Synthesis, dark toxicity and induction of in vitro DNA photodamage by a tetra(4-nido-carboranylphenyl)porphyrin

Vicente, M. Graça H.; Nurco, Daniel J.; Shetty, Shankar J.; Osterloh, Jens; Ventre, E; Hegde, Vijay; Deutsch, Walter

doi:10.1016/s1011-1344(02)00383-4

Cited by 51 publications

(22 citation statements)

References 34 publications

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“…Boron-containing porphyrins have excellent tumor-localizing properties (71 -78) and have been proposed for dual application as boron delivery agents and photosensitizers for photodynamic therapy (79 -81) of brain tumors. Despite the bulkiness of the carborane cages, carboranylporphyrins have been shown to interact with DNA and thereby produce in vitro DNA damage following light activation (82,83). A few boronated phthalocyanines also have been synthesized, although these compounds usually have had decreased water solubility and an increased tendency to aggregate compared with the corresponding porphyrins (71,72,78).…”

Section: Low Molecular Weight Agentsmentioning

confidence: 99%

Boron Neutron Capture Therapy of Cancer: Current Status and Future Prospects

Barth

Coderre²,

Vicente³

et al. 2005

Clinical Cancer Research

924

666

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Background: Boron neutron capture therapy (BNCT) is based on the nuclear reaction that occurs when boron-10 is irradiated with low-energy thermal neutrons to yield high linear energy transfer A particles and recoiling lithium-7 nuclei. Clinical interest in BNCT has focused primarily on the treatment of high-grade gliomas and either cutaneous primaries or cerebral metastases of melanoma, most recently, head and neck and liver cancer. Neutron sources for BNCT currently are limited to nuclear reactors and these are available in the United States, Japan, several European countries, and Argentina. Accelerators also can be used to produce epithermal neutrons and these are being developed in several countries, but none are currently being used for BNCT. Boron Delivery Agents: Two boron drugs have been used clinically, sodium borocaptate (Na 2 B 12 H 11 SH) and a dihydroxyboryl derivative of phenylalanine called boronophenylalanine. The major challenge in the development of boron delivery agents has been the requirement for selective tumor targeting to achieve boron concentrations (f20 Ag/g tumor) sufficient to deliver therapeutic doses of radiation to the tumor with minimal normal tissue toxicity. Over the past 20 years, other classes of boron-containing compounds have been designed and synthesized that include boroncontaining amino acids, biochemical precursors of nucleic acids, DNA-binding molecules, and porphyrin derivatives. High molecular weight delivery agents include monoclonal antibodies and their fragments, which can recognize a tumor-associated epitope, such as epidermal growth factor, and liposomes. However, it is unlikely that any single agent will target all or even most of the tumor cells, and most likely, combinations of agents will be required and their delivery will have to be optimized. Clinical Trials: Current or recently completed clinical trials have been carried out inJapan, Europe, and the United States. The vast majority of patients have had high-grade gliomas. Treatment has consisted first of ''debulking'' surgery to remove as much of the tumor as possible, followed by BNCTat varying times after surgery. Sodium borocaptate and boronophenylalanine administered i.v have been used as the boron delivery agents. The best survival data from these studies are at least comparable with those obtained by current standard therapy for glioblastoma multiforme, and the safety of the procedure has been established. Conclusions: Critical issues that must be addressed include the need for more selective and effective boron delivery agents, the development of methods to provide semiquantitative estimates of tumor boron content before treatment, improvements in clinical implementation of BNCT, and a need for randomized clinical trials with an unequivocal demonstration of therapeutic efficacy. If these issues are adequately addressed, then BNCTcould move forward as a treatment modality.

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Section: Low Molecular Weight Agentsmentioning

confidence: 99%

Boron Neutron Capture Therapy of Cancer: Current Status and Future Prospects

Barth

Coderre²,

Vicente³

et al. 2005

Clinical Cancer Research

924

666

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“…As the rapidly changing intensities of the individual cells are difficult to control, a large variance within each experiment is an unavoidable consequence of using this method. Therefore, a normalizing and variance-stabilizing logarithmic transformation was then applied to the calculated tail moments [14][15][16][17]. Cell frequency was determined by a visual scoring method [14] classifying DNA damage into the following categories: type 1 -intact nucleus, smooth outer edges; type 2 -intact nucleus, small amount of tailing; type 3 -intact nucleus, large amount of tailing; type 4 -shrinking nucleus, large amount of tailing.…”

Section: Evaluation Of Dna Damage In Whole Blood By the Neutral Cometmentioning

confidence: 99%

Age Dependent Accumulation of Spontaneous DNA Damage in Liver of Transgenic Mice over Expressing Ribosomal Protein S3

Hegde¹,

Yadavilli²,

Deutsch³

2016

Mol Biol

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Oxidative stress has been associated with the aging process and increased cancer incidence mainly due to accumulation of free radical dependent cellular damage. Reactive oxygen species (ROS) induced formation of 7,8-dihydro-8-oxoguanine (8-oxodG) has the potential to mispair with Adenine during DNA replication in key genes involved in the development of cancer. Human ribosomal protein S3 (RPS3) participates in a variety of reactions beyond its role in protein synthesis, such as processing of oxidative DNA damage. We have shown ex vivo that oxidative stress causes RPS3 to translocate to the nucleus, bind to sites of 8-oxodG with an extraordinarily high binding affinity and interferes with 8-oxodG repair in vitro. Furthermore, our in vivo studies using RPS3 over expressing transgenic mice showed translocation of RPS3 to the nucleus in mouse embryonic fibroblasts (MEFs) and co-localization to 8-oxodG foci with an increase in DNA damage. In this study, we show age dependent accumulation of DNA damage (double strand breaks [DSBs] and fragmented DNA) in aging (15-month old) transgenic mice over expressing RPS3. We also observed increase in DNA damage particularly 8-oxodG, in the liver of older transgenic mice which showed a pre-neoplastic pathology and presence of hepatic tumors. The older transgenic livers had significantly higher p53 expression compared to age matched wild-type mice. These results provide evidence for role of RPS3 over expression interfering with DNA repair and predisposing animals to carcinogenesis but also underscore the role of RPS3 expression plays in the DNA damage signaling pathway and in maintenance of genome integrity by channeling cells either towards cell survival (DNA repair) or cell death (apoptosis).

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“…High tumor and low blood boron concentrations were observed and both we and Ozawa have concluded that direct intracerebral administration of the carboranyl porphyrins by CED is superior to systemic administration. Furthermore, despite the bulkiness of the carborane cages, carboranylporphyrins have been shown to interact with DNA and thereby produce in vitro DNA damage following light activation (94,95). Boronated phthalocyanines have been synthesized, although these compounds usually have had decreased water solubility and an increased tendency to aggregate compared to the corresponding porphyrins (76,77,86,87).…”

Section: Boron-containing Porphyrins and Related Structuresmentioning

confidence: 99%