| 1 | Detection of polyol accumulation in a new ovarian carcinoma cell
line, CABA I: a(1)H NMR study.
Ferretti A, D'Ascenzo S, Knijn A, Iorio E, Dolo V, Pavan A, Podo F.
Laboratory of Cell Biology, Istituto Superiore di Sanità , Viale Regina Elena 299, 00161 Roma, Italy. Ovarian carcinomas represent a major form of gynaecological malignancies,
whose treatment consists mainly of surgery and chemotherapy. Besides the
difficulty of prognosis, therapy of ovarian carcinomas has reached scarce
improvement, as a consequence of lack of efficacy and development of drug-resistance.
The need of different biochemical and functional parameters has grown,
in order to obtain a larger view on processes of biological and clinical
significance. In this paper we report novel metabolic features detected
in a series of different human ovary carcinoma lines, by (1)H NMR spectroscopy
of intact cells and their extracts. Most importantly, a new ovarian adenocarcinoma
line CABA I, showed strong signals in the spectral region between 3.5 and
4.0 p.p.m., assigned for the first time to the polyol sorbitol (39+/-11
nmol/10(6) cells). (13)C NMR analyses of these cells incubated with [1-(13)C]-D-glucose
demonstrated labelled-sorbitol formation. The other ovarian carcinoma cell
lines (OVCAR-3, IGROV 1, SK-OV-3 and OVCA432), showed, in the same spectral
region, intense resonances from other metabolites: glutathione (up to 30
nmol/10(6) cells) and myo-inositol (up to 50 nmol/10(6) cells). Biochemical
and biological functions are suggested for these compounds in human ovarian
carcinoma cells, especially in relation to their possible role in cell
detoxification mechanisms during tumour progression. DOI: 10.1038/sj/bjc/6600189
www.bjcancer.comCopyright 2002 Cancer Research UK
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| 2 | Upregulation of the expression of endogenous Mdr1 P-glycoprotein
enhances lipid translocation in MDCK cells transfected with human MRP2.
Raggers RJ, Vogels I, van Meer G.
Present address: Numico Research B.V., Postbus 7005, 6700 CA Wageningen, The Netherlands. Various ABC transporters can translocate lipid molecules from the cytoplasmic
into the exoplasmic leaflet of the plasma membrane bilayer. Two of these,
MDR1 P-glycoprotein (Pgp) and MRP1, are multidrug transporters responsible
for the resistance of various cancers against chemotherapy. We wanted to
study whether MRP2, an ABC transporter of the bile canalicular membrane
with a substrate specificity very similar to that of MRP1, is capable of
translocating lipids. The translocation of short-chain lipids across the
apical membrane of MDCK cells transfected with MRP2 was significantly higher
than that in untransfected controls. However, the characteristics of the
lipid translocation were similar to substrate transport by MDR1 and not
MRP2: transport was strongly inhibited by classic MDR1 Pgp inhibitors,
was independent of cellular glutathione, and was insensitive to a drug
known to inhibit MRP2 activity. When tested by immunoblot, the MRP2-transfected
cells expressed high levels of MRP2 but also of endogenous Mdr1. The expression
of Mdr1 was unstable during maintenance of the cell line and correlated
with the rate of lipid translocation across the apical membrane. We conclude
that the observed increase in lipid transport in the MDCK cells transfected
with MRP2 is the consequence of the upregulation of the expression of endogenous
Mdr1 and that careful characterization of endogenous Mdr1 expression is
needed in studies aimed to identify substrates of plasma membrane transporters.
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| 3 | Flupirtine blocks apoptosis in batten patient lymphoblasts and in
human postmitotic CLN3- and CLN2-deficient neurons.
Dhar S, Bitting RL, Rylova SN, Jansen PJ, Lockhart E, Koeberl DD, Amalfitano
A, Boustany RM.
Department of Pediatrics, Duke University Medical Center, Durham, NC 27710, USA. Multiple gene defects cause Batten disease. Accelerated apoptosis accounts for neurodegeneration in the late infantile and juvenile forms that are due to defects in the CLN3 and CLN2 genes. Extensive neuronal death is seen in CLN2- and CLN3-deficient human brain as well as in CLN6-deficient sheep brain and retina. When neurons in late infantile and juvenile brain survive, they manage to do so by upregulating the neuroprotective molecule Bcl-2. The CLN3 gene has antiapoptotic properties at the molecular level. We show that the CLN2 gene is neuroprotective: it enhances growth of NT2 cells and maintains survival of human postmitotic hNT neurons. Conversely, blocking CLN3 or CLN2 expression in hNT neurons with adenoviral antisense-CLN3 or antisense-CLN2-AAV2 constructs causes apoptosis. The drug flupirtine is a triaminopyridine derivative that acts as a nonopioid analgesic. Flupirtine upregulates Bcl-2, increases glutathione levels, activates an inwardly rectifying potassium channel, and delays loss of intermitochondrial membrane calcium retention capacity. We show that flupirtine aborts etoposide-induced apoptosis in CLN1-, CLN2-, CLN3-, and CLN6-deficient as well as normal lymphoblasts. Flupirtine also prevents the death of CLN3- and CLN2-deficient postmitotic hNT neurons at the mitochondrial level. We show that a mechanism of neuroprotection exerted by flupirtine involves complete functional antagonism of N-methyl-D-aspartate or N-methyl-D-aspartate-induced neuronal apoptosis. Flupirtine may be useful as a drug capable of halting the progression of neurodegenerative diseases caused by dysregulated apoptosis. MeSH Terms:
From PubMed |
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| 4 | Update on pharmacogenetics in cancer chemotherapy.
Innocenti F, Ratain MJ.
Department of Medicine, Committee on Clinical Pharmacology and Pharmacogenomics, Cancer Research Center, The University of Chicago, Chicago, IL, USA This review describes how genetic differences among patients may change
the therapeutic outcome in cancer chemotherapy. Severe toxicity in genetically
predisposed patients is predominantly associated with mutations in drug
metabolism enzyme genes, and an update on genetic intolerance to 6-mercaptopurine,
5-fluorouracil, and irinotecan is provided. Moreover, recent findings pointed
out that the methylenetetrahydrofolate reductase (MTHFR) C677T mutation
might change patient susceptibility to the toxic effects of the cyclophosphamide,
methotrexate, 5-fluorouracil (CMF) regimen and raltitrexed. Finally, it
is emerging that not only toxicity, but also response to chemotherapy could
be influenced by pharmacogenetic determinants, and the clinical relevance
of polymorphisms in thymidylate synthase (TS) and glutathione-S-transferase
(GST) genes is discussed.
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| 5 | Switching off embolization from symptomatic carotid plaque using
S-nitrosoglutathione.
Kaposzta Z, Martin JF, Markus HS.
Clinical Neuroscience, St George's Hospital Medical School, London, UK. BACKGROUND: Current antiplatelet regimens fail to prevent the majority of recurrent strokes. Asymptomatic circulating emboli can be detected by transcranial Doppler ultrasound, are frequent in patients with symptomatic carotid stenosis, and predict recurrent stroke risk. S-nitrosoglutathione (GSNO) is a nitric oxide donor that appears to have relative platelet specificity. We evaluated its effectiveness in reducing embolization in patients with symptomatic carotid stenosis who already were taking aspirin. METHODS AND RESULTS: Twenty patients with > or =50% internal carotid artery stenosis and with > or =3 embolic signals detected during a half-hour screening recording were recruited. All had taken aspirin for at least 7 days. They were randomly assigned in a double-blind fashion to either GSNO (4.4 mmol/kg per minute) or saline placebo for 90 minutes. Transcranial Doppler recordings were made from the ipsilateral middle cerebral artery for 1 hour before treatment and at 0 to 3, 6, and 24 hours after treatment. Before treatment, the mean (range) of embolic signals per hour was 6.9 (3 to 13) in the GSNO group and 7.3 (4 to 12) in the placebo group (P=0.68). GSNO resulted in a rapid reduction in the frequency of embolic signals of 84% at 0 to 3 hours, 95% at 6 hours, and 100% at 24 hours (P<0.0001, P=0.003, and P<0.0001 versus placebo, respectively). CONCLUSIONS: Continued embolization is common in patients with carotid stenosis despite aspirin therapy. GSNO was highly effective in rapidly reducing the frequency of embolic signals in this patient group. Despite its short administration time and its short half-life, it resulted in therapeutic effects lasting 24 hours. Publication Types:
From PubMed |
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| 6 | Carboplatin AUC and gamma-glutamylcysteine synthetase gene expression
in peripheral mononuclear cells of lung cancer patients.
Oguri T, Isobe T, Mitsuta K, Masuda K, Daga H, Ishikawa N, Fujitaka
K, Miyazaki M, Kohno N.
Second Department of Internal Medicine, Hiroshima University School of Medicine, Japan. tetsuya@yahoo.co.jp BACKGROUND: To investigate the association between glutathione-related enzymes and carboplatin (CBDCA) dose, we examined gene expression levels for both subunits of gamma-glutamylcysteine synthetase (heavy; gamma-GCSh, light; gamma-GCS1) in peripheral mononuclear cells (PMN) of lung cancer patients before and after CBDCA administration. MATERIALS AND METHODS: PMN and plasma samples were obtained from 10 advanced non-small lung cancer patients before and after CBDCA administration. We analyzed the gene expression levels by reverse transcription-polymerase chain reaction. RESULTS: Gamma-GCSh expression levels in PMN increased within 24 hours after CBDCA administration, whereas gamma-GCS1 expression levels did not. However, the actual area under the concentration curve (AUC) of CBDCA did not correlate with gamma-GCSh expression at 24 hours or the increased ratio of gamma-GCSh expression in PMN. CONCLUSION: Expression of gamma-GCSh is induced by CBDCA, however, CBDCA AUC is not a determinant for the increased expression levels of gamma-GCSh in PMN. MeSH Terms:
From PubMed |
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| 7 | Gamma-tocopheryl quinone stimulates apoptosis in drug-sensitive
and multidrug-resistant cancer cells.
Jones KH, Liu JJ, Roehm JS, Eckel JJ, Eckel TT, Stickrath CR, Triola
CA, Jiang Z, Bartoli GM, Cornwell DG.
Department of Anatomy and Medical Education, The Ohio State University College of Medicine, Columbus 43210, USA. jones.4@osu.edu Chemotherapy-induced cell death is linked to apoptosis, and there is
increasing evidence that multidrug-resistance in cancer cells may be the
result of a decrease in the ability of a cell to initiate apoptosis in
response to cytotoxic agents. In previous studies, we synthesized two classes
of electrophilic tocopheryl quinones (TQ), nonarylating alpha-TQ and arylating
gamma- and delta-TQ, and found that gamma- and delta-TQ, but not alpha-TQ,
were highly cytotoxic in human acute lymphoblastic leukemia cells (CEM)
and multidrug-resistant (MDR) CEM/VLB100. We have now extended these studies
on tumor biology with CEM, HL60 and MDR HL60/MX2 human promyelocytic leukemia,
U937 human monocytic leukemia, and ZR-75-1 breast adenocarcinoma cells.
gamma-TQ, but not alpha-TQ or tocopherols, showed concentration and incubation
time-dependent effects on loss of plasma membrane integrity, diminished
viable cell number, and stimulation of apoptosis. Its cytotoxicity exceeded
that of doxorubicin in HL60/MX2 cells, which express MRP, an MDR-associated
protein. Apoptosis was confirmed by TEM, TUNEL, and DNA gel electrophoresis.
Kinetic studies showed that an induction period was required to initiate
an irreversible multiphase process. Gamma-TQ released mitochondrial cytochrome
c to the cytosol, induced the cleavage of poly(ADP-ribose)polymerase, and
depleted intracellular glutathione. Unlike xenobiotic electrophiles, gamma-TQ
is a highly cytotoxic arylating electrophile that stimulates apoptosis
in several cancer cell lines including cells that express MDR through both
P-glycoprotein and MRP-associated proteins. The biological properties of
arylating TQ electrophiles are closely associated with cytotoxicity and
may contribute to other biological effects of these highly active agents.
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| 8 | NAD(P)H:quinone oxidoreductase (NQO1) polymorphism, exposure to
benzene, and predisposition to disease: A HuGE review.
Nebert DW, Roe AL, Vandale SE, Bingham E, Oakley GG.
123. NAD(P)H:quinone oxidoreductase (NQO1) catalyzes the two- or four-electron
reduction of numerous endogenous and environmental quinones (e.g., the
vitamin E alpha-tocopherol quinone, menadione, benzene quinones). In laboratory
animals treated with various environmental chemicals, inhibition of NQO1
metabolism has long been known to increase the risk of toxicity or cancer.
Currently, there are 22 reported single-nucleotide polymorphisms (SNPs)
in the NQO1 gene. Compared with the human consensus (reference, "wild-type")
NQO1*1 allele coding for normal NQO1 enzyme and activity, the NQO1*2 allele
encodes a nonsynonymous mutation (P187S) that has negligible NQO1 activity.
The NQO1*2 allelic frequency ranges between 0.22 (Caucasian) and 0.45 (Asian)
in various ethnic populations. A large epidemiologic investigation of a
benzene-exposed population has shown that NQO1*2 homozygotes exhibit as
much as a 7-fold greater risk of bone marrow toxicity, leading to diseases
such as aplastic anemia and leukemia. The extent of the contribution of
polymorphisms in other genes involved in the metabolism of benzene and
related compounds-such as the P450 2E1 (CYP2E1), myeloperoxidase (MPO),
glutathione-S-transferase (GSTM1, GSTT1), microsomal epoxide hydrolase
(EPHX1), and other genes-should also be considered. However, it now seems
clear that a lowered or absent NQO1 activity can increase one's risk of
bone marrow toxicity, after environmental exposure to benzene and benzene-like
compounds. In cancer patients, the NQO1*2 allele appears to be associated
with increased risk of chemotherapy-related myeloid leukemia. Many other
epidemiological studies, attempting to find an association between the
NQO1 polymorphism and one or another human disease, have now begun to appear
in the medical literature.
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| 9 | Buthionine sulfoximine and myeloablative concentrations of melphalan
overcome resistance in a melphalan-resistant neuroblastoma cell line.
Anderson C P, Seeger R C, Satake N, Monforte-Munoz H L, Keshelava N,
Bailey H H, Reynolds C P.
Division of Hematology-Oncology, Children's Hospital Los Angeles, California 90027, USA. BACKGROUND: Alkylator resistance contributes to treatment failure in high-risk neuroblastoma. Buthionine sulfoximine (BSO) can deplete glutathione and synergistically enhance in vitro sensitivity to the alkylating agent melphalan (L-PAM) for many neuroblastoma cell lines, but optimal use of this combination needs to be defined because clinical responses have been less frequent and not durable. PATIENTS AND METHODS: The authors established and characterized a neuroblastoma cell line (CHLA-171) from a patient who died of progressive disease after treatment with BSO and low-dose L-PAM. RESULTS: CHLA-171 lacks MYCN amplification, expresses PGP (P-glycoprotein) 9.5 RNA, and shows cell surface antigen expression (human leukocyte antigen class I weakly positive, but HSAN 1.2 (hybridoma, SAN 1.2) and anti-GD2 (anti-ganglioside GD2 antibody) strongly positive) characteristic of neuroblastoma cell lines. Twenty-four hours of BSO treatment (0-1,000 micromol/L) maximally depleted CHLA-171 glutathione to 36% of baseline. The cytotoxic response of CHLA-171 to BSO and L-PAM, alone and in combination, was measured by digital image microscopy (DIMSCAN) over a range of drug concentrations and compared with drug levels obtained in the patient during BSO/L-PAM therapy. As single agents, CHLA-171 was highly resistant to L-PAM (LD90 = 42 micromol/L; peak plasma concentration in the patient equals 3.9 micromol/L) and moderately resistant to BSO (LD90 = 509 micromol/L; steady-state concentration in the patient equals 397 micromol/L). Treatment with a 10:1 (BSO:L-PAM) fixed ratio combination synergistically overcame resistance (3-4 logs of cell kill, combination index <1) at clinically achievable levels of BSO (100-400 micromol/L) and levels of L-PAM (10-40 micromol/L) clinically achievable only with hematopoietic stem cell support. CONCLUSIONS: The in vitro results obtained for CHLA-171 suggest that BSO/L-PAM therapy may be optimally effective for drug-resistant neuroblastoma using myeloablative doses of L-PAM. MeSH Terms:
From PubMed |
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| 10 | The multidrug resistance mechanisms and their interactions with
the radiopharmaceutical probes used for an in vivo detection.
Perek N, Denoyer D.
Laboratory of Biophysics and Radiopharmaceuticals--Cell death and neoplasia group, Faculty of Medicine Jacques Lisfranc, Saint-Etienne, France. nathalie.perek@univ-st-etienne.fr The resistance of human malignancy to multiple chemotherapeutic agents
ts remains a major obstacle in cancer therapy. This resistance phenomenon
is called "multiple" because when cells are resistant they fail to respond
to any of a wide range of anticancer agents. This leads to a complete ineffectiveness
of any treatment and has dramatic consequences for the patients. This chemoresistance
can be intrinsic--when tumour cells do not respond initially to the treatment--or
acquired--when resistance appear during the therapy. Our understanding
of the mechanisms responsible of the drug resistance has increased over
the past few years. The tumour resistance is able to develop several strategies
to inactivate the chemotherapeutic agents such as activation of the detoxification
process, and overexpression of efflux pump proteins. The phenotype resistance
of the cell is mainly characterised by an increased expression of membrane
transport proteins such as the P-glycoprotein and the Multidrug Resistance
Protein--MRPI--that act as real efflux pump to anticancer agent and contribute
to physiological alterations i.e. intracellular pH and plasma membrane
potentials. The detoxification procedure is also implicated with the Glutathione
S transferase enzymes and the major anti oxidant of the cells the glutathione
(GSH). More recently a newly reported transporter called "Breast Resistance
Cancer Protein" has appeared. The role of all these transporters and the
link with the detoxification systems in the clinical outcome of cancer
chemotherapy is the subject of intense research. Particularly, one way
of interest concerned in vivo investigations with radiolabelled compounds
used in nuclear medicine. The understanding of how the radiolabelled compounds
could interact with the phenotype resistance of the cells had a key role
for further exploration of molecular imaging of the MDR phenotype.
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| 11 | Glutathione S-transferases P1-1 and A1-1 in ovarian cyst fluids.
Boss E A, Peters W H M, Roelofs H M J, Boonstra H, Steegers E A P, Massuger
L F A G.
Departments of Gynaecology and Obstetrics, University Medical Centre, Nijmegen The Netherlands. PURPOSE: The purpose of the present study was to determine the gluthathione
S-transferases (GST) P1-1 and A1-1 levels in cyst fluid from malignant,
borderline, and benign ovarian tumors. The clinical relevance of these
enzymes in cyst fluid was investigated, including the possible relation
with resistance to chemotherapy. METHODS: A total of 90 ovarian cysts were
punctured for cyst fluid collection. GSTP1-1 and GSTA1-1 concentrations
were determined by ELISA in cyst fluid from 23 malignant, 9 borderline,
and 51 benign primary ovarian tumors, and levels were correlated with histopathological
data. RESULTS: Significantly higher GSTP1-I concentrations were found in
cyst fluid from malignant (median: 477 ng/ml), compared with benign (median:
52 ng/ml) ovarian cysts (p < 0.0001), as well as in fluid from borderline
(median: 366 ng/ml) compared with benign cysts (p < 0.0001). No significant
differences were found in cyst fluid GSTA1-1 concentrations between the
histologic subgroups. In cyst fluid from malignant tumors higher GSTPI-1
and lower GSTAI-1 concentrations were found in patients with worse prognostic
factors: FIGO II-III-IV, grade 2-3, residual tumor > 2 cm, presence of
ascites, patients with recurrent disease, and survival, but differences
were not significant. In the subgroup of patients that received cisplatin-based
chemotherapy (n = 14) significantly higher GSTP1-1 (p = 0.01) concentrations
were found in patients with recurrence compared with patients without recurrence.
Considering only FIGO stage I patients, a differentiation could be made
between patients with or without recurrence based on cyst fluid GSTP I
- I concentrations. CONCLUSIONS: Determination of glutathione S-transferases
P 1-1 in cyst fluid samples from ovarian tumors can be of additiona] value
in the differentiation between histologic subgroups. In case of possible
low malignant potential cysts where sampling of the most representative
tissue can be an issue, determination of GSTP- I concentrations in cyst
fluid may optimise histopathologic classification. Cyst fluid GSTP1-1 seems
to be a good marker for aggressiveness of the ovarian tumor, and it may
predict response to chemotherapy.
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| 12 | Catechol estrogen metabolites and conjugates in different regions
of the prostate of Noble rats treated with 4-hydroxyestradiol: implications
for estrogen-induced initiation of prostate cancer.
Cavalieri EL, Devanesan P, Bosland MC, Badawi AF, Rogan EG.
Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, 986805 Nebraska Medical Center, Omaha, NE 68198-6805, USA. ecavaalie@unmc.edu Prostate carcinomas arise in 100% of Noble rats treated with estradiol and testosterone. We hypothesize that estrogens initiate prostate cancer mainly by formation of 4-catechol estrogens (CE), followed by their oxidation to catechol estrogen-3,4-quinones (CE-3,4-Q), which can react with DNA. To avoid cancer initiation, CE can be detoxified by catechol-O-methyltransferase (COMT), and CE-3,4-Q by conjugation with glutathione (GSH) or by reduction to CE, catalyzed by quinone reductase and/or cytochrome P450 reductase. To investigate the prostatic metabolism of estrogens, Noble rats were treated with the CE 4-hydroxyestradiol (4-OHE2) or estradiol-3,4-quinone (E2-3,4-Q), and CE metabolites and conjugates were analyzed in the four regions of the prostate, which differ in susceptibility to carcinoma formation. Following treatment of rats with 4-OHE2 (6 micromol/100 g body weight in 200 microl of trioctanoin/dimethylsulfoxide (4:1) by intraperitoneal injection) for 90 min, the non-susceptible ventral (VP) and anterior (AP) prostate had higher levels of 4-methoxyCE and GSH conjugates than the susceptible dorsolateral prostate (DLP) and periurethral prostate (PUP). After treatment with the same molar amount of E2-3,4-Q, the VP and AP contained more GSH conjugates, 4-CE and 4-methoxyCE than the susceptible DLP and PUP. These results suggest that prostate areas susceptible to carcinoma induction have less protection by COMT, GSH, and quinone reductase and/or cytochrome P450 reductase, favoring reaction of CE-3,4-Q with DNA, presumably to initiate cancer. MeSH Terms:
From PubMed |
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| 13 | Dietary vitamins and selenium diminish the development of mechanically
induced osteoarthritis and increase the expression of antioxidative enzymes
in the knee joint of STR/1N mice.
Kurz B, Jost B, Schunke M.
Anatomisches Institut der CAU zu Kiel, Olshausenstr. 40, Kiel, Germany. bkurz@anat.uni-kiel.de OBJECTIVE: To study the influence of dietary vitamins and selenium on
mechanically-induced osteoarthritis (OA) and the expression of antioxidative
enzymes in male STR/1N and Balb/c mice. Male STR/1N mice are prone to develop
OA caused by a varus deformity-induced mechanical overload of the medial
tibial plateau. METHODS: After 12 months of feeding (special diet supplemented
with the vitamins E, C, A, B6, B2, and selenium) serial histological sections
of the knee joints were evaluated for development of osteoarthritic changes
(grade 0-4). Serum glutathione peroxidase activity (GSH-px) was measured
photometrically. Expression of antioxidative enzymes was demonstrated by
immunohistochemistry. RESULTS: All control STR/1N mice showed OA lesions
(grade 3-4) while the special diet decreased OA incidence significantly
down to approximately 65% (mostly grade 2). Even in Balb/c mice the incidence
was decreased by the special diet from approximately 21% (control animals;
grade 1) to approximately 14%. Serum GSH-px activity increased diet-dependently
in both mouse strains but was generally higher in Balb/c mice. In both
mouse strains the special diet increased the expression of GSH-px and Cu/Zn-SOD
in articular cartilage while there was no expression of Mn-SOD. There was
also a special diet-dependent increase in expression of GSH-px in the synovium
of both mouse strains while an increase in expression of Mn-SOD and Cu/Zn-SOD
could only be seen in the synovium of STR/1N mice. CONCLUSIONS: A diet
supplemented with vitamins/selenium might be important in prevention or
therapy of mechanically induced OA. We hypothesize that free oxygen radical
species might be involved in the mechanical induction of OA.
MeSH Terms:
From PubMed |
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| 14 | The agonist activity of tamoxifen is inhibited by the short heterodimer
partner orphan nuclear receptor in human endometrial cancer cells.
Klinge CM, Jernigan SC, Risinger KE.
Department of Biochemistry and Molecular Biology, University of Louisville School of Medicine, Louisville, Kentucky 40292, USA. carolyn.klinge@louisville.edu Short heterodimer partner (SHP) is an orphan nuclear receptor that interacts with ER(alpha) and ERbeta and inhibits E2-induced transcription. We examined how SHP affects tamoxifen's estrogen agonist activity in endometrial cells. We report that SHP interacts with 4-hydroxytamoxifen (4-OHT) or E2-occupied ER(alpha) in a temperature-dependent manner in vitro. In transient transfection assays, SHP inhibited 4-OHT-stimulated reporter gene activity from an estrogen response element (ERE) in ER-positive RL95-2 but not in HEC-1A human endometrial carcinoma cells transfected with ER(alpha) or ERbeta. SHP inhibited E2-induced transcriptional activity in ER(alpha)- or ERbeta-transfected HEC-1A or Chinese hamster ovary-K1 cells. SHP inhibition of E2 activity was greater for ER(alpha) than ERbeta from the nonpalindromic ERE in the pS2 gene promoter in Chinese hamster ovary-K1 but not HEC-1A cells. Thus, ER subtype, cell type, and ERE sequence influence SHP repressor activity. An ER(alpha) mutant lacking activator function-1 showed reduced inhibition by SHP. In glutathione S-transferase pull-down experiments, SHP inhibited ER(alpha) dimerization, providing a possible mechanism to account for the inhibitory effect of SHP on ER activity. These results identify SHP as novel target for blocking 4-OHT agonist activity in endometrial cells. MeSH Terms:
From PubMed |
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| 15 | The prognostic value of tumor markers in patients with glioblastoma
multiforme: analysis of 32 patients and review of the literature.
Reavey-Cantwell J F, Haroun R I, Zahurak M, Clatterbuck R E, Parker
R J, Mehta R, Fruehauf J P, Brem H.
Hunterian Neurosurgical Laboratory, Department of Neurosurgery, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Although several studies have examined brain tumor markers for prognostic value, few investigations have stratified analysis based on specific histologic grade. The objective of this study was to evaluate a single histologic grade of glioma, the grade IV glioma or glioblastoma (World Health Organization Classification), with a comprehensive panel of tumor markers in an attempt to identify those with prognostic significance. Tumor samples from a cohort of patients with glioblastoma multiforme (n = 32) were examined for tumor markers, DNA analysis, and clinical variables in an attempt to determine a 'profile' for this tumor. We used univariate and multivariate statistical analysis to determine the prognostic value of tumor cell ploidy, percent S-phase, DNA index, p53, and Ki-67 labeling index, as well as the variables of gender, race, age, location of tumor, history of chemotherapy, and primary versus recurrent tumor. Two additional tumor markers, multidrug resistance gene 1 and glutathione-S-transferase subtype pi, were included in the sample testing, but were not analyzed statistically. Univariate analysis indicated that increasing age had a strong association with decreased survival. Female gender, increasing Ki-67, no chemotherapy before sample collection, and primary glioblastoma showed some association with decreased survival in the univariate model. The univariate results indicated that race, side of tumor, ploidy, S-phase, DNA index, and p53 had no prognostic value. Multivariate modeling demonstrated that age, gender, and Ki-67 were the strongest factors associated with survival. The relevant literature is reviewed. Grant Support:
From PubMed |
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| 16 | Extra-cellular thiol metabolism in clones of human metastatic melanoma
with different gamma-glutamyl transpeptidase expression: implications for
cell response to platinum-based drugs.
Paolicchi A, Lorenzini E, Perego P, Supino R, Zunino F, Comporti M,
Pompella A.
Department of Experimental Pathology and Medical Biotechnologies, University of Pisa, Italy. Thiol redox status can affect important functions both intracellularly
and extracellularly. The plasma membrane enzyme gamma-glutamyl transpeptidase
(GGT), which plays a crucial role in cellular handling of thiols, is often
expressed in malignant tumors, including melanoma, although its expression
levels may vary widely among different tumors or cells of the same tumor.
In an attempt to better understand the functional significance of GGT overexpression,
we have examined the relationships between intra- and extra-cellular thiol
metabolism and GGT expression. Intra- and extra-cellular distribution of
glutathione and other low mol. wt. thiols and disulfides was investigated
in two different Me665/2 human melanoma clones that originated from the
same metastasis, but exhibiting high (2/60 clone) and low (2/21 clone)
GGT activity. Intracellular content of glutathione was lower in GGT-rich
2/60 cells, in spite of high GGT expression. A lower utilization of extracellular
cystine was also observed in these cells. In both clones, a direct secretion
of cysteine in the extracellular medium was detected, which was independent
of GGT-mediated catabolism of extracellular glutathione. Substantial amounts
of glutathione, GSSG and glutathione-cysteine disulfide were accumulated
extracellularly only in the case of GGT-poor 2/21 cells, while the same
event was apparent in 2/60 cells only after the following inhibition of
GGT activity. When exposed to the trinuclear platinum compound BBR 3464
or hydrogen peroxide, which are very reactive for sulfur-containing nucleophiles,
the 2/60 clone showed higher sensitivity than the 2/21 clone to both agents.
These results suggest that the clone-specific balance between transport
of sulfur aminoacids and GGT activity results in profound differences in
the capability of each clone to modify the thiol redox status of the extracellular
milieu. The finding may have important implications in tumor cell behavior
with particular reference to chemosensitivity, since thiols are recognized
factors in modulation of cell sensitivity to platinum-based anticancer
drugs.
MeSH Terms:
From PubMed |
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| 17 | Effects of thymic hormone on reactive oxygen species-scavengers
and renal function in tacrolimus-induced nephrotoxicity.
Tada H, Nakashima A, Awaya A, Fujisaki A, Inoue K, Kawamura K, Itoh
K, Masuda H, Suzuki T.
Department of Pharmaceutical Science, Akita University Hospital, Hondo, Japan. The effects of a thymic hormone (Facteur thymique serique; FTS) on renal reactive oxygen species-scavenging enzymes or substances in heminephrectomized rats with and without tacrolimus-induced nephrotoxicity were studied. Rats received both oral dose of tacrolimus (5 mg/kg/day) and subcutaneous administration of three dosages of FTS (5, 50, and 250 microg/kg/day) over 28 days (Group A). In Group B, they received three dosages of FTS alone (0.5, 5, and 50 microg/kg/day) or FTS 50 microg/kg/day with tacrolimus over 28 days. Each dose of FTS (Group A) partially elevated renal creatinine clearances. Tacrolimus enhanced renal glutathione reductase (GSH-R) activities and glutathione (GSH) and depressed catalase (CAT) activities. FTS increased GSH levels and GSH-R activities. Although FTS alone did not change CAT activities, CAT activities recovered as a result of concomitant use of FTS (Groups A and B). A significant positive correlation was found between CAT activity and creatinine clearance. These findings suggest that FTS is useful for the prevention of tacrolimus-induced nephrotoxicity, and that the increase of renal CAT activity in the defense mechanism of FTS might be important for cell protection against active oxygen species. MeSH Terms:
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| 18 | Effect of Nigella sativa on glucose concentration, lipid peroxidation,
anti-oxidant defence system and liver damage in experimentally-induced
diabetic rabbits.
Meral I, Yener Z, Kahraman T, Mert N.
Department of Physiology, Veterinary Medicine, Yuzuncu Yil University, Van, Turkey. imeral@hotmail.com This study was carried out to investigate whether Nigella sativa could decrease the lipid peroxidation, increase the anti-oxidant defence system and also prevent the lipid-peroxidation-induced liver damage in experimentally induced diabetic rabbits. Fifteen New Zealand male rabbits were divided into three experimental groups: control, diabetic and diabetic and N. sativa-treated. The diabetes mellitus (DMI) was induced in the rabbits using 150 mg/kg of 10% alloxan. The diabetic + N. sativa-treated group was given extract of N. sativa seeds orally every day for 2 months after induction of DM. At the end of the 2-month experiment, blood samples were collected to measure malondialdehyde (MDA), glutathione (GSH), ceruloplasmin and glucose concentration, and livers were harvested for histopathological analysis. Treatment with N. sativa decreased the elevated glucose and MDA concentrations, increased the lowered GSH and ceruloplasmin concentrations, and prevented lipid-peroxidation-induced liver damage in diabetic rabbits. It was concluded that N. sativa might be used in diabetic patients to prevent lipid peroxidation, increase anti-oxidant defence system activity and also prevent liver damage. MeSH Terms:
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| 19 | Photodynamic therapy of activated and resting lymphocytes and its
antioxidant adaptive response.
Casas A, Perotti C, Fukuda H, del C Batlle AM.
Centro de Investigaciones sobre Porfirinas y Porfirias FCEyN, University of Buenos Aires, Argentina. In this work we have studied the effects of ALA-mediated photodynamic therapy (PDT) on resting and mitogen-activated murine splenic lymphocytes, evaluating its impact on cell viability. We have also characterised the stress response, measuring the levels of antioxidant enzymes. A 2h exposure to ALA produced 50% lethality upon irradiation of activated cells with 2.1J/cm2. The decrease in cell survival with increasing time exposure to ALA, correlated well with the higher porphyrin accumulation. In resting lymphocytes, in spite of the low amount of porphyrins formed during 2h incubation with ALA, 40% of the cells died after irradiation, this response was not further increased when higher amounts of porphyrins were synthesised. Superoxide dismutase was impaired by light treatment independently of ALA exposure in activated lymphocytes and, to a lesser extent, in resting lymphocytes. PDT induced an antioxidant adaptive response in activated cells 19 h after irradiation, reflected as a net increase in GSHPx activity and a slight reversion of the catalase (CAT) activity already impaired by light treatment. PDT treatment of activated cells also produced a diminution in the GSH/GSSG ratio. Only activated cells are capable of developing an antioxidant adaptive response to PDT treatment. MeSH Terms:
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| 20 | Characterization of non-small-cell lung cancer cell lines established
before and after chemotherapy.
Kawai H, Kiura K, Tabata M, Yoshino T, Takata I, Hiraki A, Chikamori
K, Ueoka H, Tanimoto M, Harada M.
Second Department of Medicine, Okayama University Medical School, 2-5-1 Shikata-cho, Okayama 700-8558, Japan. We established several in vitro drug-resistant cell lines after continuous,
long-term exposure of each drug to elucidate mechanisms of drug resistance.
Whether drug resistance in these in vitro resistant cell lines reflects
clinical drug resistance still remains unanswered. In this study, a pair
of lung cancer cell lines was established from one patient with squamous
cell carcinoma of the lung, with one line being established before and
one line after combination chemotherapy (cisplatin/ifosfamide/vindesine).
Combination chemotherapy selected resistant EBC-2/R cells, which showed
cross-resistance to 4-hydroxyifosfamide (3.2-fold), cisplatin (2.3-fold),
and methotrexate (3.7-fold) and collateral sensitivity to vindesine (0.77-fold)
compared with parent EBC-2 cells. EBC-2/R cells showed decrease in intracellular
accumulation of cisplatin, increase in intracellular concentration of glutathione
(GSH), and overexpression of multidrug resistance-associated protein (MRP)
3 when compared with EBC-2 cells. A single cycle of chemotherapy was not
sufficient to select other mechanisms of drug resistance, such as multidrug
resistance-1/P-glycoprotein, MRPs 1, 2, 4, and 5, lung resistance-related
protein, metallothionein IIa, glutathione S-transferase pi, gamma-glutamylcysteine
synthetase (light and heavy chain), and excision repair cross complementing
1. Sequentially we established two cell lines, which cell lines showed
the differences of the cisplatin resistance, expression level of MRP3,
intracellular GSH level and intracellular accumulation of cisplatin. A
pair of cell lines will be useful to elucidate resistant mechanisms of
cisplatin in heterogeneous lung cancer cells.
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| 21 | Effects of S-adenosyl-L-methionine on liver damage in experimental
obstructive jaundice.
Tsai SM, Lee KT, Tsai LY.
Department of Health Public, School of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan. S-adenosyl-l-methionine (SAMe) is a naturally occurring molecule distributed throughout the body tissues, including the liver. It acts as a methyl group donor and as an enzyme activator in a number of biochemical reactions. Methionine is metabolized in the liver, where it is converted to SAMe by SAMe-synthetase. In patients with liver diseases, these pathways are impaired because of the decreased contents of glutathione, the major abnormality being a reduction in SAMe-synthetase activity. Exogenous SAMe may overcome the results of impaired SAMe-synthetase activities. We conducted this study to evaluate the effect of SAMe administration on liver damage induced by biliary obstruction. Rats with common bile duct ligation exhibited abnormal liver functions, increased lipid peroxide levels, and decreased reduced glutathione contents when compared with the shammed-controls, which indicated that there was oxidative stress in rats with obstructive jaundice; however, SAMe application improved these injuries. There were significant alterations of the levels of amino acid profiles in animals with obstructive jaundice. The ratio between branch chain and aromatic amino acid was depressed, which indicated that the condition of liver was worsening, but SAMe administration improved these alterations significantly. In conclusion, SAMe administration alleviated the liver damage, indicating an important hepatoprotective effect of this methyl donor. MeSH Terms:
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| 22 | 5-Fluoroindole-3-acetic acid: a prodrug activated by a peroxidase
with potential for use in targeted cancer therapy.
Folkes LK, Greco O, Dachs GU, Stratford MR, Wardman P.
Gray Cancer Institute, Mount Vernon Hospital, P.O. Box 100, Northwood, HA6 2JR, Middlesex, UK. Indole-3-acetic acid and some derivatives are oxidized by horseradish peroxidase, forming a radical-cation that rapidly fragments (eliminating CO(2)) to form cytotoxic products. No toxicity is seen when either indole-3-acetic acid or horseradish peroxidase is incubated alone at concentrations that together form potent cytotoxins. Unexpectedly, 5-fluoroindole-3-acetic acid, which is oxidized by horseradish peroxidase compound I 10-fold more slowly than indole-3-acetic acid, is much more cytotoxic towards V79 hamster fibroblasts in the presence of peroxidase than the unsubstituted indole. The fluorinated prodrug/peroxidase combination also shows potent cytotoxic activity in human and rodent tumor cell lines. Cytotoxicity is thought to arise in part from the formation of 3-methylene-2-oxindole (or analogues) that can conjugate with thiols and probably DNA or other biological nucleophiles. Levels of the fluorinated prodrug in the murine carcinoma NT after intraperitoneal administration of 50 mg/kg were about 200 microM. Although these were 4-5-fold lower than plasma levels (which reached 1mM), the integrated area under the concentration/time curve in tumors over 2 hr was approximately 20 mM min, almost double the exposure needed to achieve approximately 90-99% cell kill in human MCF7 breast or HT29 colon tumor cell lines and CaNT murine cells in vitro, although the human bladder T24 carcinoma cell line was more resistant. The high cytotoxicity of 5-fluoroindole-3-acetic acid after oxidative activation suggests its further evaluation as a prodrug for targeted cancer therapy involving antibody-, polymer-, or gene-directed delivery of horseradish peroxidase or similar activating enzymes. MeSH Terms:
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| 23 | The polymorphic human glutathione transferase T1-1, the most efficient
glutathione transferase in the denitrosation and inactivation of the anticancer
drug 1,3-bis(2-chloroethyl)-1-nitrosourea.
Lien S, Larsson AK, Mannervik B.
Department of Biochemistry, Biomedical Center, Uppsala University, Box 576, SE-751 23, Uppsala, Sweden. A member of the Theta class of human glutathione transferases (GST T1-1) was found to display the greatest catalytic activity towards the cytostatic drug 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) of the GSTs studied. In this investigation (the most extensive to date), enzymes from four classes of the soluble human GSTs were heterologously expressed, purified, and kinetically characterized. From the 12 enzymes examined, only GST M2-2, GST M3-3 and GST T1-1 had significant activities with BCNU. This establishes that the activity is not a characteristic of a particular class of GSTs. Although GST M3-3 was previously reported to have the greatest activity with BCNU, the current investigation demonstrates that GST M2-2 is equally active and that GST T1-1 has an approximately 20-fold higher specific activity than either of the Mu class enzymes. A more rigorous kinetic analysis of GST T1-1 gave the following parameters with BCNU: a k(cat) of 0.035 +/-0.003s(-1) and a K(M) of 1.0 +/- 0.1mM. The finding that GST T1-1 has the highest activity towards BCNU is significant since GST T1-1 is expressed in the brain, a common target for BCNU treatment. Furthermore, the existence of a GST T1-1 null allele in up to 60% in some populations, may influence both the sensitivity of tumors to chemotherapy and the severity of adverse side-effects in patients treated with this agent. MeSH Terms:
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| 24 | Nitric oxide donor properties of hydroxyurea in patients with sickle
cell disease.
Gladwin MT, Shelhamer JH, Ognibene FP, Pease-Fye ME, Nichols JS, Link
B, Patel DB, Jankowski MA, Pannell LK, Schechter AN, Rodgers GP.
Critical Care Medicine Department of the Warren G. Magnuson Clinical Center, Bethesda, MD 20892-1662, USA. mgladwin@nih.gov Hydroxyurea therapy reduces the rates of vaso-occlusive crisis in patients with sickle cell anaemia and recent data suggest that hydroxyurea treatment can generate nitric oxide (NO). Nitric oxide has been proposed as a novel therapy for sickle cell disease via a number of pathways. We therefore sought to determine whether hydroxyurea has NO donor properties in patients with sickle cell anaemia and explore potential mechanisms by which NO production could be therapeutic. Venous blood was collected from 19 fasting sickle cell anaemia patients, on chronic hydroxyurea therapy, at baseline and 2 and 4 h after a single morning dose of hydroxyurea, as well as 10 patients not taking hydroxyurea. The plasma and red cell NO reaction products nitrate, nitrite and nitrosylated- haemoglobin were measured using ozone-based chemiluminescent assays (using vanadium, KI and I3- reductants respectively). Consistent with NO release from hydroxyurea, baseline levels of total nitrosylated haemoglobin increased from 300 nmol/l to 500 nmol/l (P = 0.01). Plasma nitrate and nitrite levels also significantly increased with peak levels observed at 2 h. Glutathionyl-haemoglobin levels were unchanged, while plasma secretory vascular cellular adhesion molecule-1 levels were reduced in patients taking hydroxyurea (419 +/- 40 ng/ml) compared with control patients with sickle cell anaemia (653 +/- 55 ng/ml; P = 0.003), and were inversely correlated with fetal haemoglobin levels (r = -0.72; P = 0.002). These results demonstrate that hydroxyurea therapy is associated with the intravascular and intraerythrocytic generation of NO. The role of NO in the induction of fetal haemoglobin and possible synergy between NO donor therapy and classic cytostatic and differentiating medications should be explored. MeSH Terms:
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| 25 | Cytoprotective antioxidant activity of serum albumin and autocrine
catalase in chronic lymphocytic leukaemia.
Moran EC, Kamiguti AS, Cawley JC, Pettitt AR.
Department of Haematology, Royal Liverpool University Hospital, Liverpool, UK. Chronic lymphocytic leukaemia (CLL) cells are long lived in vivo but undergo spontaneous apoptosis when cultured in vitro. Intriguingly, CLL cells also appear to have a specific susceptibility to oxidative stress - a potent inducer of apoptosis. Here, we show that serum albumin can function as a cytoprotective antioxidant of potential relevance to circulating CLL cells, and that autocrine catalase - a hydrogen peroxide-inactivating enzyme that may be released extracellularly - can perform a similar role under the crowded conditions that prevail at sites of tissue involvement. Albumin lowered oxidative stress in cultured CLL cells and inhibited spontaneous and reactive oxidant-induced apoptosis. Maximal effects were observed at a concentration of 10 mg/ml - fourfold lower than that in plasma and twofold higher than that in standard culture medium containing 10% fetal calf serum. Oxidative stress and spontaneous apoptosis were also decreased by cell crowding and by conditioned medium (CM) from crowded CLL cells, indicating that these processes were subject to autocrine regulation. CLL cells were found to express catalase and release enzyme activity into the culture medium. Exogenous catalase decreased oxidative stress and spontaneous apoptosis, and the anti-apoptotic effect of CM from crowded CLL cells was abrogated by the specific catalase inhibitor, 3'-amino-1,2,4-triazole. Together, these data strongly implicate autocrine catalase as a cytoprotective antioxidant. Oxidative stress in CLL cells was greatly diminished by ruthenium red - an inhibitor of mitochondrial reactive oxidant production - and by the glutathione (GSH) precursor N-acetylcysteine, suggesting that the GSH peroxidase antioxidant system may be compromised by lack of available substrate. Our findings highlight the importance of endogenous reactive oxidants in regulating CLL-cell apoptosis, and help to explain why CLL cells survive for prolonged periods in vivo despite their vulnerability to oxidative stress and spontaneous apoptosis when cultured in vitro. MeSH Terms:
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| 26 | Vitamin E uncouples joint destruction and clinical inflammation
in a transgenic mouse model of rheumatoid arthritis.
Bandt MD, Grossin M, Driss F, Pincemail J, Babin-Chevaye C, Pasquier
C.
INSERM U479, Faculté Xavier Bichat, and Centre Hospitalo-Universitaire Xavier Bichat, 46 rue Henri Huchard, Paris 75018, France. frbandt@bichat.inserm.fr OBJECTIVE: Reactive oxygen species are thought to play a role in rheumatoid arthritis (RA) in humans. We postulated that antioxidant treatment could have a beneficial effect in this disease. We therefore investigated the effects of vitamin E in the transgenic KRN/NOD mouse model of RA. METHODS: Mice were treated by gavage with oral vitamin E (alpha-tocopherol). Clinical, histologic, and biochemical parameters were assessed for 6 weeks. RESULTS: Vitamin E treatment did not modify the clinical features of the disease (date of onset or disease intensity, as measured by the articular index), but it did prevent joint destruction, as measured by qualitative and semiquantitative analyses. Redox status did not differ between treated and control mice. White blood cell chemiluminescence was higher in transgenic KRN/NOD mice than in controls, but vitamin E treatment attenuated this difference. Vitamin E treatment of the transgenic animals led to a significant decrease in the levels of interleukin-(IL-1beta) but not tumor necrosis factor alpha. CONCLUSION: Vitamin E seems to uncouple joint inflammation and joint destruction in this model of RA, with a beneficial effect on joint destruction. Since many investigations are currently in progress to evaluate the benefit of interventions targeted toward anti-IL-1beta, our findings suggest opportunities of therapeutic interest in human RA. MeSH Terms:
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| 27 | Prognostic significance of the null genotype of glutathione S-transferase-T1
in patients with acute myeloid leukemia: increased early death after chemotherapy.
Naoe T, Tagawa Y, Kiyoi H, Kodera Y, Miyawaki S, Asou N, Kuriyama K,
Kusumoto S, Shimazaki C, Saito K, Akiyama H, Motoji T, Nishimura M, Shinagawa
K, Ueda R, Saito H, Ohno R.
Department of Infectious Diseases, Nagoya University School of Medicine, Nagoya, Japan. We investigated the prognostic significance of genetic polymorphism in glutathione-S transferase mu 1 (GSTM1), glutathione-S transferase theta 1 (GSTT1), NAD(P)H:quinone oxidoreductase (NQO1) and myeloperoxidase (MPO), the products of which are associated with drug metabolism as well as with detoxication, in 193 patients with de novo acute myeloid leukemia (AML) other than M3. Of the patients, 64.2% were either homozygous or heterozygous for GSTT1 (GSTT1(+)), while 35.8% showed homozygous deletions of GSTT1 (GSTT1(-)). The GSTT1(-) group had a worse prognosis than the GSTT1(+) group (P = 0.04), whereas other genotypes did not affect the outcome. Multivariate analysis revealed that GSTT1(-) was an independent prognostic factor for overall survival (relative risk: 1.53; P = 0.026) but not for disease-free survival of 140 patients who achieved complete remission (CR). The rate of early death after the initiation of chemotherapy was higher in the GSTT1(-) group than the GSTT1(+) group (within 45 days after initial chemotherapy, P = 0.073; within 120 days, P = 0.028), whereas CR rates and relapse frequencies were similar. The null genotype of GSTT1 might be associated with increased toxicity after chemotherapy. Publication Types:
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| 28 | Glibenclamide vs gliclazide in reducing oxidative stress in patients
of noninsulin dependent diabetes mellitus--a double blind randomized study.
Chugh SN, Dhawan R, Kishore K, Sharma A, Chugh K.
Department of Medicine, Pt. BD Sharma PGIMS, Rohtak, Haryana. OBJECTIVE: Parameters of oxidative stress were quantitated in 50 patients with type 2 diabetes mellitus in uncontrolled state and after control using oral glibenclamide or gliclazide. The estimates were further compared between the two groups irrespective of drug used to evaluate the difference, if any. METHODS: The study was a double blind, uncontrolled, noncrossover and randomized trial. Fifty patients of uncontrolled type 2 diabetes were divided in to two groups. Group I (25 patients) received capsule A (glibenclamide) while Group II (25 patients) received capsule B (gliclazide). The parameters studied were Superoxide dismutase (SOD), malonyl-dialdehyde (MDA) and reduced glutathione (GSH). They were done at (a) uncontrolled stage (FBS--165 +/- 16.7 mg/dl, PP--240 +/- 30.1 mg/dl and HbA1--10.5 +/- 0.9% in group I and FBS--150 +/- 15.8 mg/dl, PP--246 +/- 29.1 mg/dl HbA1 10.6 +/- 0.8% in group II) and during controlled stage at 12 weeks (FBS--120 +/- 18.5 mg/dl, PP--180 +/- 19.1 mg/dl and HbA1--8.4 +/- 0.29% in group I and FBS--118 +/- 17.6 mg/dl, PP--176 +/- 20.1 mg/dl and HbA1--8.5 +/- 0.39% in group II patients). RESULTS: The significantly raised levels of MDA and SOD, and decreased levels of reduced glutathione (GSH) during uncontrolled stage of diabetes indicated free radical stress induced lipid peroxidation. The significant fall of MDA and SOD and increased levels of GSH in blood in both groups after control revealed beneficial effects of glycemic control on oxidative stress. The levels were not normalized and stayed higher than those in controls. On intergroup comparison; the control of diabetes with gliclazide (group II) showed improvement in oxidative stress (MDA, GSH) better (p < 0.001) than glibenclamide (group I). CONCLUSION: Oxidative stress in uncontrolled diabetes is decreased with glycemic control. The control of diabetes with gliclazide reduced oxidative stress more than glibenclamide, indicating higher antioxidant properties of gliclazide. Normalization of oxidative stress was not achieved. Further studies are required to see long-term effect of drug therapy in combating oxidative stress after achieving acceptable control of diabetes. Publication Types:
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| 29 | Effects of S-adenosyl-L-methionine on lipid peroxidation and glutathione
levels in rat brain slices exposed to reoxygenation after oxygen-glucose
deprivation.
De La Cruz JP, Villalobos MA, Cuerda MA, Guerrero A, Gonzalez-Correa
JA, Sanchez De La Cuesta F.
Department of Pharmacology and Therapeutics, School of Medicine, University of Málaga, 29071 Málaga, Spain. jpcruz@uma.es We analyzed the effects of S-adenosyl-L-methionine (AdoMet) on tissue oxidative stress in rat brain slices exposed to reoxygenation after oxygen-glucose deprivation. The thiobarbituric acid reactive substances (TBARS), total and oxidized glutathione, and lactate-dehydrogenase efflux (LDH) from tissue to the incubation medium, were measured. Brain slices were incubated without glucose and with N2, then glucose was added and O2 was perfused. After the anoxic-reoxygenation period, increase in TBARS, oxidized glutathione and LDH efflux, and decrease in total glutathione levels, were observed. The incubation with AdoMet before the anoxic period reduced TBARS (31-1000 micromol/l), glutathione production was increased (31-1000 micromol/l), LDH efflux decreased 6.41% with 15 micromol/l and 61.5% with 500 micromol/l). In the ex vivo experiments, we administered 50 mg/kg per day p.o., AdoMet for 3 days, then brain slices were collected and the anoxia-reoxygenation experiment was carried out. AdoMet led to the inhibition of brain lipid peroxidation and increased total glutathione production, after 3 h-reoxygenation. The increase of LDH efflux in non-treated rats was reduced by 77%. We conclude that AdoMet exerts citoprotective effects in an experimental model of brain slices reoxygenation after oxygen-glucose deprivation. MeSH Terms:
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| 30 | Cellular antioxidant effects of atorvastatin in vitro and in vivo.
Wassmann S, Laufs U, Muller K, Konkol C, Ahlbory K, Baumer AT, Linz
W, Bohm M, Nickenig G.
Medizinische Klinik und Poliklinik-Innere Medizin III, Universitätskliniken des Saarlandes, Homburg/Saar, Germany. 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) may exert direct effects on vascular cells and beneficially influence endothelial dysfunction. Because reactive oxygen species (ROS) may lead to vascular damage and dysfunction, we investigated the effect of atorvastatin on ROS production and the underlying mechanisms in vitro and in vivo. Cultured rat aortic vascular smooth muscle cells were incubated with 10 micromol/L atorvastatin. Angiotensin II-induced and epidermal growth factor-induced ROS production were significantly reduced by atorvastatin (dichlorofluorescein fluorescence laser microscopy). Atorvastatin downregulated mRNA expression of the NAD(P)H oxidase subunit nox1, whereas p22phox mRNA expression was not significantly altered (reverse transcription-polymerase chain reaction, Northern analysis). Membrane translocation of rac1 GTPase, which is required for the activation of NAD(P)H oxidase, was inhibited by atorvastatin (Western blot). mRNA expression of superoxide dismutase isoforms and glutathione peroxidase was not modified by atorvastatin, whereas catalase expression was upregulated at mRNA and protein levels, resulting in an increased enzymatic activity. Effects of atorvastatin on ROS production and nox1, rac1, and catalase expression were inhibited by L-mevalonate but not by 25-hydroxycholesterol. In addition, spontaneously hypertensive rats were treated with atorvastatin for 30 days. ROS production in aortic segments was significantly reduced in statin-treated rats (lucigenin chemiluminescence). Treatment with atorvastatin reduced vascular mRNA expression of p22phox and nox1 and increased aortic catalase expression. mRNA expression of superoxide dismutases, glutathione peroxidase, and NAD(P)H oxidase subunits gp91phox, p40phox, p47phox, and p67phox remained unchanged. Translocation of rac1 from the cytosol to the cell membrane was also reduced in vivo. Thus, atorvastatin exerts cellular antioxidant effects in cultured rat vascular smooth muscle cells and in the vasculature of spontaneously hypertensive rats mediated by decreased expression of essential NAD(P)H oxidase subunits and by upregulation of catalase expression. These effects of atorvastatin may contribute to the vasoprotective effects of statins. MeSH Terms:
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| 31 | Cell necrosis and apoptosis are differentially regulated during
goitre development and iodine-induced involution.
Mutaku JF, Poma JF, Many MC, Denef JF, van Den Hove MF.
Laboratory of Histology, Catholic University of Louvain, Medical School, Brussels, Belgium. Necrosis and apoptosis coexist in the thyroid during goitre development and involution, but little is known about their respective causes. To test the possible role of free radicals, we analysed separately necrosis and apoptosis in male Wistar rats with depressed or normal antioxidant protection. Vitamin E-deficient and -sufficient rats were made goitrous with perchlorate in drinking water; involution was induced by repeated injection of NaI, without or with methimazole. Increase of thyroid malondialdehyde concentration and decrease of glutathione peroxidase activity confirmed the depressed antioxidant protection in vitamin E-deficient rats. Plasma thyroxine and TSH levels were not modified. Necrosis (swollen cells) and apoptosis (pyknotic cells) were quantified on histological sections. In vitamin E-sufficient rats, dead cells were very rare in control thyroids, increased 3-fold in goitre and still further during involution. Necrotic epithelial cells predominated in the goitre and their number declined after iodide supplementation, without or with methimazole. In contrast, the number of apoptotic cells and the caspase-3 activity were increased in goitre and further increased after involution, with two-thirds of pyknotic cells being observed in the interstitium. Apoptosis was prevented by methimazole. Vitamin E deficiency significantly increased total cell death and epithelial cell necrosis and induced the occurrence of much cell debris in the follicular lumen during involution, with no modification of the apoptotic reaction. These results show that the type of cell death is differentially regulated during goitre development and involution: necrosis is related to the oxidative status of the cells, while apoptosis comes with iodine-induced involution. MeSH Terms:
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| 32 | The therapeutic potential of inhibitors of the trypanothione cycle.
D'Silva C.
Department of Chemistry & Materials, The Manchester Metropolitan University, John Dalton Building, Chester Street, Manchester M1 5GD, UK. There is an urgent need for new drugs in the treatment of human African
trypanosomiasis, Chagas' disease and leishmaniasis. This article provides
an overview of current drugs, formulations and their deficiencies. Targets
for the design of new drugs and the rational provided for targeting enzymes
of the trypanothione cycle are described. Biochemical aspects of the cycle
and the currently investigated target trypanothione reductase are discussed
as are the several classes of inhibitors and their in vitro potencies.
Evidence is provided for considering the tryparedoxins as a new target
for antiprotozoal chemotherapy and a summary of glutathione-based inhibitors
with significant in vitro activity is reported.
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| 33 | Serum copper, zinc, selenium, glutathione peroxidase and superoxide
dismutase levels in epileptic children before and after 1 year of sodium
valproate and carbamazepine therapy.
Verrotti A, Basciani F, Trotta D, Pomilio MP, Morgese G, Chiarelli F.
Department of Medicine, Division of Pediatrics, University of Chieti, Ospedale Policlinico, via dei Vestini 5, I-66100 Chieti, Italy. averrott@obelix.unich.it To assess whether epileptic children have abnormal values of serum copper (Cu), zinc (Zn), selenium (Se), glutathione peroxidase (GSH-PX) and superoxide dismutase (CuZn-SOD), and to evaluate the effect of long-term therapy with sodium valproate (VPA) and carbamazepine (CBZ) on these parameters, we studied 36 epileptic patients before the beginning of therapy and after 1 year of therapy with VPA or CBZ. Before the beginning of therapy, there were no differences in levels of all parameters studied between controls and epileptics. After 1 year of therapy, patients treated with VPA and CBZ continued to show normal values. In conclusion our study demonstrates that epilepsy per se and treatment with VPA and CBZ do not affect levels of Cu, Zn, Se, GSH-PX and CuZn-SOD concentrations. MeSH Terms:
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| 34 | Involvement of protein tyrosine phosphorylation and reduction of
cellular sulfhydryl groups in cell death induced by 1' -acetoxychavicol
acetate in Ehrlich ascites tumor cells.
Moffatt J, Kennedy DO, Kojima A, Hasuma T, Yano Y, Otani S, Murakami
A, Koshimizu K, Ohigashi H, Matsui-Yuasa I.
Department of Food and Human Health Sciences, Graduate School of Human Life Science, Osaka City University, 3-3-138 Sugimoto, Sumiyoshi-ku, Osaka 558-8585, Japan. Elucidation of the mechanisms underlying potential anticancer drugs continues and unraveling these mechanisms would not only provide a conceptual framework for drug design but also promote use of natural products for chemotherapy. To further evaluate the efficacy of the anticancer activity of 1'-acetoxychavicol acetate (ACA), this study investigates the underlying mechanisms by which ACA induces death of Ehrlich ascites tumor cells. ACA treatment induced loss of cell viability, and Western blotting analysis revealed that the compound stimulated tyrosine phosphorylation of several proteins with 27 and 70 kDa proteins being regulated in both dose- and time-dependent manner prior to loss of viability. Protein tyrosine kinase inhibitor herbimycin A moderately protected cells from ACA-induced toxicity. In addition, cellular glutathione and protein sulfydryl groups were also significantly reduced both dose- and time-dependently during evidence of cell death. Replenishing thiol levels by antioxidant, N-acetylcysteine (NAC), an excellent supplier of glutathione and precursor of glutathione, substantially recovered the viability loss, but the recovery being time-dependent, as late addition of NAC (at least 30 min after ACA addition to cultures) was, however, ineffective. Addition of NAC to ACA treated cultures also abolished tyrosine phosphorylation of the 27 kDa protein. These results, at least partly, identify cellular sulfhydryl groups and protein tyrosine phosphorylation as targets of ACA cytotoxicity in tumor cells. MeSH Terms:
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| 35 | The role of P-glycoprotein in human gastric cancer xenografts in
response to chemotherapy.
Monden N, Abe S, Hishikawa Y, Yoshimura H, Kinugasa S, Dhar DK, Tachibana
M, Nagasue N.
The Second Department of Surgery, Shimane Medical University, Izumo, Japan. BACKGROUND: To clarify the contribution of P-glycoprotein (P-GP) to drug resistance of gastric cancer, the correlation between chemosensitivity of the tumor and expression of P-GP was examined using human gastric cancer xenografts in nude mice. METHODS: Two strains, P-GP-positive and -negative, were established using primary explants from patients who had not received chemotherapy. Their stable growth was obtained by serial passages as subcutaneous tumors in nude mice. Mitomycin C (MMC, 3.25 mg/kg), adriamycin (ADR, 6mg/kg), or cisplatin (CDDP, 6mg/kg) was administered intraperitoneally once a week for 3 weeks. RESULTS: In the P-GP-negative strain, all three drugs significantly suppressed the tumor growth, while in the P-GP-positive strain, only MMC did so. However, the growth inhibition of MMC was apparently greater in the P-GP-negative strain than in the positive tumor. The expressions of metallothionein (MT), glutathione-S-transferase-pi (GST-pi), and p53 were not different between the strains. Bcl-2 was expressed only in the P-GP-negative strain. Induction of P-GP expression was observed in some specimens after treatment with MMC and with CDDP. CONCLUSIONS: P-GP might affect inherent and acquired resistance against chemotherapeutic agents in gastric cancer. MeSH Terms:
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| 36 | Chemical-Biological Interactions of the resin monomer triethyleneglycol-dimethacrylate
(TEGDMA).
Geurtsen- W, Leyhausen G.
Department of Conservative Dentistry and Periodontology, Medical University Hannover, Germany. geurtsenwerner@mh-hannover.de Most dental resinous materials contain high quantities of the diluent monomer triethyleneglycol-dimethacrylate (TEGDMA). Due to its 'hydrophilic' nature, significant amounts of this substance leach into an aqueous environment, such as the oral cavity. Therefore, it is hypothesized that TEGDMA frequently interferes with oral and/or systemic tissues. In vitro studies revealed that TEGDMA is considerably cytotoxic in various cell cultures. It has also been observed that TEGDMA can easily penetrate membranes and subsequently may react with intracellular molecules. The formation of glutathione-TEGDMA adducts is of specific interest, since the nearly complete exhaustion of this molecule significantly reduces its cellular detoxifying potency. Large deletions of DNA sequences were caused by TEGDMA, resulting in high mutation frequency. In addition, TEGDMA has been identified as an important resinous sensitizer in patients and professionals. Taken together, available in vitro information, in vivo studies with animals, and clinical data as well indicate that TEGDMA may contribute considerably to local and systemic adverse effects caused by dental resins. Publication Types:
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| 37 | Preneoplastic prostate lesions: an opportunity for prostate cancer
prevention.
Nelson WG, De Marzo AM, Deweese TL, Lin X, Brooks JD, Putzi MJ, Nelson
CP, Groopman JD, Kensler TW.
The Johns Hopkins Comprehensive Cancer Center, Baltimore, Maryland 21231-1000, USA. bnelson@jhmi.edu Environmental factors, especially the diet, play a prominent role in the epidemic of prostate cancer (PCA), in the United States. Many candidate dietary components have been proposed to influence human prostatic carcinogenesis, including fat, calories, fruits and vegetables, anti-oxidants, and various micronutrients, but the specific roles dietary agents play in promoting or preventing PCA remain controversial. We have collected evidence to suggest that GSTP1, the gene encoding the pi-class glutathione S-transferase (GST), may serve a "caretaker" function for prostatic cells. Although GSTP1 can be detected in normal prostatic epithelium, in almost all PCA cases, PCA cells fail to express GSTP1 polypeptides, and lack of GSTP1 expression most often appears to be the result of somatic "CpG island" DNA methylation changes. Loss of GSTP1 function also appears to be characteristic of prostatic epithelial neoplasia (PIN) lesions, thought to represent PCA precursors. We have recently learned that a new candidate early PCA precursor lesion, proliferative inflammatory atrophy (PIA), characterized by proliferating prostatic cells juxtaposed to inflammatory cells, contains epithelial cells that express high levels of GSTP1. These findings have formed the basis for a new model of prostatic carcinogenesis, in which prostatic cells in PIA lesions, subjected to a barrage of inflammatory oxidants, induce GSTP1 expression as a defense against oxidative genome damage. When cells with defective GSTP1 genes appear amongst the PIA cells, such cells become vulnerable to oxidants and electrophiles that inflict genome damage that tends to promote neoplastic transformation to PIN and PCA cells. Subsequently, PIN and PCA cells with defective GSTPI genes remain vulnerable to similar stresses tending to promote malignant progression. This new model for prostatic carcinogenesis has implications for the design of new prostate cancer prevention strategies. Rational prevention approaches might include: (i) restoration of GSTPI expression via treatment with inhibitors of CpG methylation, (ii) compensation for inadequate GSTPI activity via treatment with inducers of general GST activity, and (iii) abrogation of genome-damaging stresses via avoidance of exogenous carcinogens and/or reduction of endogenous carcinogenic (particularly oxidant) stresses. Publication Types:
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| 38 | Ebselen blocks the quinolinic acid-induced production of thiobarbituric
acid reactive species but does not prevent the behavioral alterations produced
by intra-striatal quinolinic acid administration in the rat.
Rossato JI, Zeni G, Mello CF, Rubin MA, Rocha JB.
Departamento de QuÃmica, Centro de Ciências Naturais e Exatas, Universidade Federal de Santa Maria, 97105-900, RS, Santa Maria, Brazil. Ebselen (EBS) is a seleno-organic compound with glutathione peroxidase-like activity which is neuroprotective in acute stroke ischemia. In this study, we investigated the effect of EBS on quinolinic acid (QA)-induced neurotoxicity. EBS inhibited QA-induced production of thiobarbituric acid reactive species (TBARS) by striatal homogenates in vitro with an IC(50) of 1.85 microM. Intra-striatal injection of QA (360 nmol) increased striatal content of TBARS and induced convulsions and contralateral rotational behavior. Intra-striatal pre-injection of EBS (10 nmol) 15 min before QA abolished QA-induced TBARS production but did not alter QA-induced behavioral effects. The present findings suggest that EBS acts on post-receptor events, neutralizing free radicals produced by overstimulation of N-methyl-D-aspartate receptors. MeSH Terms:
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| 39 | Effects of immunophilin ligands on hydrogen peroxide-induced apoptosis
in C6 glioma cells.
Tanaka K, Fujita N, Higashi Y, Ogawa N.
Department of Brain Science, Graduate School of Medicine and Dentistry, Okayama University, 2-5-1 Shikata-cho, Okayama 700-8558, Japan. kntanaka@cc.okayama-u.ac.jp MeSH Terms:
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| 40 | Effects of early decrease in oxidative stress after medical therapy
in patients with class IV congestive heart failure.
Castro PF, Diaz-Araya G, Nettle D, Corbalan R, Perez O, Nazzal C, Larrain
G, Lavandero S.
Department of Cardiovascular Diseases, Faculty of Medicine, P. Catholic University of Chile, Santiago, Chile. pcastro@med.puc.cl MeSH Terms:
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| 41 | Poly[Lys-(AEDTP)]: a cationic polymer that allows dissociation of
pDNA/cationic polymer complexes in a reductive medium and enhances polyfection.
Pichon C, LeCam E, Guerin B, Coulaud D, Delain E, Midoux P.
Centre de Biophysique Moléculaire, CNRS UPR 4301, rue Charles Sadron, F-45071 Orléans Cedex 02, France. Polyplexes of high stability resulting from the condensation of a plasmid DNA by a cationic polymer are widely used to develop polymer-based gene delivery systems. However, the plasmid must be released from its vector once inside the cells for an efficient expression of the exogenous gene in the cell nucleus. We have designed a disulfide-containing cationic polymer termed poly[Lys-(AEDTP)] which allowed for the formation of polyplexes and the release of the plasmid in a reductive medium. The amino groups of polylysine were substituted with 3-(2-aminoethyldithio)propionyl residues in order to have each amino group of poly[Lys-(AEDTP)] interacting with a phosphate DNA linked to the polymer backbone via a disulfide bond. As evidenced by agarose gel electrophoresis and ethidium bromide/pDNA fluorescence restoration, poly[Lys-(AEDTP)] polyplexes were decondensed and the plasmid released upon treatment with either dithiothreitol, glutathione in the presence of glutathione reductase, or the thioredoxin reductase. Electron microscopy showed that polyplexes exhibiting spherical particles of a mean size at about 100 nm were decondensed in the presence of glutathione and exhibited filamentous aggregates. Finally, we found that the transfection of 293T7 and HepG2 cells was 10- and 50-fold more efficient with poly[Lys-(AEDTP)] polyplexes, respectively, than with poly[Lys] polyplexes. These results indicate that disulfide-containing cationic polymers must be borne in mind for developing polymer-base gene delivery systems. MeSH Terms:
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| 42 | Resistant mechanisms of anthracyclines--pirarubicin might partly
break through the P-glycoprotein-mediated drug-resistance of human breast
cancer tissues.
Kubota T, Furukawa T, Tanino H, Suto A, Otan Y, Watanabe M, Ikeda T,
Kitajima M.
Department of Surgery, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. tkubota@sc.itc.keio.ac.jp Juliano and Ling initially reported the expression of a 170 kDa glycoprotein in the membrane of Chinese hamster ovarian cells in 1976, and named this glycoprotein P-glycoprotein (P-gp) based on its predicted role of causing "permeability" of the cell membrane. After much research on anthracycline-resistance, this P-gp was finally characterized as a multidrug-resistant protein coded by the mdr1 gene. Multidrug resistance associated protein (MRP) was initially cloned from H69AR, a human small cell-lung carcinoma cell line which is resistant to doxorubicin (DXR) but does not express P-gp. MRP also excretes substrates through the cell membrane using energy from ATP catabolism. The substrate of MRP is conjugated with glutathione before active efflux from cell membrane. Recently, membrane transporter proteins were re-categorized as members of "ATP-Binding Cassette transporter"(ABC-transporter) superfamily, as shown at http://www.med.rug.nl/mdl/humanabc.htm and http://www.gene.ucl.ac.uk/nomenclature/genefamily/abc.html. A total of ABC transporters have been defined, and MDR1 and multidrug resistance associated protein 1 (MRP1) were reclassified as ABCB1 and ABCC1, respectively. Their associated superfamilies include 11 and 13 other protein, in addition to ABCB and ABCC, respectively. Lung resistance-related protein (LRP) is not a member of the superfamily of ABC transporter proteins, because it shows nuclear membrane expression and transports substrate between nucleus and cytoplasm. LRP was initially cloned from a non-small cell lung carcinoma cell line, SW1573/2R120 which is resistant to DXR, vincristine, etoposide and gramicidin D and does not express P-gp. The mechanisms of resistance remains unclear, and why some resistant cell lines express P-gp and others express MRP and/or LRP is likewise unclear. MeSH Terms:
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| 43 | Cellular sensitivity determinants to docetaxel in human gastrointestinal
cancers.
Park JS, Yamamoto W, Sekikawa T, Matsukawa M, Okamoto R, Sasaki M, Ukon
K, Tanimoto K, Kumazaki T, Nishiyama M.
Department of Biochemistry and Biophysics, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan. beta-tubulin (beta-TUB), Bcl-XL, and additionally glutathione S-transferase pi (GSTpi) were found to participate in sensitivity to docetaxel (TXT) in 7 human gastrointestinal cancer cell lines. The gene expression level of beta-TUB, Bcl-XL, and GSTpi was closely correlated with the IC50 for TXT. beta-TUB amount related to TXT resistance, and GST activity was correlated with IC50 for TXT in the 30-min treatment setting. Bcl-XL transfection increased TXT resistance of COLO201 cells, whereas GST inhibition by ethacrynic acid enhanced TXT cytotoxicity. Continuous TXT treatment increased beta-TUB and GSTpi expression, but the increased GSTpi mRNA was observed in TXT-resistant HCC-48 cells alone. MeSH Terms:
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| 44 | Influence of clinical factors, diet, and drugs on the human upper
gastrointestinal glutathione system.
Hoensch H, Morgenstern I, Petereit G, Siepmann M, Peters WH, Roelofs
HM, Kirch W.
Department of Gastroenterology, General Hospital of Gross-Gerau, Gross-Gerau, Germany. H.P.Hoensch@vff.uni-frankfurt.de BACKGROUND: Glutathione (GSH) and the cytosolic glutathione S-transferases (GSTs) protect the gastrointestinal mucosa against the toxic effects of a wide variety of compounds, such as reactive oxygen species and electrophiles. AIMS: We wished to investigate the distribution along the upper gastrointestinal mucosa and the influence of clinical variables on components of the GSH system to learn more about factors which control its cytoprotective properties. METHODS: Antral and duodenal biopsies of normal appearing mucosa were collected from 202 patients (104 males, 98 females; mean age 62 years) undergoing upper gastrointestinal endoscopy. GSH content was examined by high pressure liquid chromatography, GST enzyme activity by 1-chloro-, 2, 4-dinitrobenzene conjugation, and levels of the GST classes alpha, pi, and theta by western blot. RESULTS: GSH, GST enzyme activity, and GST alpha levels were significantly lower (p<0.001) in the antrum than in the duodenum (antrum v duodenum: GSH 23.0 (0.7) v 35.0 (1.0) nmol/mg protein; GST activity 626 (19) v 832 (22) nmol/mg protein/min; GST alpha 4.5 (0.5) v 20.0 (0.7) microg/mg protein) while GST pi content was significantly higher (p<0.001) in antral than in duodenal biopsies (16.5 (0.7) v 11.2 (0.5) microg/mg protein). Antral GSH and GST activities were markedly lower in males compared with females (p<0.01). Some drugs (cisapride, diuretics, cortisol, analgesics) increased GST pi and GST alpha content but cytostatic drugs suppressed duodenal GST activity. High intake (>3 days a week) of vegetables enhanced duodenal GST alpha and GST pi and high intake of fruits the antral content of GST theta 1. CONCLUSIONS: The gastrointestinal GSH system represents the antitoxic barrier of the mucosa; its activity is influenced by localisation, sex, and drugs, and its enzymes are stimulated by a high intake of vegetables and fruits. MeSH Terms:
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