Cancer chemotherapy--the first twenty-five years.

Scott, Ronald Bodley

doi:10.1136/bmj.4.5730.259

Cited by 41 publications

(23 citation statements)

References 78 publications

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“…Because of this capability, nitrogen mustard was used for chemotherapy [24]. Indeed, chemotherapeutic agents often exert neurobehavioral teratogenicity via their cytotoxic action [22].…”

Section: Discussionmentioning

confidence: 99%

“…SM is expected to perturb neurobehavioral development due to it cytotoxic and mutagenic properties, which is particularly potent in the developing cells and adversely affects rapidly proliferating cells. Because of the specific cytotoxicity of SM, nitrogen mustard was widely employed in cancer chemotherapy [24]. Findings of various studies suggest that SM affects neurotransmission systems.…”

Section: Introductionmentioning

confidence: 99%

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A chick model for the mechanisms of mustard gas neurobehavioral teratogenicity

Wormser

Izrael

Zee

et al. 2005

Neurotoxicology and Teratology

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Citation for published version (APA): Wormser, U., Izrael, M., Van der Zee, E. A., Brodsky, B., & Yanai, J. (2005). A chick model for the mechanisms of mustard gas neurobehavioral teratogenicity. Neurotoxicology and Teratology, 27(1), 65-71. DOI: 10.101665-71. DOI: 10. /j.ntt.2004 Copyright Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons the number of authors shown on this cover page is limited to 10 maximum. AbstractThe chemical warfare blistering agent, sulfur mustard (SM), is a powerful mutagen and carcinogen. Due to its similarity to the related chemotherapy agents nitrogen mustard (mechlorethamine), it is expected to act as a developmental neurotoxicant. The present study was designed to establish a chick model for the mechanisms of SM on neurobehavioral teratogenicity, free of confounds related to mammalian maternal effects. Chicken eggs were injected with SM at a dose range of 0.0017-17.0 Ag/kg of egg, which is below the threshold for dysmorphology, on incubation days (ID) 2 and 7, and then tests were conducted posthatching. Exposure to SM elicited significant deficits in the intermedial part of the hyperstriatum ventrale (IMHV)-related imprinting behavior. Parallel decreases were found in the level of membrane PKCg in the IMHV, while eliciting no net change in cytosolic PKCg. The chick, thus, provides a suitable model for the rapid evaluation of SM behavioral teratogenicity and elucidation of the mechanisms underlying behavioral anomalies. The results obtained, using a model that controls for confounding maternal effects, may be replicated in the mammalian model and provide the groundwork for studies designed to offset or reverse the SM-induced neurobehavioral defects in both avian and mammals. D

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“…Because of this capability, nitrogen mustard was used for chemotherapy [24]. Indeed, chemotherapeutic agents often exert neurobehavioral teratogenicity via their cytotoxic action [22].…”

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A chick model for the mechanisms of mustard gas neurobehavioral teratogenicity

Wormser

Izrael

Zee

et al. 2005

Neurotoxicology and Teratology

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“…Docking was the next stage after the pharmacophore fi ltration. GOLD 4.1 [ 14 ] was used for the docking purpose. The kinase structure was prepared using protein preparation protocol of Accelry's discovery studio; the protein structure was protonated, the water molecules were deleted and the structure was minimized using 500 steps of conjugate gradient minimization method.…”

Section: Docking and Scaff Old Selectionmentioning

confidence: 99%

Virtual Screening and Synthesis of New Chemical Scaffolds as VEGFR-2 Kinase Inhibitors

Elsayed

El‐Araby

Serya

et al. 2012

Arzneimittelforschung

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VEGFR-2 tyrosine kinase inhibitors are currently receiving high interest in drug discovery process as anticancer agents. We have used virtual screening techniques in order to discover new scaffolds that can be used for developing new VEGFR-2 kinase inhibitors.Similarity ensemble approach was used to reduce the chemical space of ZINC database to select a subset of compounds. A validated structure-based pharmacophore was developed and adopted to screen the selected subset. Initial hits mapped to the pharmacophore were filtered using docking and scoring. Selected compounds were synthesized and biologically tested. Compound 9 showed very good cytotoxicity profile against the NCI 60 cancer cell lines, while compound 8 showed reasonable inhibition of VEGFR-2 tyrosine kinase.Stepwise virtual screening of databases such as ZINC may result in new scaffolds for developing VEGFR-2 kinase inhibitors.

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“…They are harmful to normal cells, especially cells that divide frequently, such as those in the gastrointestinal tract, bone marrow, testicles, and ovaries, where they can cause loss of fertility. As early as the 1940s, it was discovered that they could be used as part of chemotherapy in different types of cancers (Goodman et al, 1946;Scott, 1970;Wiedemann et.al., 1996). One early example is busulfan, a cancer drug in use since 1959; in 1999 it was approved by the US Food and Drug Administration for treatment of chronic myeloid leukemia.…”

Section: Introductionmentioning

confidence: 99%

Biotransformation and Rearrangement of Laromustine

Nassar

Wisnewski

King

2016

Drug Metabolism and Disposition

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This review highlights the recent research into the biotransformations and rearrangement of the sulfonylhydrazine-alkylating agent laromustine. Incubation of [ 14 C]laromustine with rat, dog, monkey, and human liver microsomes produced eight radioactive components (C-1 to C-8). There was little difference in the metabolite profile among the species examined, partly because NADPH was not required for the formation of most components, which instead involved decomposition and/or hydrolysis. The exception was C-7, a hydroxylated metabolite, largely formed by CYP2B6 and CYP3A4/5. Liquid chromatography-multistage mass spectrometry (LC-MS n ) studies determined that collision-induced dissociation, and not biotransformation or enzyme catalysis, produced the unique mass spectral rearrangement. Accurate mass measurements performed with a Fourier-transform ion cyclotron resonance mass spectrometer (FTICR-MS) significantly aided determination of the elemental compositions of the fragments and in the case of laromustine revealed the possibility of rearrangement. Further, collision-induced dissociation produced the loss of nitrogen (N 2 ) and methylsulfonyl and methyl isocyanate moieties. The rearrangement, metabolite/decomposition products, and conjugation reactions were analyzed utilizing hydrogendeuterium exchange, exact mass, 13 C-labeled laromustine, nuclear magnetic resonance spectroscopy (NMR), and LC-MS n experiments to assist with the assignments of these fragments and possible mechanistic rearrangement. Such techniques produced valuable insights into these functions: 1) Cytochrome P450 is involved in C-7 formation but plays little or no role in the conversion of [ 14 C]laromustine to C-1 through C-6 and C-8; 2) the relative abundance of individual degradation/metabolite products was not species-dependent; and 3) laromustine produces several reactive intermediates that may produce the toxicities seen in the clinical trials.

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Cancer chemotherapy--the first twenty-five years.

Cited by 41 publications

References 78 publications

A chick model for the mechanisms of mustard gas neurobehavioral teratogenicity

A chick model for the mechanisms of mustard gas neurobehavioral teratogenicity

Virtual Screening and Synthesis of New Chemical Scaffolds as VEGFR-2 Kinase Inhibitors

Biotransformation and Rearrangement of Laromustine

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