Robert J

References (15)

Title : The Endothelium Is Both a Target and a Barrier of HDL's Protective Functions - Robert_2021_Cells_10_
Author(s) : Robert J , Osto E , von Eckardstein A
Ref : Cells , 10 : , 2021
Abstract : The vascular endothelium serves as a barrier between the intravascular and extravascular compartments. High-density lipoproteins (HDL) have two kinds of interactions with this barrier. First, bloodborne HDL must pass the endothelium to access extravascular tissues, for example the arterial wall or the brain, to mediate cholesterol efflux from macrophages and other cells or exert other functions. To complete reverse cholesterol transport, HDL must even pass the endothelium a second time to re-enter circulation via the lymphatics. Transendothelial HDL transport is a regulated process involving scavenger receptor SR-BI, endothelial lipase, and ATP binding cassette transporters A1 and G1. Second, HDL helps to maintain the integrity of the endothelial barrier by (i) promoting junction closure as well as (ii) repair by stimulating the proliferation and migration of endothelial cells and their progenitor cells, and by preventing (iii) loss of glycocalix, (iv) apoptosis, as well as (v) transmigration of inflammatory cells. Additional vasoprotective functions of HDL include (vi) the induction of nitric oxide (NO) production and (vii) the inhibition of reactive oxygen species (ROS) production. These vasoprotective functions are exerted by the interactions of HDL particles with SR-BI as well as specific agonists carried by HDL, notably sphingosine-1-phophate (S1P), with their specific cellular counterparts, e.g., S1P receptors. Various diseases modify the protein and lipid composition and thereby the endothelial functionality of HDL. Thorough understanding of the structure-function relationships underlying the multiple interactions of HDL with endothelial cells is expected to elucidate new targets and strategies for the treatment or prevention of various diseases.
ESTHER : Robert_2021_Cells_10_
PubMedSearch : Robert_2021_Cells_10_
PubMedID: 33924941

Title : Genome evolution in the allotetraploid frog Xenopus laevis - Session_2016_Nature_538_336
Author(s) : Session AM , Uno Y , Kwon T , Chapman JA , Toyoda A , Takahashi S , Fukui A , Hikosaka A , Suzuki A , Kondo M , van Heeringen SJ , Quigley I , Heinz S , Ogino H , Ochi H , Hellsten U , Lyons JB , Simakov O , Putnam N , Stites J , Kuroki Y , Tanaka T , Michiue T , Watanabe M , Bogdanovic O , Lister R , Georgiou G , Paranjpe SS , van Kruijsbergen I , Shu S , Carlson J , Kinoshita T , Ohta Y , Mawaribuchi S , Jenkins J , Grimwood J , Schmutz J , Mitros T , Mozaffari SV , Suzuki Y , Haramoto Y , Yamamoto TS , Takagi C , Heald R , Miller K , Haudenschild C , Kitzman J , Nakayama T , Izutsu Y , Robert J , Fortriede J , Burns K , Lotay V , Karimi K , Yasuoka Y , Dichmann DS , Flajnik MF , Houston DW , Shendure J , DuPasquier L , Vize PD , Zorn AM , Ito M , Marcotte EM , Wallingford JB , Ito Y , Asashima M , Ueno N , Matsuda Y , Veenstra GJ , Fujiyama A , Harland RM , Taira M , Rokhsar DS
Ref : Nature , 538 :336 , 2016
Abstract : To explore the origins and consequences of tetraploidy in the African clawed frog, we sequenced the Xenopus laevis genome and compared it to the related diploid X. tropicalis genome. We characterize the allotetraploid origin of X. laevis by partitioning its genome into two homoeologous subgenomes, marked by distinct families of 'fossil' transposable elements. On the basis of the activity of these elements and the age of hundreds of unitary pseudogenes, we estimate that the two diploid progenitor species diverged around 34 million years ago (Ma) and combined to form an allotetraploid around 17-18 Ma. More than 56% of all genes were retained in two homoeologous copies. Protein function, gene expression, and the amount of conserved flanking sequence all correlate with retention rates. The subgenomes have evolved asymmetrically, with one chromosome set more often preserving the ancestral state and the other experiencing more gene loss, deletion, rearrangement, and reduced gene expression.
ESTHER : Session_2016_Nature_538_336
PubMedSearch : Session_2016_Nature_538_336
PubMedID: 27762356
Gene_locus related to this paper: xenla-a0a1l8f4t7 , xenla-a0a1l8fbc6 , xenla-a0a1l8fct2 , xenla-q2tap9 , xenla-q4klb6 , xenla-q5xh09 , xenla-q6ax59 , xenla-q6dcw6 , xenla-q6irp4 , xenla-q6pad5 , xenla-q7sz70 , xenla-Q7ZXQ6 , xenla-q66kx1 , xenla-q640y7 , xenla-q642r3 , xenla-Q860X9 , xenla-BCHE2 , xenla-a0a1l8g7v4 , xenla-a0a1l8g1u7 , xenla-a0a1l8fmc5 , xenla-a0a1l8g467 , xenla-a0a1l8g4e4 , xenla-a0a1l8ga66 , xenla-a0a1l8gaw4 , xenla-a0a1l8gt68 , xenla-a0a1l8h0b2 , xenla-a0a1l8fdr1 , xenla-a0a1l8fdt7 , xenla-a0a1l8fi72 , xenla-a0a1l8fi73 , xenla-a0a1l8fi77 , xenla-a0a1l8fi96 , xenla-a0a1l8hc38 , xenla-a0a1l8hn27 , xenla-a0a1l8hry6 , xenla-a0a1l8hw96 , xenla-a0a1l8i2x6 , xenla-a0a1l8hei7 , xenla-a0a1l8gnd1 , xenla-a0a1l8i2g3 , xenla-a0a1l8hdn0 , xenla-a0a1l8h622

Title : The genome of the Western clawed frog Xenopus tropicalis - Hellsten_2010_Science_328_633
Author(s) : Hellsten U , Harland RM , Gilchrist MJ , Hendrix D , Jurka J , Kapitonov V , Ovcharenko I , Putnam NH , Shu S , Taher L , Blitz IL , Blumberg B , Dichmann DS , Dubchak I , Amaya E , Detter JC , Fletcher R , Gerhard DS , Goodstein D , Graves T , Grigoriev IV , Grimwood J , Kawashima T , Lindquist E , Lucas SM , Mead PE , Mitros T , Ogino H , Ohta Y , Poliakov AV , Pollet N , Robert J , Salamov A , Sater AK , Schmutz J , Terry A , Vize PD , Warren WC , Wells D , Wills A , Wilson RK , Zimmerman LB , Zorn AM , Grainger R , Grammer T , Khokha MK , Richardson PM , Rokhsar DS
Ref : Science , 328 :633 , 2010
Abstract : The western clawed frog Xenopus tropicalis is an important model for vertebrate development that combines experimental advantages of the African clawed frog Xenopus laevis with more tractable genetics. Here we present a draft genome sequence assembly of X. tropicalis. This genome encodes more than 20,000 protein-coding genes, including orthologs of at least 1700 human disease genes. Over 1 million expressed sequence tags validated the annotation. More than one-third of the genome consists of transposable elements, with unusually prevalent DNA transposons. Like that of other tetrapods, the genome of X. tropicalis contains gene deserts enriched for conserved noncoding elements. The genome exhibits substantial shared synteny with human and chicken over major parts of large chromosomes, broken by lineage-specific chromosome fusions and fissions, mainly in the mammalian lineage.
ESTHER : Hellsten_2010_Science_328_633
PubMedSearch : Hellsten_2010_Science_328_633
PubMedID: 20431018
Gene_locus related to this paper: xenla-q6pcj9 , xentr-a9umk0 , xentr-abhdb , xentr-ACHE , xentr-b0bm77 , xentr-b1h0y7 , xentr-b2guc4 , xentr-b7zt03 , xentr-b7ztj4 , xentr-BCHE1 , xentr-BCHE2 , xentr-cxest2 , xentr-d2x2k4 , xentr-d2x2k6 , xentr-f6rff6 , xentr-f6v0g3 , xentr-f6v2j6 , xentr-f6v3z1 , xentr-f6y4c8 , xentr-f6yve5 , xentr-f7a4y9 , xentr-f7acc5 , xentr-f7e2e2 , xentr-LOC394897 , xentr-ndrg1 , xentr-q0vfb6 , xentr-f7cpl7 , xentr-f6yj44 , xentr-f7ejk4 , xentr-f6q8j8 , xentr-f6z8f0 , xentr-f7d709 , xentr-b0bmb8 , xentr-f7af63 , xentr-a0a1b8y2w9 , xentr-f7d4k9 , xentr-f6r032 , xentr-f6yvq3 , xentr-a0a1b8y2z3 , xentr-f7afg4 , xentr-f6xb15 , xentr-f7e1r2 , xentr-a4ihf1 , xentr-f7eue5 , xentr-f6u7u3 , xentr-f172a , xentr-f7equ8 , xentr-f7dd89 , xentr-a9jtx5

Title : Recommended nomenclature for five mammalian carboxylesterase gene families: human, mouse, and rat genes and proteins - Holmes_2010_Mamm.Genome_21_427
Author(s) : Holmes RS , Wright MW , Laulederkind SJ , Cox LA , Hosokawa M , Imai T , Ishibashi S , Lehner R , Miyazaki M , Perkins EJ , Potter PM , Redinbo MR , Robert J , Satoh T , Yamashita T , Yan B , Yokoi T , Zechner R , Maltais LJ
Ref : Mamm Genome , 21 :427 , 2010
Abstract : Mammalian carboxylesterase (CES or Ces) genes encode enzymes that participate in xenobiotic, drug, and lipid metabolism in the body and are members of at least five gene families. Tandem duplications have added more genes for some families, particularly for mouse and rat genomes, which has caused confusion in naming rodent Ces genes. This article describes a new nomenclature system for human, mouse, and rat carboxylesterase genes that identifies homolog gene families and allocates a unique name for each gene. The guidelines of human, mouse, and rat gene nomenclature committees were followed and "CES" (human) and "Ces" (mouse and rat) root symbols were used followed by the family number (e.g., human CES1). Where multiple genes were identified for a family or where a clash occurred with an existing gene name, a letter was added (e.g., human CES4A; mouse and rat Ces1a) that reflected gene relatedness among rodent species (e.g., mouse and rat Ces1a). Pseudogenes were named by adding "P" and a number to the human gene name (e.g., human CES1P1) or by using a new letter followed by ps for mouse and rat Ces pseudogenes (e.g., Ces2d-ps). Gene transcript isoforms were named by adding the GenBank accession ID to the gene symbol (e.g., human CES1_AB119995 or mouse Ces1e_BC019208). This nomenclature improves our understanding of human, mouse, and rat CES/Ces gene families and facilitates research into the structure, function, and evolution of these gene families. It also serves as a model for naming CES genes from other mammalian species.
ESTHER : Holmes_2010_Mamm.Genome_21_427
PubMedSearch : Holmes_2010_Mamm.Genome_21_427
PubMedID: 20931200
Gene_locus related to this paper: human-CES1 , human-CES2 , human-CES3 , human-CES4A , human-CES5A

Title : Functional study of the 830C>G polymorphism of the human carboxylesterase 2 gene - Bellott_2008_Cancer.Chemother.Pharmacol_61_481
Author(s) : Bellott R , Le Morvan V , Charasson V , Laurand A , Colotte M , Zanger UM , Klein K , Smith D , Bonnet J , Robert J
Ref : Cancer Chemother Pharmacol , 61 :481 , 2008
Abstract : PURPOSE: Carboxylesterase 2 (CES2) is involved in the activation of the anticancer drug irinotecan to its active metabolite SN-38. We previously identified a single nucleotide polymorphism (SNP), with an allele frequency around 10%, as possibly involved in enzyme expression (Clin Pharmacol Ther 76:528-535, 2004), which could explain the large individual variation in SN-38 disposition. METHODS: The 830C>G SNP, located in the 5' untranslated region of the gene, was analysed in various DNA samples extracted from: (1) the National Cancer Institute NCI-60 panel of human tumour cell lines; (2) a collection of 104 samples of normal tissue from colorectal cancer patients; (3) blood samples from a population of 95 normal subjects; (4) a collection of 285 human livers. CES2 genotypes were tentatively related to irinotecan cytotoxicity and CES2 expression in the NCI-60 panel; to response to treatment and event-free survival in colorectal cancer patients; and to CES2 expression and catalytic activity in subsets of the human liver collection. RESULTS: No significant relationship was found in the NCI-60 panel between CES2 830C>G genotype and irinotecan cytotoxicity or CES2 expression. No significant relationship was found between CES2 830C>G genotype and the toxicity and therapeutic efficacy (tumour response, event-free survival) of irinotecan in colorectal cancer patients. There was no significant relationship between CES2 830C>G genotype and CES2 expression and catalytic activity determined in a subset of genotype-selected liver samples. CONCLUSION: The 830C>G SNP of CES2 is unlikely to have significant functional consequences on CES2 expression, activity or function.
ESTHER : Bellott_2008_Cancer.Chemother.Pharmacol_61_481
PubMedSearch : Bellott_2008_Cancer.Chemother.Pharmacol_61_481
PubMedID: 17483951
Gene_locus related to this paper: human-CES2

Title : Cellular parameters predictive of the clinical response of colorectal cancers to irinotecan. A preliminary study - Pavillard_2004_Anticancer.Res_24_579
Author(s) : Pavillard V , Charasson V , Laroche-Clary A , Soubeyran I , Robert J
Ref : Anticancer Research , 24 :579 , 2004
Abstract : BACKGROUND: We have examined, in this study, the feasibility of determining cellular factors contributing to irinotecan activity in colorectal cancers. Irinotecan is a camptothecin derivative requiting carboxylesterase activation to SN-38, which interacts with its target enzyme, topoisomerase I. MATERIALS AND
METHODS: In 9 surgical or biopsy samples of colorectal tumours and corresponding normal tissue, kept in a tumour bank, we evaluated topoisomerase I expression and activity, respectively by Western blotting and DNA relaxation assay, carboxylesterase activity using two different substrates and p53 status by immunohistochenistry.
RESULTS: Topoisomerase I expression and activity were significantly correlated, as were the two types of determinations for carboxylesterase activity. Topoisomerase I was significantly more active in tumours than in corresponding normal tissue. The three samples presenting the highest topoisomerase I expression and activity originated from the patients who responded to irinotecan treatment. No such features were apparent for carboxylesterase activity and p53 staining. CONCLUSION: Topoisomerase I expression appeared as the parameter most likely to predict response to irinotecan therapy in the clinical setting.
ESTHER : Pavillard_2004_Anticancer.Res_24_579
PubMedSearch : Pavillard_2004_Anticancer.Res_24_579
PubMedID: 15160997

Title : Pharmacogenetics of human carboxylesterase 2, an enzyme involved in the activation of irinotecan into SN-38 - Charasson_2004_Clin.Pharmacol.Ther_76_528
Author(s) : Charasson V , Bellott R , Meynard D , Longy M , Gorry P , Robert J
Ref : Clinical Pharmacology & Therapeutics , 76 :528 , 2004
Abstract : PURPOSE: Irinotecan, a drug widely used in the treatment of advanced colorectal cancers, is a prodrug requiring activation to 7-ethyl-10-hydroxycamptothecin (SN-38) by carboxylesterase 2 (hCE2). The existence of functional polymorphisms in the gene encoding this enzyme could explain the individual variability in drug efficacy and toxicity. We have explored this possibility in looking for single nucleotide polymorphisms and their functional consequence.
METHODS: In a series of 115 human deoxyribonucleic acid samples, we have explored the 12 exons of the hCE2 gene, the intron-exon junctions, and the 5'- and 3'-untranslated regions, by denaturing HPLC and sequencing of polymerase chain reaction products. The functionality of the variations identified was studied in 60 human liver samples by measuring hCE2 gene expression by real-time reverse transcriptase-polymerase chain reaction of messenger ribonucleic acid extracts and carboxylesterase activity by use of irinotecan as a substrate.
RESULTS: We have identified a total of 11 single nucleotide polymorphisms, none of them able to alter the amino acid sequence of the protein. They are distributed in 10 distinct genotypes in addition to the wild type. The most frequent variation (localized in IVS10) has an allele frequency of 0.17 and has been identified at the homozygous state in 1 sample. hCE2 gene expression and carboxylesterase activity in the variants identified were not significantly different from those measured in wild-type samples. CONCLUSION: The hCE2 gene presents several polymorphisms, none of which seems to be involved in significant variations in protein activity and, therefore, in irinotecan activation.
ESTHER : Charasson_2004_Clin.Pharmacol.Ther_76_528
PubMedSearch : Charasson_2004_Clin.Pharmacol.Ther_76_528
PubMedID: 15592324
Gene_locus related to this paper: human-CES2

Title : Pharmacology of irinotecan - Robert_1998_Drugs.Today.(Barc)_34_777
Author(s) : Robert J , Rivory L
Ref : Drugs Today (Barc) , 34 :777 , 1998
Abstract : Irinotecan (CPT-11) is a semisynthetic derivative of camptothecin, an alkaloid extracted from the Chinese plant Camptotheca acuminata. It bears a bis-piperidine moiety and was selected for its water solubility and promising preclinical antitumor activity in in vitro and in vivo models. The target of drugs of the camptothecin family is DNA topoisomerase I, a nuclear enzyme involved in the relaxation of the DNA double helix required for replication and transcription activities. They stabilize the enzyme-DNA complex and prevent the religation of the single-strand breaks created by the enzyme, which are converted to double-strand breaks upon the collision with a replication fork during the S-phase. Resistance to irinotecan appears not to be mediated by P-glycoprotein, but by qualitative and/or quantitative alterations of its target, topoisomerase I, or by alterations occurring downstream of this interaction. As with all camptothecin derivatives, irinotecan contains a lactone ring that can be spontaneously and reversibly hydrolyzed to a carboxylate open ring form, which predominates at neutral and alkaline pH and is inactive on topoisomerase I-DNA complexes. Irinotecan is, in fact, much less active than its metabolite SN-38 and is generally considered as a prodrug of this compound. The carboxylesterase which carries out this conversion is preferentially active on the lactone form of irinotecan and directly generates the lactone form of SN-38, which may explain the superiority of irinotecan over SN-38 in vivo. Further metabolism of SN-38 to a beta-glucuronide conjugate is a major pathway of detoxification and plays an important role in determining irinotecan toxicity in the clinical setting. Other metabolic pathways of irinotecan involve oxidations occurring on the bis-piperidine rings, which are carried out by cytochrome P450. Irinotecan has shown an important activity in advanced and metastatic colorectal carcinoma and is now used for this indication in several countries, with two different recommended schedules: weekly administration of 125 mg/m(2) with a 2-week drug-free interval every 4 administrations or 3-weekly administration of 350 mg/m(2), a dose that can be increased to 500 mg/m(2) with the support of antidiarrhetics. Other possible indications of irinotecan include lung and cervix cancer, which are presently under investigation. The dose-limiting toxicity of irinotecan is mainly diarrhea, which occurs 7-10 days after treatment and can be life-threatening when associated with neutropenia, another frequent side effect. High-dose loperamide has shown good efficacy for treating this diarrhea and has allowed an increase in irinotecan doses tolerated by patients. The pharmacokinetics of irinotecan are characterized by a 2- or 3-compartment decay, with a terminal half-life of about 10 h, a total volume of distribution of 150 l/m(2) and a total plasma clearance of 15 l/h/m(2). SN-38 AUC is only a small fraction of that of irinotecan (2-4%) and SN-38 is eliminated from plasma with a half-life of about 12 h. SN-38 glucuronide is present in plasma at higher concentrations than SN-38 and is eliminated at the same rate. APC, produced by the action of cytochrome P450, isoenzyme 3A4, is present in plasma at concentrations close to those of irinotecan itself. Only a small fraction of irinotecan and its metabolites is eliminated in urine and a higher proportion in the bile, with an enterohepatic cycle of SN-38 glucuronide and SN-38. Significant relationships have been established between the AUCs of both irinotecan and SN-38 and hematological and intestinal toxicities, suggesting a potential use for monitoring of this drug.
ESTHER : Robert_1998_Drugs.Today.(Barc)_34_777
PubMedSearch : Robert_1998_Drugs.Today.(Barc)_34_777
PubMedID: 14988754

Title : Identification of a new metabolite of CPT-11 (irinotecan): pharmacological properties and activation to SN-38 - Dodds_1998_J.Pharmacol.Exp.Ther_286_578
Author(s) : Dodds HM , Haaz MC , Riou JF , Robert J , Rivory LP
Ref : Journal of Pharmacology & Experimental Therapeutics , 286 :578 , 1998
Abstract : Irinotecan, or CPT-11 (7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecine++ +), is a water-soluble derivative of camptothecine with promising activity against several types of malignancies. In addition to 7-ethyl-10-hydroxycamptothecine (SN-38), its active metabolite, we were able to identify several metabolites in the plasma of patients treated with this drug, especially an oxidative metabolite, 7-ethyl-10[4-N-(5-aminopentanoic acid)-1-piperidino] carbonyloxy-camptothecine. During our study of the biosynthesis of 7-ethyl-10[4-N-(5-aminopentanoic acid)-1-piperidino] carbonyloxy-camptothecine from CPT-11 by human liver microsomes, we were able to detect another quantitatively important polar metabolite, which was also present in the plasma and urine of patients treated with CPT-11. On the basis of preliminary experiments, the structure of this compound was postulated to be 7-ethyl-10-(4-amino-1-piperidino)carbonyloxycamptothecine, and this structure was synthesized by Rhone-Poulenc Rorer. Urine samples and human liver microsomal extracts were studied by high-performance liquid chromatography/atmospheric pressure chemical ionization/tandem mass spectrometry to identify its structure formally. The identification of the metabolite was supported by identical retention time, mass-to-charge ratio and tandem mass spectrometry fragmentation as a synthetic standard. Like irinotecan, 7-ethyl-10-(4-amino-1-piperidino) carbonyloxycamptothecine was a weak inhibitor of cell growth of P388 cells in culture (IC50 = 3.4 micrograms/ml vs. 2.8 micrograms/ml for irinotecan and 0.001 microgram/ml for SN-38). It was also a poor inducer of topoisomerase I-DNA cleavable complexes (100-fold less potent than SN-38). However, unlike 7-ethyl-10[4-N-(5-aminopentanoic acid)-1-piperidino] carbonyloxy-camptothecine, this new metabolite could be hydrolyzed to SN-38 by human liver microsomes and purified human liver carboxylesterase, though to a lesser extent than irinotecan. This compound can therefore contribute to the activity and toxicity profile of irinotecan in vivo.
ESTHER : Dodds_1998_J.Pharmacol.Exp.Ther_286_578
PubMedSearch : Dodds_1998_J.Pharmacol.Exp.Ther_286_578
PubMedID: 9655905

Title : The transformation of irinotecan (CPT-11) to its active metabolite SN-38 by human liver microsomes. Differential hydrolysis for the lactone and carboxylate forms - Haaz_1997_Naunyn.Schmiedebergs.Arch.Pharmacol_356_257
Author(s) : Haaz MC , Rivory LP , Riche C , Robert J
Ref : Naunyn Schmiedebergs Arch Pharmacol , 356 :257 , 1997
Abstract : Irinotecan (CPT-11) is a new camptothecine derivative presently in development for the treatment of several advanced malignancies. It is converted in vivo to a highly potent metabolite, SN-38, by carboxylesterases. All camptothecine derivatives undergo lactonolysis in a pH-dependent reversible manner, generating inactive carboxylate forms. We have investigated in vitro the kinetics of transformation of CPT-11 to SN-38 by human liver microsomes originating from several donors. Microsomes from seven livers were studied individually or as a pooled preparation. CPT-11, either in its lactone or its carboxylate form, was added at a range of concentrations. The SN-38 formed was measured by HPLC with fluorometric detection. In the deacylation-limited carboxylesterase reaction, the linear steady-state kinetics between 10 and 60 min were determined. At all concentrations of CPT-11, the steady-state velocity of SN-38 formation as well as the intercept concentrations of SN-38 were about 2-fold higher when the substrate was under the lactone form than under the carboxylate form. We estimated the values (+/-SD) of K'm and Vmax to be 23.3 +/- 5.3 microM and 1.43 +/- 0.15 pmol/min/mg for the lactone and 48.9 +/- 5.5 microM and 1.09 +/- 0.06 pmol/min/mg for the carboxylate form of CPT-11, respectively. We conclude that the greater rate of conversion of CPT-11 lactone may contribute to the plasma predominance of SN-38 lactone observed in vivo. The inter-individual variation of SN-38 formation was relatively high (ratio of 4 between extreme values) but no large age- or gender-related differences were seen. The effect of twelve drugs of different therapeutic classes (antibiotics, antiemetics, antineoplastics, antidiarrhoeics, analgesics), which could be administered in association with irinotecan in the clinical setting, was evaluated in this system (drug concentration: 100 microM; CPT-11 lactone concentration: 10 microM). Loperamide and ciprofloxacine where the only drugs exerting a weak inhibition of CPT-11 conversion to SN-38.
ESTHER : Haaz_1997_Naunyn.Schmiedebergs.Arch.Pharmacol_356_257
PubMedSearch : Haaz_1997_Naunyn.Schmiedebergs.Arch.Pharmacol_356_257
PubMedID: 9272733

Title : Conversion of irinotecan (CPT-11) to its active metabolite, 7-ethyl-10-hydroxycamptothecin (SN-38), by human liver carboxylesterase - Rivory_1996_Biochem.Pharmacol_52_1103
Author(s) : Rivory LP , Bowles MR , Robert J , Pond SM
Ref : Biochemical Pharmacology , 52 :1103 , 1996
Abstract : We have investigated the conversion of the novel anti-topoisomerase I agent CPT-11 (irinotecan; 7-ethyl-10[4-(1-piperidino)-1-piperidno]carbonyloxycamptothecin ) to its active metabolite, SN-38 (7-ethyl-10-hydroxycamptothecin), by human liver carboxylesterase (HLC). Production of SN-38 was relatively inefficient and was enzyme deacylation rate-limited with a steady-state phase occurring after 15-20 min of incubation. This later phase followed Michaelis-Menten kinetics with an apparent Km of 52.9 +/- 5.9 microM and a specific activity of 200 +/- 10 mumol/sec/mol. However, the total enzyme concentration estimated from the intercept concentrations of SN-38 was much lower than that estimated directly from the titration of active sites with paraoxon (0.65 vs. 2.0 microM, respectively). Because deacylation rate-limiting kinetics result in the accumulation of inactive acyl-enzyme complex, we postulated that incubation of CPT-11 with HLC would result in an inhibition of the HLC-catalysed hydrolysis of p-nitrophenylacetate (p-NPA), an excellent substrate for this enzyme. Indeed, this was found to be the case although complete inhibition could not be attained. Analysis of possible kinetic schemes revealed that the most likely explanation for the disparity in estimated enzyme concentrations and the incomplete inhibition of p-NPA hydrolysis is that CPT-11 also interacts at a modulator site on the enzyme, which profoundly reduces substrate hydrolysis. Furthermore, loperamide, a drug often used for the treatment of CPT-11-associated diarrhea, was found to inhibit both CPT-11 and p-NPA HLC-catalysed hydrolysis, most likely by a similar interaction. These observations have direct implications for the clinical use of CPT-11.
ESTHER : Rivory_1996_Biochem.Pharmacol_52_1103
PubMedSearch : Rivory_1996_Biochem.Pharmacol_52_1103
PubMedID: 8831730

Title : Identification and properties of a major plasma metabolite of irinotecan (CPT-11) isolated from the plasma of patients - Rivory_1996_Cancer.Res_56_3689
Author(s) : Rivory LP , Riou JF , Haaz MC , Sable S , Vuilhorgne M , Commercon A , Pond SM , Robert J
Ref : Cancer Research , 56 :3689 , 1996
Abstract : Irinotecan [7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin (CPT-11)] is a promising water-soluble analogue of camptothecin [S. Sawada et al., Chem. & Pharm. Bull. (Tokyo), 39: 1446-1454, 1991]. We have reported previously the presence of an important polar metabolite, in addition to 7-ethyl-10-hydroxycamptothecin (SN-38) beta-glucuronide, in samples of plasma taken from patients undergoing treatment with CPT-11 (L.P. Rivory and J. Robert, Cancer Chemother. Pharmacol. 36: 176-179, 1995; L. P. Rivory and J. Robert, J. Cromatogr., 661: 133-141, 1994). Plasma samples (0.5 ml) containing comparatively large amounts of this metabolite were extracted by solid-phase columns and subjected to high-performance liquid chromatography and mass spectrometry in parallel to fluorometric detection. The metabolite yielded [M + 1] ions with a m/z of 619, representing the addition of 32 atomic mass units to CPT-11. Purified fractions were subjected to proton nuclear magnetic resonance, and the structure determined, 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]carbonyloxycampothecin (APC), was further validated following synthesis. Like CPT-11, APC was found to be only a weak inhibitor of the cell growth of KB cells in culture (IC50, 2.1 versus 5.5 micrograms/ml for CPT-11 and 0.01 microgram/ml for SN-38, the active metabolite of CPT-11) and was a poor inducer of topoisomerase I DNA-cleavable complexes (100-fold less potent than SN-38). In contrast to CPT-11, APC was not hydrolyzed to SN-38 by human liver microsomes or purified human liver carboxylesterase. Furthermore, APC did not inhibit the hydrolysis of CPT-11 in these preparations. Interestingly, APC was only a weak inhibitor of acetylcholinesterase in comparison to CPT-11 and neostigmine. It appears likely, therefore, that APC does not contribute directly to the activity and toxicity profile of CPT-11 in vivo.
ESTHER : Rivory_1996_Cancer.Res_56_3689
PubMedSearch : Rivory_1996_Cancer.Res_56_3689
PubMedID: 8706009

Title : Choline uptake and metabolism by nerve cell cultures -
Author(s) : Massarelli R , Yong TY , Froissart C , Robert J
Ref : Prog Brain Res , 49 :89 , 1979
PubMedID: 515444

Title : Dynamics of phospholipids in cultured cells of neural origin -
Author(s) : Yavin E , Robert J
Ref : Biochemical Society Transactions , 7 :341 , 1979
PubMedID: 428641

Title : Polar head groups manipulation of phospholipids in cultured neuroblastoma cells -
Author(s) : Robert J , Rebel G , Mandel P , Yavin E
Ref : Life Sciences , 22 :211 , 1978
PubMedID: 628312