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Edited by Kostas Fountas. Published: November 21st DOI: Tribble Open access peer-reviewed 2. Katzin Open access peer-reviewed 3. Radioisotopes and Nanomedicine By Nathan C. Wang Open access peer-reviewed 4. Veltkamp Open access peer-reviewed 6. Gibson Open access peer-reviewed 9. Hutson Edited Volume and chapters are indexed in. Open access peer-reviewed 1.
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Open access peer-reviewed 2. Open access peer-reviewed 3. Open access peer-reviewed 4. Open access peer-reviewed 5. Finally, even if the sampled material needs fractionation to specific biomolecules prior to quantitation, the sample sizes are reduced to amounts that can be obtained from well-defined, and often non-invasive procedures.
For a practical AMS measurement, biological samples containing 0. In a quartz tube, and using excess copper oxide CuO , the sample's biological carbon is oxidized to CO 2. The CO 2 is then reduced to solid carbon by both reduction with titanium hydride and zinc powder and catalyzation with either iron or cobalt.
Because this process is independent of the chemical nature of the sample, it eliminates interference or suppression from other sample components. Therefore, AMS provides one piece of information about the sample of carbon measured: the precise 12 C: 14 C ratio. In AMS, one measures the isotope ratio with respect to that of a well-known external standard in order to produce an absolute isotope concentration for the combusted sample [ 13 , 14 ].
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With AMS, experimenters only need the fractional elemental abundance of the sample and the specific activity of the tracer compound in order to obtain, in the units most useful for interpretation, the concentration of the tracer in the sampled material. The mechanics of an AMS instrument, the mathematical conversions of the measured values to meaningful "Modern" values, and the comparisons with LSC are well reviewed in the literature [ 3 , 11 , 15 — 17 ].
For the first time in , sensitive and precise quantitation of 14 C was applied to the analysis of biological samples containing enriched 14 C-labeled carcinogens for toxicology and cancer studies by Turteltaub et al. Their research quantified chemical binding of the 14 C-labeled carcinogens to DNA at the level of 1 binding in 10 11 bases.
The benefits of using AMS for the analysis of samples derived from radiotracer studies with humans soon became apparent, since AMS produces very specific quantitation with simple analysis [ 19 ]. Any isotope concentration greater than the known stable natural 14 C background must arise from an introduced isotope label "introduced" includes contamination, which must be carefully controlled and avoided.
In the simplest experimental design, there is only one external radioactive source, perhaps a radiolabeled compound introduced into the biological system at a specific time. The isotope ratio of the isolated sample is then easily converted to the concentration of the labeled compound and its metabolites per g or ml of the analyte. Not surprisingly, AMS has soon become a tool of choice for pharmacokinetic analyses [ 10 , 11 , 16 ].
All the metabolites of the compound that contain the labeled moiety can be directly quantified in chromatographic separations without resorting either to secondary standards or to prior knowledge of metabolic pathways. Although some fluorescent methods quantitate into the amol levels [ 20 , 21 ], they require derivatization procedures that are not suitable for in vivo tracing, create tracers that are not chemically equivalent, and are less general in applicability across many biological systems. Conversely, AMS is specific only to the labeled compound in any chemical or biological medium.
Such specificity requires neither prior speciation nor the introduction of either molecular modifications or internal standards. With AMS, it is possible to conduct radiotracer studies in human with the administration of such low levels of 14 C [ 10 , 11 ]. The most recent innovation using AMS technology is the so-called "microdosing" concept [ 10 ].
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Choosing a drug for clinical trials from numerous candidates is very much a hit-and-miss business. Presented with a choice of good candidates, it would be better to take them all into human subjects. This would, however, be prohibitively expensive, as each compound would require a significant package of toxicological safety testing. At these levels, only a limited toxicology package is required and in vivo human data can be acquired for candidate selection [ 22 ].
After the first biomedical application of sensitive and precise quantitation of 14 C by AMS in [ 18 ], the technique has been explored for using animals and for fractionating tissues, cells and molecules in the study of metabolism, covalent macromolecule-ligand interactions, and non-covalent macromolecule-ligand interactions with amol sensitivity [ 8 — 10 ]. For example, Phillips et al. They investigated covalent interactions of metabolic products with DNA and proteins, both in animal hosts and in humans. The heterocyclic amines are compounds that are found in cooked meat and are potent carcinogens in rodent models.
However, their role in human cancer remains largely unknown. Using AMS, Felton's group at the Lawrence Livermore National Laboratory has identified the metabolites of [2- 14 C]2-aminomethylphenylimidazo [4,5-b]pyridine PhIP in humans and the relationships between the activities of key enzymes involved in PhIP metabolism and metabolite profiles [ 24 , 25 ]. Through these works, it has been possible to establish the scaling factors between animal hosts and humans for DNA and protein adduct formation, as well as to establish plasma and urinary biomarkers of PhIP exposure.
The sensitivity of AMS is required to keep both the chemical and the radiation doses to human volunteers to levels that do not exceed commonly accepted risks.
steranlokangvest.tk The work with heterocyclic amine carcinogen has been expanded to the development of chemopreventive strategies for reducing the amount of DNA damage following carcinogen exposure and to the quantitation of the ability of certain dietary agents to reduce the levels of DNA adducts from two heterocyclic amines, PhIP and 2-aminomethylimidazo [4,5-f]quinoline IQ [ 30 ]. It was found that chlorophyllin a stable form of chlorophyll that is found in green leafy vegetables and the isothiocyanate found in broccoli caused the greatest adduct reductions in prostate, liver and colon of rodents, presumably by modifying the metabolic processes leading to the final reactive metabolites.
Turesky et al. Various animal models were also used to study covalent binding levels of toxic compounds, including a quantitation of chromatin adducts of acrylamide in male germ cells of mice that was related to pre-implantation abnormalities in embryos [ 32 ]. The sample material available for analysis was so small that AMS quantitation could be the only reasonable route for obtaining very pure chromatin. Very recently, AMS was successfully used to measure the kinetics and repair of DNA adducts formed by two chemotherapeutic compounds, carboplatin and oxaliplatin [ 33 , 34 ].
The kinetics observed for the first time for reaction with genomic DNA revealed that the rate of carboplatin-DNA adduct formation was approximately fold slower than that reported for the more potent analog cisplatin, which may explain the lower toxicity of the compound. In addition, the rate of oxaliplatin adduction to salmon sperm DNA was measured, and oxaliplatin-DNA adduct distribution was further investigated at the nucleoside level by high-performance liquid chromatography HPLC -AMS following enzymatic digestion [ 33 ].
Importantly, rates of cellular drug influx, efflux, DNA damage and DNA repair in cultured platinum-sensitive testicular K and platinum-resistant breast and bladder MDA-MB and T24, respectively cancer cells incubated with a subpharmacological dose of oxaliplatin 0. Radiolabeled adriamycin, also known as doxorubicin, was introduced to MCF-7 human breast cancer cells by Coldwell et al.
With many potential alternative mechanisms of action cited and reviewed, the technology of AMS has provided the first direct evidence of adriamycin-DNA adducts at clinically-relevant adriamycin concentrations.
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Kwok et al. Two studies [ 37 , 38 ] looked at the genotoxicity potential of benzene by quantifying species and strain differences of the protein and DNA binding at very low doses and by testing for histone-specific binding of benzene metabolites using gel separations and MS analysis with AMS quantitations.
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It should be noted that no specificity toward individual histone species was found though protein adducts of benzene or its metabolites were indicated by elevated levels of 14 C and that these studies used realistic inhalation doses. The incorporation of 14 C was largely proportional to the density of gel staining, giving little evidence that the proteins were specific targets for selective labeling, implying high reactivity of benzene toward proteins which enables such attack to occur at multiple sites within multiple targets.
In addition, Goldman et al.