging with high spatial resolution: Applications in biomedicine

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