Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.1.1.17 (ornithine decarboxylase)
 6,351 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Polyamine (tissue) concentrations have been studied in hippocampus and temporal neocortex from patients with temporal lobe epilepsy. Depth electrode recordings demonstrated hippocampal origin of the seizures, the temporal neocortex being involved during the discharge propagation. Neuropathological examination of excised tissues showed glial proliferation or glioma in Ammon's horn (CA), whereas the temporal neocortex did not exhibit any histological abnormality. Polyamine (putrescine or PUT, spermidine or SPD, spermine or SPM) concentrations were determined on surgical samples from the hippocampus and various areas of temporal neocortex. Human post-mortem tissue from temporal lobe regions was used for controls. In post-mortem controls and temporal neocortex specimens from epileptic patients, polyamine levels were similar (in nmol/g wet weight: PUT = 40-100; SPD = 200-350; SPM = 100-200). In CA, polyamine levels exhibited striking changes: SPD content was significantly increased (350-700 nmol/g) while SPM was lowered (50-100). PUT was only increased in CA invaded by the tumoral process (100-180). Accordingly, a very high SPD/SPM molar ratio in the abnormal CA region was observed, indicating an acceleration of polyamine neosynthesis which is usually related to ornithine decarboxylase induction. Metabolic changes in polyamines appear to be selective of human epileptic hippocampus. A relationship between glial proliferation (gliosis or neoplasia), epileptic firing and polyamines is discussed.
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PMID:Polyamine metabolism in epileptic cortex. 139 40

DL-alpha-Difluoromethylornithine (DFMO) is a specific inhibitor of the rate-limiting enzyme in polyamine biosynthesis, ornithine decarboxylase (ODC). DFMO (1 mM) added to C57BL/6 anti-DBA/2 murine mixed lymphocyte cultures (MLC) inhibited cytolytic T lymphocyte (CTL) activity on days 3 and 5 by 88% and 96%. Putrescine (PUT; 1 mM) and spermidine (SPD; 0.01 mM) reversed DFMO inhibition, indicating that DFMO inhibition was caused by ODC antagonism. T helper (Th) cell and accessory cell functions were not affected since DFMO did not inhibit MLC proliferation or lymphokine production. Furthermore, exogenous IL-1, IL-2, IL-4, interferon-gamma, or a rat Con A supernatant failed to abrogate DFMO inhibition. Inhibition was reversible within 48 h of removing cells from DFMO; moreover, subsequent development of DFMO-blocked CTL did not require CD4+ cells. Clonal expansion of CTL treated with 1 mM DFMO for three days in MLC, determined by subsequent analysis in limiting dilution microcultures, was only approx. 1 cell division less than control. These results indicate DFMO inhibition is exerted directly on the CTL, and that the process of differentiation was more affected by a reduction in polyamine biosynthesis than proliferation. This may be a useful model to the study stages and events of CTL development, and the roles played by polyamines in supporting these processes.
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PMID:Difluoromethylornithine (DFMO) arrests murine CTL development in the late, pre-effector stage. 183 10

alpha-Difluoromethylornithine (DFMO) is a suicide inhibitor of ornithine decarboxylase and potent antiproliferative chemopreventive agent. We conducted a dose de-escalation Phase I trial of DFMO in patients with grade 3 cervical intraepithelial neoplasia to determine an optimal dose of DFMO using ornithine decarboxylase activity and polyamine modulation as surrogate biomarkers and to evaluate its toxicity. Thirty patients with biopsy-confirmed grade 3 cervical intraepithelial neoplasia were assigned sequentially to one of five DFMO doses (1.000, 0.500, 0.250, 0.125, or 0.060 g/m2) given daily for 31 days. One patient was excluded from analysis for protocol violation. Polyamine levels were assessed in cervical tissue, plasma, and RBCs. Tissue and blood samples were obtained before and after treatment with DFMO. All patients underwent loop excision of the cervix at the end of the study for complete histological evaluation and definitive treatment of the premalignant condition. No major clinical toxicity was observed at any DFMO dose. A reduction in tissue spermidine to spermine (SPD:SPM) ratio and an increase in plasma arginine levels were observed among patients receiving 1.000 g/m2/day (P < 0.05). A nonsignificant reduction in SPD:SPM ratio was also observed in the 0.500 g/m2/day dose group, and a nonsignificant increase in plasma arginine level was observed down to the 0.125 g/m2/day dose level. There was no evidence of modulation of other polyamines or precursors. Fifteen patients experienced a complete (5 patients) or partial (10 patients) histological response. In conclusion, DFMO was well tolerated and significantly modulated tissue SPD:SPM ratio and plasma arginine level at the dose of 1.000 g/m2/day. To clarify whether DFMO has activity at lower doses, these results will be tested in a three-armed double-blinded Phase II study using placebo and DFMO doses of 0.500 and 0.125 g/m2/day.
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PMID:Phase I dose de-escalation trial of alpha-difluoromethylornithine in patients with grade 3 cervical intraepithelial neoplasia. 951 15

The use of a combination of monofluorescein adducts of spermidine (FL-SPD) and spermine (FL-SPM) with confocal laser scanning microscopy (CLSM) provides a useful means for monitoring the fate and time-dependent changes in the distribution of transported polyamines within living cells. Polyamine-fluorescein adducts were synthesized from fluorescein isothiocyanate and the appropriate polyamine. Monofluorescein polyamine adducts (ratio 1:1) were isolated using thin layer chromatography, and the structure and molecular weight of the monofluorescein polyamine adducts were confirmed using NMR and mass spectroscopy, respectively. The covalent linkage of the fluorescent adduct moiety to SPD and SPM did not influence their rate of uptake by bovine pulmonary artery smooth muscle cells (PASMC). Similar to 14C-SPD and 14C-SPM, the rate of uptake of 14C-FL-SPD and 14C-FL-SPM in PASMC was temperature-dependent. Treatment for 24 h with difluoromethylornithine (DFMO), a selective blocker of the enzyme ornithine decarboxylase and an inducer of the polyamine transport system, significantly increased the cellular uptake of 14C-FL-SPD and 14C-FL-SPM compared to that of control cells. When compared to control cells, treatment of PASMC with the pyrrolizidine alkaloid monocrotaline for 24 h also significantly increased the cellular uptake of 14C-FL-SPD and 14C-FL-SPM. On the other hand, 24 h treatment of PASMC with a polymer of SPM, a selective blocker of the polyamine transport system, or with free spermine, markedly reduced the cellular accumulation of 14C-FL-SPD and 14C-FL-SPM. After a 20-min treatment of PASMC with FL-SPD or FL-SPM, CLSM revealed that adduct fluorescence was localized in the cytoplasm of living cells. Treatment with DFMO increased the cytoplasmic accumulation of both FL-SPD and FL-SPM. In addition, the fluorescence observed in the cytoplasm of chinese hamster ovary cells (CHO) was significantly higher than that detected in the cytoplasm of their polyamine transport deficient variants (CHOMGBG). The results of this study provide the first evidence of the utility of a novel method for visualizing the uptake, distribution, and cellular localization of transported polyamines in viable cultured mammalian cells.
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PMID:A novel technique for visualizing the intracellular localization and distribution of transported polyamines in cultured pulmonary artery smooth muscle cells. 963 84

We have recently demonstrated the inverse correlation between transglutaminase (TGase) activity and DNA synthesis in periportal hepatocytes (PPH) and perivenous hepatocytes (PVH) at 1 d after partial hepatectomy. In order to elucidate a role of polyamines as substrates of TGase in the differential growth capacities between PPH and PVH from regenerating liver, we investigated the zonal differences in alteration of ornithine decarboxylase (ODC) activity and polyamines. In two subpopulations, the inverse correlation between DNA synthesis and epsilon-(gamma-glutamyl) lysine (Gln-Lys) cross-linking catalyzed by TGase was demonstrated at 1 d after partial hepatectomy. ODC activity in PPH significantly increased with a peak at 1 d after partial hepatectomy, whereas did not in PVH. Protein-binding SPD in PPH also transiently increased with a peak at 1 d after partial hepatectomy, but did not in PVH. These results suggest that at 1 d after partial hepatectomy, in PPH, the inhibition of Gln-Lys cross-linking by the formation of N-gamma-glutamyl SPD leads to the increase of DNA synthesis, whereas in PVH, enhanced formation of Gln-Lys cross-linking leads to the lower DNA synthesis.
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PMID:The involvement of polyamines as substrates of transglutaminase in zonal different hepatocyte proliferation after partial hepatectomy. 1568 97