Previous investigations in gene expression changes in blood after radiation exposure have highlighted its potential to provide biomarkers of exposure. Here, FDXR transcriptional changes in blood were investigated in humans undergoing a range of external radiation exposure procedures covering several orders of magnitude (cardiac fluoroscopy, diagnostic computed tomography (CT)) and treatments (total body and local radiotherapy). Moreover, a method was developed to assess the dose to the blood using physical exposure parameters. FDXR expression was significantly up-regulated 24 hr after radiotherapy in most patients and continuously during the fractionated treatment. Significance was reached even after diagnostic CT 2 hours post-exposure. We further showed that no significant differences in expression were found between ex vivo and in vivo samples from the same patients. Moreover, potential confounding factors such as gender, infection status and anti-oxidants only affect moderately FDXR transcription. Finally, we provided a first in vivo dose-response showing dose-dependency even for very low doses or partial body exposure showing good correlation between physically and biologically assessed doses. In conclusion, we report the remarkable responsiveness of FDXR to ionising radiation at the transcriptional level which, when measured in the right time window, provides accurate in vivo dose estimates.
- MeSH
- biologické markery metabolismus MeSH
- celotělové ozáření * MeSH
- dospělí MeSH
- ferredoxin-NADP-reduktasa genetika metabolismus MeSH
- kurkumin farmakologie MeSH
- lidé středního věku MeSH
- lidé MeSH
- lipopolysacharidy farmakologie MeSH
- mladý dospělý MeSH
- nádory metabolismus radioterapie MeSH
- počítačová rentgenová tomografie MeSH
- RNA krev účinky léků MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- upregulace účinky léků MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
Despite recent advances in targeted therapeutics, administration of 5-fluorouracil (5-FU) remains a common clinical strategy for post-surgical treatment of solid tumors. Although it has been proposed that RNA metabolism is disturbed by 5-FU treatment, the key cytotoxic response is believed to be enzymatic inhibition of thymidylate synthase resulting in nucleotide pool disproportions. An operating p53 tumor suppressor signaling network is in many cases essential for the efficiency of chemotherapy, and malfunctions within this system remain a clinical obstacle. Since the fate of chemotherapy-insensitive tumor cells is rarely described, we performed a comparative analysis of 5-FU toxicity in p53-deficient cells and conclude that p53 acts as a facilitator rather than a gatekeeper of cell death. Although p53 can act as a regulator of several cellular stress responses, no rerouting of cell death mode was observed in absence of the tumor suppressor. Thus, the final death outcome of 5-FU-treated p53-/- cells is demonstrated to be caspase-dependent, but due to a slow pace, accumulation of mitochondrial reactive oxygen species contributes to necrotic characteristics. The oligomerization status of the p53 target gene DR5 is determined as a significant limiting factor for the initiation of caspase activity in an intracellular TRAIL-dependent manner. Using several experimental approaches, we further conclude that RNA-rather than DNA-related stress follows by caspase activation irrespectively of p53 status. A distinct 5-FU-induced stress mechanism is thereby functionally connected to a successive and discrete cell death signaling pathway. Finally, we provide evidence that silencing of PARP-1 function may be an approach to specifically target p53-deficient cells in 5-FU combinatorial treatment strategies. Together, our results disclose details of impaired cell death signaling engaged as a consequence of 5-FU chemotherapy. Obtained data will contribute to the comprehension of factors restraining 5-FU efficiency, and by excluding DNA as the main stress target in some cell types they propose alternatives to currently used and suggested synergistic treatment regimens.
- MeSH
- antimetabolity antitumorózní farmakologie MeSH
- apoptóza účinky léků MeSH
- fluorescenční protilátková technika MeSH
- fluorouracil farmakologie MeSH
- imunoblotting MeSH
- imunoprecipitace MeSH
- lidé MeSH
- nádorové buněčné linie MeSH
- nádorový supresorový protein p53 metabolismus MeSH
- polymerázová řetězová reakce MeSH
- protein TRAIL metabolismus MeSH
- RNA účinky léků MeSH
- signální transdukce účinky léků fyziologie MeSH
- transdukce genetická MeSH
- transmisní elektronová mikroskopie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
We investigated the effect of long-term exposure to carbamazepine (CBZ) on the enzymatic alterations and RNA/DNA ratio in intestine tissue of rainbow trout. Fish were exposed to sublethal concentrations of CBZ (1.0 microg/l, 0.2 or 2.0 mg/l) for 42 days. Digestive enzymes (proteolytic enzymes and amylase) and energy metabolic enzyme (Na(+)-K(+)-ATPase) and antioxidant enzymes (superoxide dismutase [SOD], catalase [CAT], glutathione peroxidase [GPx], and glutathione reductase [GR]) in fish intestine were measured. In addition, intestinal RNA/DNA ratio was determined after 42 days exposure. Carbamazepine exposure at 2.0 mg/l led to significantly inhibited (P < 0.05) activity of Na(+)-K(+)-ATPase. Activities of the antioxidant enzymes SOD, CAT, and GPx in CBZ-treated groups gradually increased at lower concentration of CBZ (1.0 microg/l and 0.2 mg/l), then significantly inhibited (P < 0.05) at 2.0 mg/l. After 42 days, the RNA/DNA ratio in fish intestine was significantly lower (P < 0.05) in groups exposed to CBZ at 2.0 mg/l than in other groups. However, there was no statistical significance (P > 0.05) in the activities of digestive enzymes (proteolytic enzyme and amylase) and GR in all groups. In short, prolonged exposure to CBZ resulted in different responses of various enzymes and significantly lower RNA/DNA ratio in fish intestine. Furthermore, molecular and genetic mechanisms of these physiological responses in fish are not clear, which need to be further studied.
- MeSH
- antioxidancia metabolismus MeSH
- časové faktory MeSH
- chemické látky znečišťující vodu aplikace a dávkování toxicita MeSH
- DNA účinky léků metabolismus MeSH
- karbamazepin aplikace a dávkování toxicita MeSH
- Oncorhynchus mykiss MeSH
- RNA účinky léků metabolismus MeSH
- sodíko-draslíková ATPasa antagonisté a inhibitory metabolismus MeSH
- střeva účinky léků enzymologie metabolismus MeSH
- trávicí systém účinky léků enzymologie MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Using biochemical methods, we have examined the effect of two factors that might play a role in the mechanism of the biological activity of cisplatin at elevated temperatures (>37 degrees C). We show that increased temperatures result in distinct alterations in the modification of the target DNA by cisplatin, and in the repair of these modifications. Our in vitro results support the view that the enhanced DNA-cross-linking efficiency of cisplatin and the lower efficiency of native DNA repair mechanisms at higher temperature play at least a partial role in the potentiation of the antitumor effects of cisplatin under conditions of mild hyperthermia.
- MeSH
- antitumorózní látky farmakologie chemie MeSH
- časové faktory MeSH
- cisplatina farmakologie chemie MeSH
- DNA řízené RNA-polymerasy antagonisté a inhibitory chemie MeSH
- DNA chemie účinky léků MeSH
- financování organizované MeSH
- HeLa buňky MeSH
- lidé MeSH
- oprava DNA MeSH
- RNA chemická syntéza chemie účinky léků MeSH
- skot MeSH
- teplota MeSH
- vazebná místa MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- skot MeSH
- zvířata MeSH
- MeSH
- časové faktory MeSH
- DNA účinky léků účinky záření MeSH
- experimentální radiační poranění farmakoterapie metabolismus MeSH
- krysa rodu rattus MeSH
- preklinické hodnocení léčiv MeSH
- radioprotektivní látky terapeutické užití MeSH
- RNA účinky léků účinky záření MeSH
- silymarin terapeutické užití MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- srovnávací studie MeSH
- MeSH
- DNA účinky léků účinky záření MeSH
- játra účinky léků účinky záření MeSH
- kostní dřeň účinky léků účinky záření MeSH
- krysa rodu rattus MeSH
- radioprotektivní látky farmakologie MeSH
- RNA účinky léků účinky záření MeSH
- silymarin farmakologie MeSH
- slezina účinky léků účinky záření MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
