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At least 19 recordsLinked to original sources
PubMed1992

High-performance liquid chromatography determination of polydeoxyribonucleotides in plasma: its application to the determination of defibrotide's pharmacokinetics in the rabbit.

We describe an HPLC method for the determination of whole polydeoxyribonucleotides in animal plasma. This method was compared to a colorimetric method, which evaluates the sugar moiety of polydeoxyribonucleotides, and to an agarose gel electrophoresis method, which evaluates the whole polydeoxyribonucleotides as does the HPLC method, and was found to give results very close to those obtained with these two other methods. A pharmacokinetic study of the antithrombotic, profibrinolytic, polydeoxyribonucleotidic drug defibrotide was carried out by evaluating the plasma drug levels by these three methods. The pharmacokinetic parameters calculated from the data are very similar.

Animals↗
PubMed1993

Defibrotide, a single-stranded polydeoxyribonucleotide acting as an adenosine receptor agonist.

The binding of single-stranded polydeoxyribonucleotides to adenosine A1 and A2 receptors was investigated. Defibrotide, a natural substance with established anti-thrombotic and anti-ischaemic effects, displaced [3H]CHA (N6-cyclohexyl-adenosine) and [3H]NECA (5'-N-ethylcarboxamido-adenosine) concentration dependently, completely and competitively. Ki values of 371 +/- 68 and 688 +/- 115 micrograms/ml (mean +/- S.E.M. of 4-5 replications) were computed for adenosine A1 and A2 sites, respectively. Higher and lower molecular weight polydeoxyribonucleotides displayed comparable affinity, whereas a double-stranded polydeoxyribonucleotide and a polyanion with a negative charge comparable to that of defibrotide were inactive. Defibrotide did not affect the total number of binding sites in radioligand saturation experiments. Defibrotide relaxed the K(+)-contracted guinea-pig trachealis muscle (IC50 = 4001 micrograms/ml) about one-third as potently as the CHA-contracted preparation and as potently as the resting preparation. NECA, a mixed adenosine A1/A2 receptor agonist, behaved similarly. The effects were abolished by the adenosine A1/A2 receptor blocker 8-phenyltheophylline, but not by the selective A1 blocker, 1,3-dipropyl-8-(2-amino-4-chlorophenyl)-xanthine. These results demonstrate that defibrotide binds to adenosine receptors and triggers pharmacological responses comparable to those of a known agonist.

Adenosine↗
PubMed1979

Cromatin and core particles formed from the inner histones and synthetic polydeoxyribonucleotides of defined sequence.

Chicken erythrocyte inner histones (H2A, H2B, H3 and H4) were associated with the two complementary homopolymeric polydeoxyribonucleotides and the two alternating copolymeric polydeoxyribonucleotides. No evidence for formation of chromatin-like structures was obtained for the complexes with poly(dG) . poly(dC) or poly(dA) . poly(dT). Both poly (dGdC) . poly(dGdC) and poly(dAdT) . poly(dAdT) could be folded by histones to yield material digested by DNAase I to multiples of about 10 and by staphylococcal nuclease to 146 bp core particles. Due to the lack of sequence heterogeniety in the complex of histones with poly(dAdT) . poly(dAdT), core particles with remarkable fine structural detail are obtained. The internal organization of DNA in the AT-containing and GC-containing core particles appears not to be identical.

Animals↗
PubMed1980

A DNA glycosylase from Escherichia coli that releases free urea from a polydeoxyribonucleotide containing fragments of base residues.

A poly (dA, [2-14C]dT) copolymer has been synthesized using terminal deoxynucleotidyltransferase. Treatment of the polydeoxyribonucleotide with potassium permanganate converts the thymine residues to urea and N-substituted urea derivatives, while the adenine residues are resistant to oxidation. This damaged polymer has been annealed with an equimolar amount of poly (dT) to generate a double-stranded polydeoxyribonucleotide containing scattered fragmented base residues, which are radioactively labeled selectively. On incubation of the latter with crude cell extracts from E. coli, free urea is released by a DNA glycosylase activity. The enzyme has been partly purified, and appears to be different from previously studied DNA glycosylase. It shows a strong preference for a double-stranded substrate, exhibits no cofactor requirement, and has a molecular weight of 20000 - 25000. Since fragmentation of pyrimidine residues is a major type of base lesion introduced in DNA by exposure to ionizing radiation, it seems likely this DNA glycosylase is active in repair of X-ray-induced lesions.

DNA↗
PubMed1986

Sensitization of the Escherichia coli cyclic AMP receptor protein to trypsin cleavage by polydeoxyribonucleotides and polyribonucleotides.

In the absence of cAMP the cyclic AMP receptor protein (CRP) is relatively resistant to trypsin whereas the cAMP X CRP complex is attacked yielding N-terminal core fragments of 14,300 and 18,500 Da which still bind cAMP. The DNA X CRP complex formed at low ionic strength in the absence of cAMP is cleaved by trypsin with the formation of 9,700- and 6,000-Da fragments and the concomitant loss of cAMP binding activity. DNA X CRP remains as resistant to attack by subtilisin, clostripain, and the Staphylococcus aureus V8 protease as unliganded CRP but is slowly digested by chymotrypsin. All of the double-stranded polydeoxyribonucleotides and several of the single-stranded polydeoxyribonucleotides and polyribonucleotides tested render CRP sensitive to cleavage by trypsin. CRP is less rapidly cleaved by trypsin in the presence of d(A)n, d(I)n, and r(C)n indicative of a weaker affinity of CRP for these polynucleotides. The 9,700-Da fragment is N-terminal in CRP and probably terminates at Lys-89. The loss of cAMP binding activity following trypsin cleavage of DNA X CRP indicates that regions beyond this residue are important in the function of the cAMP-binding domain of CRP. The 6,000-Da fragment extends from Val-131 to Arg-185 or Lys-188 and contains part of the F helix involved in DNA binding by CRP.

Amino Acid Sequence↗
PubMed1999

Effect of polydeoxyribonucleotides on human fibroblasts in primary culture.

The effects of a mixture of oligo- and polydeoxyribonucleotides (PDRN) on the growth and protein secretion of cultured human skin fibroblasts were investigated. Both intact and DNAase-digested PDRN stimulated cell proliferation to a similar extent. When cultured fibroblasts were incubated with radioactive amino acids in the presence of intact or digested PDRN the incorporation of the tracer into secreted proteins increased significantly. This stimulation appears to be specific for certain protein components, including fibronectin. These results are interpreted assuming that PDRN and the nucleotides and nucleosides resulting from its degradation, can act as signal transducers or, alternatively, can be internalized and utilized to provide purine and pyrimidine rings for the salvage pathways.

Cell Division↗
PubMed1997

Evaluation of the trophic effect of human placental polydeoxyribonucleotide on human knee skin fibroblasts in primary culture.

A simple assay capable of evaluating the trophic effect of growth factors or active principles on human skin diploid fibroblasts in primary culture has been developed. The results indicate that at physiological concentrations (20-100 micrograms/ml) a human placental polydeoxyribonucleotide (PDRN) preparation enhances the growth of human skin diploid fibroblasts of the knee in primary culture. This effect is consistently reproducible in the case of patients over 60 years of age, and may explain previously reported data on the successful clinical applications of human placental preparations, suggesting a selective benefit of PDRN in wound healing when compared to other treatments.

Cell Line↗
PubMed1977

Interaction of cis- and trans-dichlorodiammine-platinum(II) with synthetic polydeoxyribonucleotides: effect of equilibrium buoyant densities.

Equilibrium buoyant densities in CS2SO4 of four synthetic double-stranded polydeoxyribonucleotides were compared following reaction with either cis-Pt(NH3)2Cl2, trans-Pt(NH3)2Cl2 or PtCl4. While both Pt(NH3)2Cl2 isomers caused significant increases in the buoyant densities (rho) of the two G + C polymers, the cis- isomer increased the rho of poly [d(G-C)] and the trans- isomer increased the rho of poly(dG) - poly(dC) more sharply than the corresponding isomer at low molar ratios of metal ion to polymer. Chloroplatinic acid was without effect. Only cis-Pt(NH3)2Cl2 produced substantial increases in the rho of poly[d(A-T)] and poly(dA) - poly(dT) with increasing metal ion concentrations. These increases were accompanied by a proportional decrease in the thermal transition temperature (Tm) of poly(dA)-poly(dT) and a sharp increase in the Tm of poly[d(A-T)]. Our results indicate that the cis- isomer reacts with all four polymers to produce rho changes clearly distinct from those values observed after reaction with either the trans- isomer or PtCl4. These results help explain the observation by others that the cis- isomer produces greater rho changes in native DNA than the trans- isomer. On the basis of our data and the published results of others, one may rationalize the quantitative differences between the cis- and trans-compounds of the buoyant densities of naturally occurring DNA; however, additional studies are clearly needed.

Binding Sites↗
PubMed1997

Polydeoxyribonucleotide (defibrotide) protects against post-ischemic behavioral, electroencephalographic and neuronal damage in the gerbil.

The effectiveness of defibrotide, a single-stranded polydeoxyribonucleotide compound, in preventing damage caused by cerebral ischemia was studied. Global ischemia was induced in anesthetized gerbils by bilateral carotid artery occlusion for 10 min. Defibrotide (100 mg/kg) or saline was injected, i.v., immediately after reperfusion. The following parameters were evaluated simultaneously: (1) electroencephalographic (EEG) spectral power, recorded before, during and after the ischemic period; (2) body temperature, monitored with a rectal thermistor probe after reperfusion for 120 min; (3) spontaneous motility, evaluated through a photocell system and quantified in terms of total distance travelled in 30 min, 1 h after recirculation and at periods over 15 days; (4) mnemonic functions assessed by passive avoidance test from 3 to 15 days after ischemia; (5) histological examination, 7 days after reperfusion, counting CA1 hippocampal neuronal cells. The ischemia-induced complete flattening of spectral power was significantly reversed (P < 0.01) by post-ischemic treatment with defibrotide between 30 and 90 min after ischemia. A complete recovery of total EEG spectral power was seen in the defibrotide group at 6 h and the saline ischemic group at 1 day. Seven days after bilateral carotid occlusion, there was a significant decrease in spectral power (-70% +/- 6) together with a loss of the number of CA1 cells in the saline ischemic group (-64%). Treatment with defibrotide significantly protected against the decrease in spectral power (-30% +/- 7) and cell loss (-9%). Finally, the number of animals found to be protected against the ischemia-induced flattening was significantly larger for defibrotide-treated gerbils than for saline-treated animals throughout the experiment except for the third day. Body temperature was significantly decreased only at 30 min after reperfusion in both ischemic and sham-operated groups. Defibrotide reduced ischemia-induced hypermotility but only 6 h after the insult. The ischemia-induced impairment of memory was partially reversed within 3 days in the defibrotide-treated animals and fully reversed within 7 days in the defibrotide group and 15 days in the saline group. Our results demonstrate that defibrotide, even when administered after the post-ischemic period, possesses anti-ischemic properties. The mechanism by which defibrotide protects the ischemic reperfused brain is still largely unknown. However, a neuroprotection via adenosine A1 and A2 subtype receptor interaction can be put forward.

Animals↗
PubMed2003

Polydeoxyribonucleotide C photoconjugated with lysine or arginine present unique epitopes for human anti-DNA autoantibodies.

Studies have been carried out to synthesize and characterize the photoconjugates between positively charged amino acids (lysine and arginine) and the polydeoxyribonucleotide C [poly(dC)]. Poly(dC) was covalently crosslinked with lysine or arginine under ultraviolet light. Both lysine and arginine were found covalently photoconjugated to poly(dC), resulting in the formation of photoadduct. Photoaddition of lysine or arginine to poly(dC) rendered them thermodynamically more stable than their native form. A strong recognition of photoadducts was observed with anti-DNA autoantobodies found in the sera of systemic lupus erythematosus (SLE) patients. Poly(dC)-lysine was recognized more strongly than poly(dC)-argine photoadduct. Poly(dC)-lysine photoadduct appears to provide an immunodominant epitope for SLE autoantibody recognition. The result suggests for the possible involvement of these photoadducts as a potential trigger for anti-DNA autoantibody production.

Antibodies, Antinuclear↗
PubMed2000

Thienocoumarin derivatives: interaction with nucleic acids and synthetic polydeoxyribonucleotides.

This paper reports the photobiological properties of two new thienocoumarins, 4,6,9-trimethyl-2H-thieno[3,2-g]-1-benzopyran-2-one (compound I) and the 6,9-dimethyl-4-methoxymethyl-2H-thieno[3,2-g]-1-benzopyran-2-one (compound II). Cell growth inhibition studies have revealed significant antiproliferative potency on human tumor cell lines. The photoaddition process of these tritium-labeled derivatives was investigated using various nucleic acid structures (calf thymus DNA, bacterial DNA, and synthetic polydeoxyribonucleotides). The results obtained show that both compounds photobind to DNA to a higher extent than 8-MOP, taken as the reference drug. The capacity to form interstrand crosslinks into DNA helix was also evaluated. Interestingly, notwithstanding the lack of cutaneous phototoxicity, II revealed a good ability to induce diadduct formation.

Animals↗
PubMed1984

Enzymatic excision from gamma-irradiated polydeoxyribonucleotides of adenine residues whose imidazole rings have been ruptured.

The main forms of base damage in polydeoxyadenylic acid gamma-irradiated under hypoxic conditions are due to saturation and fragmentation of the adenine imidazole ring. An irradiated polymer was annealed with an equimolar amount of poly (dT) to generate a double-stranded polydeoxyribonucleotide containing scattered damaged base residues. On incubation of the latter with partially purified cell extracts of E.coli, imidazole ring-opened adenine, i.e. 4,6-diamino-5-formamidopyrimidine, was released in free form by a DNA glycosylase activity. The enzyme has been purified 4,500-fold, has Mr = 29,000, and appears to be identical with the previously described DNA repair enzyme formamidopyrimidine-DNA glycosylase.

Adenine↗
PubMed1980

Solid-phase synthesis of polynucleotides. IV. Usage of polystyrene resins for the synthesis of polydeoxyribonucleotides by the phosphostriester method.

Contrary to the expectation, the Merrifield polystyrene resin, 2% cross-linked by divinylbenzene, is as efficient as the polyacrylmorpholide resin for the synthesis of polydeoxyribonucleotides using a phosphotriester method. On the Merrifield resin, the tetradecamer, dTpCpGpTpCpApApCpTpGpGpCpTpT, and the hexadecamer, dCpCpApGpTpCpApCpGpApCpGpTpTpGpT, were synthesized by the phosphotriester method using di and trinucleotide blocks as coupling units.

Base Sequence↗
PubMed1995

Polydeoxyribonucleotides and nitric oxide release from guinea-pig hearts during ischaemia and reperfusion.

1. Two polydeoxyribonucleotides, produced by the controlled hydrolysis of DNA of mammalian lung (defibrotide and its lower molecular weight fraction, P.O. 085 DV), were studied for their ability to modify the release of nitrite and the coronary flow in perfusates collected from isolated, normally perfused hearts of guinea-pigs and from hearts subjected to regional ischaemia and reperfusion. 2. In guinea-pig normally perfused hearts, both defibrotide (DFT) and its fraction, P.O. 085 DV, increase the amount of nitrite appearing in perfusates in a concentration-dependent fashion. At the highest concentration studied (10(-6) M), P.O. 085 DV was more effective than DFT. A concomitant increase in the coronary flow was observed. 3. The increase in nitrite in perfusates and the increase in coronary flow induced by both DFT and P.O. 085 DV were significantly reduced by NG-monomethyl-L-arginine (L-NMMA, 10(-4) M), an inhibitor of nitric oxide synthase (NOS). 4. The endothelium-dependent vasodilator, acetylcholine (ACh), enhances the formation of nitrite and the coronary flow. Both the increase in coronary flow and in the formation of nitrite were significantly reduced by L-NMMA (10(-4) M). 5. In guinea-pig hearts subjected to ischaemia and reperfusion, the effect of both compounds in increasing the amount of nitrite in perfusates was more evident and more pronounced with P.O. 085 DV. 6. Reperfusion-induced arrhythmias were significantly reduced by both compounds to the extent of complete protection afforded by compound P.O. 085 DV. 7. The cardioprotective and antiarrhythmic effects of DFT and P.O. 085 DV are discussed.

Acetylcholine↗
PubMed2004

Evaluation of the efficacy of polydeoxyribonucleotides in the healing process of autologous skin graft donor sites: a pilot study.

OBJECTIVE: The article presents the results of a pilot study performed to evaluate the efficacy of polydeoxyribonucleotides (PDRNs) in shortening the healing times of autologous skin graft donor sites. RESEARCH DESIGN, METHODS: Two groups of patients were studied, the PDRN group (n = 20) and a control group (n = 20). In the control group dressings were performed with non-adherent gauzes and bulky gauzes with cloramine solution, whereas in the PDRN group a PDRN ointment was spread under the same medication as the controls. RESULTS: In the PDRN group, dressing procedures were not painful (whereas in the controls they often were), re-epithelialisation occurred earlier (12.5 vs 24.45 days) and there were no infections (9 in the controls). CONCLUSIONS: Results are encouraging for the use of PDRNs in shortening the healing times of autologous skin graft donor sites, although further studies are necessary to obtain clinically relevant results.

Adult↗
PubMed1983

The interaction in vitro of the intermediate filament protein vimentin with synthetic polyribo- and polydeoxyribonucleotides.

In a continuation of our studies on the association of the intermediate filament protein vimentin with unfolded ribosomal subunits, rRNA and various naturally occurring RNAs and DNAs, we have investigated the binding of vimentin to a variety of synthetic polyribo- and polydeoxyribonucleotides. The vimentin-binding potentials of the different nucleic acids were determined in competition with 28S rRNA from Ehrlich ascites tumor cells. The reaction products were analysed by sucrose gradient centrifugation at low ionic strength and in the presence of EDTA. Among the homopolynucleotides tested, poly(rG), poly(rX), poly(rI), poly(rs4U) and poly(dG) were very good competitors, whereas poly(dC) was moderately so. Poly(rA), poly(rU), poly(rC), poly(dA), poly(dU), poly(dT) and poly(dI) were very weak competitors. Annealing of the active homopolymers to their complementary homopolymer strands resulted in a reduction of the vimentin-binding potential; however, the resulting duplexes still had substantial vimentin-binding capacity. A similar reduction was observed when the mononucleotides of the active homopolymers were randomly copolymerized with their complementary nucleotides or incorporated into strictly alternating, double-stranded DNAs. DNA-type copolymers, duplexes and alternating copolymers containing the nuclear bases adenine, thymine and uracil were moderate competitors, but, in general, they were significantly more active than the corresponding homopolymers. This result, together with those of the analysis of a series of random heteropolyribonucleotides, indicates that there is some influence of the base sequence and/or secondary structure of the nucleic acids on their vimentin-binding capacities. Whereas the minimum length of oligo(dG) for efficient vimentin binding was between 11 and 18 nucleotides, (dT)18 was still incapable of interacting with vimentin. In order to obtain information on the salt stability of vimentin-nucleic acid adducts, we have also performed affinity chromatographies on single-stranded calf thymus DNA-cellulose and on rRNA and homopolyribonucleotides covalently coupled to agarose. Although because of unspecific secondary interaction of vimentin with the matrix, these nucleic acid-substituted absorbents could not be used for this purpose under non-denaturing conditions, in the presence of 6M urea a relationship between the nucleic acid substitution and the salt stability of vimentin binding was observed. Finally, the nucleic acid-binding properties of vimentin are compared with those of cytosolic steroid hormone receptors, particularly with those of the androgen receptor.

Animals↗
PubMedDate not supplied

[Interaction of topotecan, DNA topoisomerase I inhibitor, with double-stranded polydeoxyribonucleotides. 4. Topotecan binds preferably to the GC base pairs of DNA].

Interaction of topotecan (TPT) with synthetic double-stranded polydeoxyribonucleotides has been studied in solutions of low ionic strength at pH = 6.8 by linear flow dichroism (LD), circular dichroism (CD), UV-Vis absorption and Raman spectroscopy. The complexes of TPT with poly(dG-dC).poly(dG-dC), poly(dG).poly(dC), poly(dA-dC).poly(dG-dT), poly(dA).poly(dT) and previously studied by us complexes of TPT with calf thymus DNA and coliphage T4 DNA have been shown to have negative LD in the long-wavelength absorption band of TPT, whereas the complex of TPT with poly(dA-dT).poly(dA-dT) has positive LD in this absorption band of TPT. Thus, there are two different types of TPT complexes with the polymers. TPT has been established to bind preferably to GC base pairs because its affinity to the polymers of different GC composition decreases in the following order: poly(dG-dC).poly(dG-dC) > poly(dG).poly(dC) > poly(dA-dC).poly(dG-dT) > poly(dA).poly(dT). The presence of DNA has been shown to shift monomer-dimer equilibrium in TPT solutions toward dimer formation. Several duplexes of the synthetic polynucleotides bound together by the bridges of TPT dimers may participate in the formation of the studied type of TPT-polynucleotide complexes. Molecular models of TPT complex with linear and ring supercoiled DNAs and with deoxyguanosine have been considered. TPT (and presumably all camptothecin family) proved to be a representative of a new class of DNA-specific ligands whose biological action is associated with formation of dimeric bridges between two DNA duplexes.

Base Pairing↗
PubMed2003

A human placental polydeoxyribonucleotide (PDRN) may promote the growth of human corneal fibroblasts and iris pigment epithelial cells in primary culture.

The optimal concentration of a human placental polydeoxyribonucleotide (PDRN) preparation (100 microg/ml) enhances the growth of human corneal fibroblasts in primary culture depending upon the donor age. In particular, this effect is very consistently reproducible with donors over 60 years of age (p = 0.0028), suggesting a selective benefit of PDRN in the tissue culture of senescent cells. Moreover, this drug may promote the development of human iris pigment epithelium (IPE) cells with much lower concentrations of fetal bovine serum than those suitable for the culture of IPE. Lastly, the use of a 'gauze disk' on the pieces of the corneal explants improves the efficiency of growth of the control fibroblast primary cultures.

Adolescent↗