Biomedical subjects

S Moreau

Publications and source records attributed to S Moreau.

At least 55 records · Page 3Linked to original sources

PubMed1997

[Oxaliplatin, folinic acid and 5-fluorouracil (folfox) in pretreated patients with metastatic advanced cancer. The GERCOD].

Preliminary studies suggest synergy between oxaliplatin and fluorouracil (5-FU). To assess this issue, we performed a study in pretreated patients with advanced colorectal cancer (CRC) resistant to leucovorin and 5-FU. Regimen consisted of oxaliplatin day 1, 130 mg/m2 every two cycles (folfox 1) or 100 mg/m2/cycle (folfox 2) or 85 mg/m2/cycle (folfox 3) and leucovorin 500 mg/m2 as a 2-hour infusion, followed by 5-FU 22 h infusion 1.5-2 g/m2 for two consecutive days every 2 weeks. One hundred and thirteen patients have been treated. One complete response (CR) and 32 partial responses (PRs) were observed for an overall response rate of 29.2%. Sixty-seven patients had prior documented progression while receiving the same schedule of leucovorin and 5-FU than the one used in the folfox regimens, among them 18 had PRs (26.9%). The best response rate was observed in patients treated with the folfox 2 regimen: 41.7%. From start of folfox, median progression-free survival was 6 months and median survival 13 months. Limiting toxicities were peripheral neuropathy and neutropenia. Fifty-four percent of the patients experienced WHO toxicity > or = grade 3 with the folfox1 regimen, 45% with the folfox2 and 40% with the folfox3. The folfox regimens achieve a high response rate in pretreated patients with CRC. Further studies are needed to determine the best oxaliplatin dose-intensity.

Adult↗

PubMed1997

Pharmacophore requirements in new series of pyridazinyl alkanoic acids, N-[(pyridazin-2-yl) alkyl] succinyl and glutaryl amides, inhibitors of thromboxane A2 biosynthesis.

New series of 5-benzyl-6-methyl-4-oxo pyridazin-2-yl alkanoic acids, N-[(pyridazin-2-yl)alkyl] succinyl and glutaryl amides have been synthesized and evaluated in vitro as TXA2 biosynthesis inhibitors. The experiments were carried out using arachidonic acid (32.8 microM) as a substrate and horse platelet microsomes as sources of TXA2 synthase. The presence of TXB2, a stable metabolite of TXA2, was determined by RIA. The potency of active compounds (1.10(-4) < IC 50 < 1.10(-6) M) greatly depends on the length of the chain at the N-2 position on the pyridazine ring. Furthermore, enzyme inhibition in vitro is increased with the presence of a halogen atom on the aromatic moiety of the benzyl group at C-5. Compound 4f having a pentanoic side chain and a 4-fluoro benzyl moiety was the most active derivative with an IC50 value of 6.69 x 10(-6) M. Molecular modelling studies were done on all the synthesized pyridazinones and on prostaglandin H2 (PGH2) suggesting spatial features and volumes of TXA2 synthase pharmacophore mode in these series of derivatives.

Amides↗

PubMed1997

Oxaliplatin with high-dose leucovorin and 5-fluorouracil 48-hour continuous infusion in pretreated metastatic colorectal cancer.

Oxaliplatin has shown in vivo cytotoxic activity against colorectal cell lines. Preliminary studies suggest potentiation of fluorouracil (5-FU). To assess this issue, we performed a phase II study in pretreated patients with advanced colorectal cancer (CRC) resistant to leucovorin and 5-FU. The regimen (FOLFOX2) consisted of oxaliplatin 100 mg/m2 as a 2-h infusion on day 1; leucovorin 500 mg/m2 as a 2-h infusion, followed by 5-FU 24-h infusion 1.5-2 g/m2 for two consecutive days every 2 weeks. The initial 5-FU dose was 1.5 g/m2 for two cycles and increased to 2 g/m2 in case of no toxicity > grade 2. 46 patients were treated, all with disease progression on leucovorin and 5-FU therapy for metastatic disease, or relapse less than 6 months after the end of adjuvant therapy. One complete response (CR) and 20 partial responses (PRs) were observed for an overall response rate of 46%. 22 patients had prior documented progression while receiving the same schedule of leucovorin and 5-FU as the one used in the FOLFOX2 regimen, and among them, 10 had PRs (45%). From the start of FOLFOX2, median progression-free survival was 7 months and median survival 17 months. WHO toxicity > or = grade 3 per patient was: peripheral neuropathy 9%, nausea 4%, diarrhoea 9%, mucositis 13%, neutropenia 39%, thrombocytopenia 11%, alopecia 9%, and allergy 2%. Overall, 21 patients (46%) experienced grade 3-4 toxicity. This combination of leucovorin, 5-FU and oxaliplatin achieves a high response rate in pretreated patients with CRC resistant to leucovorin and 5-FU. Limiting toxicities are neutropenia and peripheral neuropathy.

Adenocarcinoma↗

PubMed1997

Phosphorothioate oligonucleotides derived from human immunodeficiency virus type 1 (HIV-1) primer tRNALys3 are strong inhibitors of HIV-1 reverse transcriptase and arrest viral replication in infected cells.

Retroviral reverse transcriptase (RT) is involved in the selection of a specific tRNA primer which initiates proviral DNA minus-strand synthesis. Studies of the interactions between human immunodeficiency virus type 1 (HIV-1) RT and primer tRNALys3 have shown that the dihydrouridine (diHU), anticodon, and pseudouridine regions of tRNA are highly protected in the RT-tRNA complex. The CCA 3' end of tRNA is also in close contact with the enzyme during the cDNA initiation step. Using synthetic oligoribonucleotides corresponding to the anticodon and diHU regions, we have previously shown a low but significant inhibition of HIV-1 RT activity. We extend this observation and show that primer tRNA-derived oligodeoxynucleotides (ODNs) carrying a phosphorothioate (PS) modification are strong inhibitors of HIV-1 RT. The affinity of PS-ODNs for the enzyme was monitored by gel mobility shift electrophoresis. Experiments with HIV-1-infected human cells (MT-2 cells) were performed with the latter ODNs. A PS-ODN corresponding to the 3' end of tRNALys3 (acceptor stem [AS]) was able to inhibit HIV-1 replication. No effect of the other modified ODNs was observed in infected cells. The analysis of HIV-1 RNase H activity in a cell-free system strongly suggests that the inhibitory effect of the PS-AS may be mediated via both a sense and an antisense mechanism.

Adsorption↗

PubMed1997

[Temporal fibrous dysplasia with labyrinthine involvement. Apropos of a case and review of the literature].

Craniofacial fibrous dysplasia manifests clinically with dysmorphic syndrome, ophtalmologic or otologic signs. We report a case of temporal polyostotic fibrous dysplasia with vertigo and sensorineural hearing loss. Sensorineural hearing loss, with no cholesteatoma associated, as described in our case is rarely described. We review the literature concerning main clinical, diagnostic and therapeutic aspects of this disease.

Aged↗

PubMed1996

Leghemoglobin-derived radicals. Evidence for multiple protein-derived radicals and the initiation of peribacteroid membrane damage.

Reaction of H2O2 with ferric leghemoglobin (metLb, the monomeric, oxygen-carrying, heme protein from root nodules of nitrogen-fixing plants) has been previously shown to generate an iron(IV)-oxo (ferryl) species and at least one protein radical. The latter has been suggested to be a tyrosine-derived phenoxyl radical present at Tyr-133 in the soybean protein and Tyr-138 in the lupin protein. To obtain further information on these protein radicals and their potential interaction with the physiologically important peribacteroid membrane (which surrounds the microsymbiont in vivo), EPR spin trapping studies have been carried out with soybean metLb. Evidence has been obtained for at least two additional protein-derived radicals in addition to the phenoxyl radical; these radicals are transient and reactive in nature. These species are carbon-centered, and at least one is a tertiary species (.CR1R2R3); these radicals may be side chain- or alpha-carbon-derived, their exact sites have not been determined. Some of these radicals are on the protein surface and may be key intermediates in the formation of protein dimers. These radicals have been shown to be capable of reacting with peribacteroid membrane fractions, with the consequent generation of lipid-derived radicals. The formation of such radicals may result in the depletion of membrane antioxidants and the initiation of lipid peroxidation. This transfer of damage from the heme center via the protein surface to neighboring membranes may be of considerable biological significance; the destruction of this membrane is one of the earliest observable events in root nodule senescence and is associated with the loss of nitrogen-fixing activity.

Electron Spin Resonance Spectroscopy↗

PubMed1996

Quinazoline-2,4(1H,3H)-dione as a substitute for thymine in triple-helix forming oligonucleotides: a reassessment.

A major limitation in triple-helix formation arises from the weak energy of interaction between the third strand and the double-stranded target. We tried to increase the stacking interaction contribution within the third strand by extending the aromatic domain of thymine. We report here the use of 2,4-quinazolinedione as a substitute for thymine in the canonical TA*T triplet. The synthesis and the characterization of the quinazoline beta nucleoside Q and of its phosphoramidite derivative is described. Triple-helix- forming oligonucleotides incorporating Q have been prepared and their ability to form triplexes has been evaluated by UV-monitored thermal denaturation measurements. The introduction of one or multiple Q residues, either contiguous or remote from each other, slightly destabilized triple-stranded structures, whatever the nucleic acid base composition (pyrimidine or GT) of the third strand.

Drug Stability↗

PubMed1996

Antisense oligonucleotides inhibit in vitro cDNA synthesis by HIV-1 reverse transcriptase.

The inhibition of reverse transcription by various chemically modified antisense oligonucleotides was studied in a cell-free system, composed of an RNA template, a primer oligodeoxynucleotide, and the HIV-1 reverse transcriptase (RT). Different mechanisms of inhibition were observed depending on the chemical structure of the antisense molecule. (1) The hybridization of 2'-O-allyl oligonucleotide to the RNA template promotes a physical arrest of the polymerase. (2) The antisense effect of phosphodiester or phosphorothioate oligonucleotides is essentially due to the RNase H-mediated cleavage of the RNA. (3) A third mechanism was observed with phosphorothioate oligonucleotides that directly interact with the enzyme. Chimeric oligonucleotides, composed of an unmodified region flanked by 2'-O-methyl groups, led to less efficient inhibition than the parent unmodified oligomer, although the inhibitory mechanism was the same. No inhibitory effect was detected when alpha or methylphosphonate oligomers were used.

Antiviral Agents↗

PubMed1996

Cloning and characterization of the katA gene of Rhizobium meliloti encoding a hydrogen peroxide-inducible catalase.

To investigate the involvement of bacterial catalases of the symbiotic gram-negative bacterium Rhizobium meliloti in the development of Medicago-Rhizobium functional nodules, we cloned a putative kat gene by screening a cosmid library with a catalase-specific DNA probe amplified by PCR from the R. meliloti genome. Nucleotide sequence analysis of a 1.8-kb DNA fragment revealed an open reading frame, called katA, encoding a peptide of 562 amino acid residues with a calculated molecular mass of 62.9 kDa. The predicted amino acid sequence showed a high homology with the primary structure of monofunctional catalases from eucaryotes and procaryotes. The katA gene was localized on the chromosome, and the katA gene product was essentially found in the periplasmic space. A katA::Tn5 mutant was obtained and showed a drastic sensitivity to hydrogen peroxide, indicating an essential protective role of KatA. However, neither Nod nor Fix phenotypes were impaired in the mutant, suggesting that KatA is not essential for nodulation and establishment of nitrogen fixation. Exposure to a sublethal concentration of H2O2 enhanced KatA activity (100-fold) and also increased survival to subsequent H2O2 exposure at higher concentrations. No protection is observed in katA::Tn5, indicating that KatA is the major component of an adaptive response.

Adaptation, Physiological↗

PubMed1996

Genetic characterization of site-specific integration functions of phi AAU2 infecting "Arthrobacter aureus" C70.

All the essential genetic determinants for site-specific integration of corynephage phi AAU2 are contained within a 1,756-bp DNA fragment, carried on the integrative plasmid p5510, and are shown to be functional in Escherichia coli. One open reading frame, ORF4, encoding a protein of 266 amino acids was shown to represent the phi AAU2 integrase. The nucleotide sequence of the phi AAU2 attachment site, attP, and the attB, attL, and attR sequences in the host "Arthrobacter aureus" C70 were determined. Identical nucleotide sequences were shown to be responsible for the integration of p5510 in the chromosomes of Corynebacterium glutamicum, Brevibacterium divaricatum, and B. lactofermentum, and a sequence almost identical to attB was found to be present in these three strains. In contrast to other phage site-specific recombination systems, a plasmid encompassing only int-attP failed to integrate into the host chromosome. This led to the identification of an 800-bp noncoding region, immediately upstream of int, absolutely required for site-specific integration of p5510.

Amino Acid Sequence↗

PubMed1996

Antibodies to cardiolipin and beta 2 glycoprotein I in patients with polymyalgia rheumatica and giant cell arteritis.

IgG antibodies to cardiolipin and beta 2-glycoprotein I were looked for using an enzyme-linked immunosorbent assay (ELISA) in 19 patients with giant cell arteritis (meeting 1990 American College of Rheumatology criteria), including 16 with concomitant polymyalgia rheumatica (meeting Bird's criteria) and in three patients with isolated polymyalgia rheumatica. IgG anti-cardiolipin antibodies were demonstrated in eight patients (36%) and IgG anti-beta 2-glycoprotein I antibodies in two patients (9%) including one without anti-cardiolipin antibodies. Titers of anti-cardiolipin antibodies ranged from 27 to 190 units of IgG antiphospholipid antibodies (UGPL) (mean 71 UGPL). Of the eight patients with anti-cardiolipin antibodies, two had giant cell arteritis without polymyalgia rheumatica and six had polymyalgia rheumatica with clinical (n = 2) or histologic (n = 4) evidence of giant cell arteritis. None of the three patients with polymyalgia rheumatica but no giant cell arteritis had anti-cardiolipin or anti-beta 2 glycoprotein I antibodies. The VDRL was negative in the 14 patients who had this test. Tests for lupus anticoagulant were performed routinely, always with negative results. Among giant cell arteritis patients, those who tested positive for anticardiolipin antibody had significantly higher values for the erythrocyte sedimentation rate (p < 0.006) and for serum C-reactive protein (p < 0.03) and fibrinogen values (p = 0.05), and a trend toward higher platelet counts, as compared to those who tested negative for anticardiolipin antibody. The mean daily prednisone dose at the time of sampling was significantly lower in giant cell arteritis patients with anti-cardiolipin antibodies (p < 0.05); this difference may account for the apparent correlation between anti-cardiolipin antibodies and laboratory markers for inflammation. These data, as well as findings from serial measurements, suggest that anti-cardiolipin antibodies are present early in the course of giant cell arteritis and disappear within a few weeks of initiation of corticosteroid therapy in a dose of more than 25 mg prednisone per day. In this study, only one patient without anticardiolipin antibodies developed a cerebrovascular accident. Positive tests for anti-cardiolipin antibody or anti-beta 2 glycoprotein I antibody in a patient with polymyalgia rheumatica suggest a diagnosis of concomitant giant cell arteritis, which is usually symptomatic.

Aged↗

PubMed1996

Dual modulation of 5-fluorouracil with folinic acid and hydroxyurea in metastatic colorectal cancer.

Leucovorin and 5-fluorouracil (5-FU) can be further modulated with hydroxyurea. Sixty-eight patients with advanced colorectal cancer received every 2 weeks hydroxyurea per os 1.5 g to 2 g days -1, 1, and 2; leucovorin 200 mg/m2 iv over 2 hours started at least 1 hour after hydroxyurea and per os 100 mg/m2 12 hours later, on days 1 and 2; 5-FU, bolus 400 mg/m2 during leucovorin infusion and 24 hours continuous infusion 600 mg/m2, repeated on days 1 and 2. Two complete responses (7%), 8 partial responses (30%), 12 no change (44%), and 5 progressions (19%) were observed among 31 nonpreviously treated patients. Four partial response (11%), 15 no change (43%), and 16 progressions (46%) were observed among 37 pretreated patients. Nineteen were treated after progression on the same regimen without oral leucovorin and hydroxyurea, 1 achieved PR and 10 showed no change. Among them, 6 experienced response or stabilization of longer duration than with previous treatment. Twelve-month survival was 61% in non-pretreated and 43% in pretreated patients as of the start of chemotherapy. Toxicity was mild with nausea in 46%, diarrhea in 37%, and mucositis in 36%. The first-line response rate is in the range of leucovorin and 5-FU alone. Some pretreated patients benefited from this regimen.

Adenocarcinoma↗

PubMed1996

[A case of Kikuchi disease. Review of the literature].

We report a case of Kikuchi's disease in a young man. It is a rare entity, described for the first time in 1972. It manifests clinically with cervical adenopathy and fever, often associated with other non-specific clinical signs. Laboratory tests are often normal. The diagnosis is established on the basis of histologic of lymph node excisional biopsy. Kikuchi's disease is likely to be misinterpreted as malignant lymphoma or systemic lupus erythematosus. It generally needs no treatment because it runs a spontaneously benign course with complete resolution of the symptoms within 6 months. Secondary systemic lupus erythematosus may develop. For this reason, regular follow-up of patients is recommended. The etiopathogenesis of this disease is still unknown, perhaps due to an immunologic phenomenon. It could be a hyperimmune reaction induced by various antigenic agents (infectious, neoplasic), or an autoimmune process.

Adult↗

PubMed1996

Synthesis of peripherally acting analgesic 3-arylpiperazinyl-5-benzyl-pyridazines.

A series of 3-arylpiperazinyl-5-benzyl-pyridazines was synthesized and evaluated for analgesic activity. The structures of these new pyridazine derivatives were confirmed by IR, 1H-NMR spectra and by elementary analysis. With ED50 values ranging from 6.0 to 71.5 mg/kg i.p. most of the compounds were several times more potent than acetaminophen (ED50 = 228.6 mg/kg i.p.) and noramidopyrine ((ED50 = 68.8 mg/kg i.p.) in the phenylbenzoquinone-induced writhing test (PBQ-test). Quantitative structure-activity relationships were accomplished by a Hansch analysis. The most active pyridazines 2h-j exhibited sedative properties from the dose of 25 mg/kg i.p. Their lack of activity in the hot plate test was in favour of peripherally acting agents. In the PBQ test, analgesic activity of 2h-j was antagonized by naloxone. However, their antinociceptive effect added up to those of 5-hydroxytryptophan when given in association with carbidopa. These results demonstrated that analgesic properties of pyridazine derivatives might involve a serotonergic pathway without interaction with opiodergic systems.

5-Hydroxytryptophan↗

PubMed1995

Improved leishmanicidal effect of phosphorotioate antisense oligonucleotides by LDL-mediated delivery.

We have designed antisense oligonucleotides that can interact with lipoproteins in order to use them as vectors to facilitate the uptake by those cells expressing the corresponding receptor. Phosphorothioate (PS) oligonucleotides were linked at the 5' end to a palmityl group giving rise to PSPal conjugates. Such a modification enables the oligonucleotide to form a stable non-covalent complex with low density lipoproteins (LDL) through hydrophobic interactions. The antisense effect of LDL-oligonucleotide complexes was assayed by targeting the mini-exon sequence of Leishmania amazonensis in infected mouse peritoneal macrophages. A 16-mer antisense PSPal oligonucleotide/LDL complex exerted a more pronounced sequence-specific effect than the free oligomer: about 25% and 10% of infected macrophages were cured by a 48 h incubation in the presence of 2.5 microM of the complexed and the free oligomer, respectively. When oxidized LDL was used instead of the native one for complexation, a further 2-fold increase in the antisense effect was observed suggesting that alternative (unregulated) scavenger receptor can be used for more efficient delivery of antisense oligonucleotides into macrophages. In addition, a significant reduction of the parasitic load was observed in those cells that were not fully cured.

Animals↗

PubMed1995

Reaction of ferric leghemoglobin with H2O2: formation of heme-protein cross-links and dimeric species.

Ferric leghemoglobin in the presence of H2O2 is known to give rise to protein radicals, at least one of which is centred on a tyrosine residue. These radicals are quenched by at least two processes. The first one involves an intramolecular heme-protein cross-link probably involving the tyrosine radical; this leads to the formation of a green compound with spectral characteristics differing markedly from those of ferryl and ferric leghemoglobin. This green compound cannot be reduced by dithionite or ascorbate, precluding any role for this species as an oxygen carrier. It exhibits modified EPR and pyridine haemochromogen spectra, indicating that alterations occur at the porphyrin macrocycle level. The additional compound previously described [Puppo, A., Monny, C. and Davies, M.J. (1993) Biochem. J. 289, 435-438] appears to be a mixture of ferry Lb and this green compound. The second quenching route results in the formation of intermolecular cross-links and hence dimeric forms of the protein. Ascorbate and glutathione inhibit both this intermolecular dimer formation and the formation of the intramolecular haem-protein cross-links and are likely to play a protective role in vivo.

Electron Spin Resonance Spectroscopy↗

PubMed1995

Uptake of iron by symbiosomes and bacteroids from soybean nodules.

Symbiosomes and bacteroids isolated from soybean nodules are able to take up the iron-citrate complex. The kinetics are characterized by initial high rates of iron internalization, and ATPase inhibitors significantly lower the uptake. This is consistent with an energy-dependent process on both membranes, although the involvement of a simultaneous facilitated diffusion can not be completely ruled out. Citrate alone is poorly absorbed by symbiosomes; this uptake is greatly enhanced by addition of iron. Iron-citrate was found both in the nodule cytosol and in the bacteroids. These results provide the first experimental evidence for the existence, at least in young nodules, of an important iron trafficking system from the plant host cell to the microsymbiont, through the peribacteroid membrane.

Arsenates↗

PubMed1995

The reactivity of ascorbate with different redox states of leghaemoglobin.

Ascorbate has been previously shown to reduce the short-lived and reactive ferryl [Fe(IV) = O] states of myoglobin and haemoglobin. In this study it is shown that ascorbate is also able to reduce the otherwise long-lived and stable ferryl species [Lb(IV)] formed by the reaction of ferric or ferrous soybean leghaemoglobin with H2O2. The conversion of the ferryl species to ferric Lb, which appears to be moderately fast, is followed by a slow conversion of ferric Lb to oxyLb, by way of dexoy ferrous Lb. No reaction between ascorbate and oxyLb has been observed, in contrast to the previously reported pro-oxidant effect of ascorbate on oxymyoglobin. The addition of ascorbate prior to H2O2 to ferric Lb also prevents the formation of an additional species (which is not observed with myoglobin or haemoglobin); the optical spectra and migration on isoelectric focusing gels of this compound differ markedly from that of Lb(IV). When added after H2O2, ascorbate is able to reduce slowly this additional compound to oxyLb. These reactions are likely to occur in vivo as high ascorbate concentrations have been detected in soybean nodules. The reduction of Lb(IV) to ferric Lb is accompanied by oxidation of ascorbate, which has been detected by loss of the parent molecule in optical experiments and by the direct detection of ascorbate radicals by electron paramagnetic resonance (EPR) spectroscopy.(ABSTRACT TRUNCATED AT 250 WORDS)

Ascorbic Acid↗