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Biomedical subjects

Z Chen

Publications and source records attributed to Z Chen.

At least 109 records · Page 6Linked to original sources
PubMed2002

Reliability of the comet assay in cryopreserved human sperm.

BACKGROUND: Although the comet assay has potential value for measuring DNA damage in large epidemiological human sperm studies, it is impractical to perform the assay daily on fresh semen samples. Therefore, before its use in epidemiological studies, the reliability of the comet assay in measuring DNA damage in cryopreserved sperm should be compared with that in fresh human sperm. METHODS: Semen samples from 16 men were cryopreserved in liquid nitrogen (LN) using four methods: flash freezing with and without cryopreservative, and programmable freezing with and without cryopreservative. Neutral microgel electrophoresis was performed and comets were stained with YOYO-1. Comet length was measured using an eyepiece micrometer at x400 magnification. RESULTS: The highest correlation was between comet assay results obtained from fresh human semen compared with semen flash frozen without cryopreservative (R = 0.88). However, the method of cryopreservation, as compared with other sources of variability, accounted for only 6% of the variability. Inter-individual variability accounted for 20%, and individual sperm-to-sperm variability within an ejaculate accounted for 65%. CONCLUSIONS: Flash-freezing in LN without cryopreservative most closely reproduced the results obtained using fresh human semen samples, and thereby represents the most appropriate cryopreservation method for human semen in epidemiological studies utilizing the neutral comet assay.

Adult↗
PubMed2002

Using fluorescence-activated cell sorting followed by fluorescence in situ hybridization to study lineage relationships: the 8;21 translocation is present in neutrophils but not monocytes in a patient with severe congenital neutropenia and a granulocyte colony-stimulating factor-responsive clonal abnormality.

UNLABELLED: Severe congenital neutropenia (Kostmann syndrome) is a disorder that presents in the neonatal period, but predisposes to leukemia later in life. This report describes a 4-y-old female with a history of severe congenital neutropenia, who developed a clonal abnormality associated with the translocation (7;21;8) (q32;q22;q22) (AML-1/ETO). She had circulating peripheral blasts and bone marrow blast counts as high as 64% when she received recombinant granulocyte colony-stimulating factor (rG-CSF). Her marrow blasts decreased to 4-20% when rG-CSF was discontinued. Fluorescence in situ hybridization analysis was performed on bone marrow cell populations sorted by flow cytometry to determine which cell populations had the AML-1/ETO translocation. The translocation was found in mature neutrophils and blasts, but not in monocytes, lymphocytes or stem cells. CONCLUSION: These findings suggest that the translocation occurred in a neutrophil progenitor, past the point in ontogeny where monocytes and neutrophils separate. The techniques described may be useful in understanding lineage relationships and leukemogenesis in other clonal abnormalities associated with myelodysplasia and leukemia.

Bone Marrow Transplantation↗
PubMed2002

Interest of two-dimensional electrophoretic analysis for the characterization of the individual sensitization to latex allergens.

BACKGROUND/OBJECTIVE: Latex allergy is a type 1 hypersensitivity reaction that mainly affects high-risk populations such as health care workers, spina bifida-affected or multiply-operated children. Ten molecules have so far been identified and registered as latex allergens (Hev b 1 to Hev b 10). The aim of the present investigation was to identify the major latex allergens by an individual analysis of the IgE response of latex-allergic patients to latex proteins separated by two-dimensional (2-D) gel electrophoresis. MATERIALS AND METHODS: Latex proteins from a sap or a glove extract were separated by 2-D electrophoresis and transferred to a nitrocellulose membrane. Each membrane was incubated with the serum of one latex-allergic patient. The most frequently recognized latex allergens were characterized in sap and glove extracts using monoclonal antibodies or amino acid microsequencing. RESULTS: The one-dimensional screening of 54 patient sera revealed 4 major bands recognized by IgE. The 2-D analysis of the sensitization to latex allergens allows the identification of allergen isoforms and the characterization of an individual response diversity. Hev b 6.01 was recognized by 88.9% of the patients. Protein spots around 14 kD were recognized by 48.1% of the patients and corresponded to Hev b 6.03 as well as other proteins. A not yet characterized doublet of acidic proteins with molecular masses of 43 and 94 kD was recognized by 20.4% of the sera. Only 5.5% of the sera did not recognize any of these 4 major allergens. Hev b 1 is the main protein from the glove extract but was not constantly found in sap extracts. CONCLUSIONS: One-dimensional electrophoretic analysis of the allergen is usually not sufficient to characterize the individual specificity of the IgE response to latex allergens. Latex-glove proteins which are allergens can be absent from the sap extracts and the sensitization to these allergens could be underestimated. Individual 2-D analysis of the sensitization to latex allergens is useful to define the best allergen mixture required for diagnosis and needed for individual therapy monitoring.

Allergens↗
PubMed2002

A DNA vaccine encoding a cell-surface protein antigen of Streptococcus mutans protects gnotobiotic rats from caries.

A cell-surface protein antigen (PAc) of Streptococcus mutans is considered a virulence factor because it may mediate initial attachment of Streptococcus mutans to tooth surfaces. Thus, inhibiting PAc is predicted to provide protection against caries. To develop vaccines against dental caries, we constructed a DNA vaccine, pCIA-P, which encodes two high-conservative regions of PAc. Expression of the recombinant protein was obtained in eukaryotic cells in vitro and in vivo. In this report, we provide evidence that fewer caries lesions, and high levels of PAc-specific salivary IgA antibody and serum IgG antibody, were observed in gnotobiotic rats following targeted salivary gland (TSG) administration of pCIA-P. This study shows that the recombinant DNA vaccine pCIA-P could induce protective anti-caries immune responses and that TSG immunization is a promising strategy for the inhibition of dental caries.

Analysis of Variance↗
PubMed2002

Haemorrhagic hypersensitivity pneumonitis due to naphthylene-1,5-diisocyanate.

Symptoms of hypersensitivity pneumonitis and massive pulmonary haemorrhage occurred in a 24-yr-old male shortly after occupational exposure to naphthylene-1,5-diisocyanate (NDI). The present examination was performed approximately 1-yr after the initial life-threatening haemoptysis and following an uneventful recovery after resection of the middle lobe, which had been identified bronchoscopically as the bleeding source. Histological re-examination of the lung was compatible with hypersensitivity pneumonitis. After a chamber challenge with NDI (5 parts per billion (ppb) for 10 min, 10 ppb for 110 min), rales were heard in both lungs, and a fall in vital capacity and partial pressure of arterial oxygen as well as a rise in body temperature were documented. Isocyanate-specific immunoglobulin-G antibodies could not be detected in the patient's serum, possibly due to the long period without exposure to isocyanates. The authors conclude that naphthylene-1,5-diisocyanate may cause immunological pulmonary haemorrhage. The underlying disease is consistent with hypersensitivity pneumonitis and may be triggered by low concentrations of the diisocyanate.

Adult↗
PubMed2002

Serum cholesterol changes from 1983-1984 to 1993-1994 in the People's Republic of China.

BACKGROUND AND AIM: Increasing cardiovascular disease (CVD) mortality in the People's Republic of China (PRC) led to the 1981 establishment of the PRC-USA Study of Cardiovascular and Cardiopulmonary Epidemiology which, among other objectives, is concerned with the correlates of CVD morbidity and mortality in Chinese populations among other objectives. This report describes changes in total cholesterol (TC) levels in four PRC populations from 1983 to 1993 and identifies factors related to the changes. METHODS AND RESULTS: Population screenings carried out in 1983-1984, 1987-1988 and 1993-1994 involved the collection of demographic data, specimens (including blood), medical history and physical examination data. The data from cohort and independent samples were used to assess TC changes in urban and rural men and women over the decade, with and without adjustment for age and body mass index (BMI) changes. For Guangzhou men and women, the cohort analyses (aged 35-54 at baseline) showed increases in TC of 10-20 mg/dL after adjustment for age and changes in BMI; the independent sample analyses (aged 35-44) also showed higher average TC levels in 1993-1994 than in 1983-1984. For the Beijing cohorts, the results showed decreases in TC during the decade in men, an increase in TC in urban women and no change in rural women; the independent sample analyses indicated declines in TC for Beijing men and women. Possible reasons for the Guangzhou TC increases are economic growth, and dietary and BMI changes. The mean age-adjusted BMI significantly increased (5-10%) over the 10-year period in all of the studied groups. CONCLUSIONS: TC increased 10-20 mg/dL in Guangzhou men and women, probably as a result of socioeconomic development during the decade. The inconsistent patterns of TC changes in Beijing require further study.

Adult↗
PubMed2001

Insight into hepatocellular carcinogenesis at transcriptome level by comparing gene expression profiles of hepatocellular carcinoma with those of corresponding noncancerous liver.

Human hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. In this work, we report on a comprehensive characterization of gene expression profiles of hepatitis B virus-positive HCC through the generation of a large set of 5'-read expressed sequence tag (EST) clusters (11,065 in total) from HCC and noncancerous liver samples, which then were applied to a cDNA microarray system containing 12,393 genes/ESTs and to comparison with a public database. The commercial cDNA microarray, which contains 1,176 known genes related to oncogenesis, was used also for profiling gene expression. Integrated data from the above approaches identified 2,253 genes/ESTs as candidates with differential expression. A number of genes related to oncogenesis and hepatic function/differentiation were selected for further semiquantitative reverse transcriptase-PCR analysis in 29 paired HCC/noncancerous liver samples. Many genes involved in cell cycle regulation such as cyclins, cyclin-dependent kinases, and cell cycle negative regulators were deregulated in most patients with HCC. Aberrant expression of the Wnt-beta-catenin pathway and enzymes for DNA replication also could contribute to the pathogenesis of HCC. The alteration of transcription levels was noted in a large number of genes implicated in metabolism, whereas a profile change of others might represent a status of dedifferentiation of the malignant hepatocytes, both considered as potential markers of diagnostic value. Notably, the altered transcriptome profiles in HCC could be correlated to a number of chromosome regions with amplification or loss of heterozygosity, providing one of the underlying causes of the transcription anomaly of HCC.

Carcinoma, Hepatocellular↗
PubMed2001

Ovarian epithelial carcinoma tyrosine phosphorylation, cell proliferation, and ezrin translocation are stimulated by interleukin 1alpha and epidermal growth factor.

BACKGROUND: Ezrin is a member of the ezrin, radixin, and moesin family. These proteins are membrane-actin cross-linking proteins. Furthermore, ezrin is an important signal transduction protein that undergoes phosphorylation and translocation on stimulation by growth factors. Ezrin phosphorylation and translocation are thought to be correlated with cell motility, invasion, and carcinoma metastasis. Recently, the authors reported that an ezrin antisense phosphorothionate could significantly inhibit endometrial carcinoma cells' penetration in the Matrigel membrane cancer invasion assay. In the current study, the authors measured ezrin content in clinical ovarian epithelial carcinoma (OVCA) specimens and cell lines and investigated whether interleukin (IL)-1alpha and epidermal growth factor (EGF) induce an invasive phenotype in OVCA cells via ezrin phosphorylation and translocation. METHODS: Twenty-five normal ovary, 25 primary OVCA, 21 metastatic OVCA tissue (7 in omentum, 16 in ascites), and 3 OVCA cell lines were collected for Western blot detection of ezrin content. The OVCA cell line SKOV3 was treated with IL-1alpha or EGF. Indirect immunofluorescence staining followed by confocal laser scanning and double-staining electron microscopic immunohistochemistry were used to investigate changes in the intracellular distribution of ezrin and cell morphology after IL-1alpha or EGF treatment. The content of ezrin was measured by Western blotting and analyzed by the National Institutes of Health Image computer program. Immunoprecipitation and Western blot techniques were used for ezrin phosphorylation studies. Genistein was used to block tyrosine phosphorylation. RESULTS: (1) Ezrin was overexpressed in OVCA, with the highest values in metastases. (2) Interleukin-1alpha and EGF significantly increased OVCA tyrosine phosphorylation, ezrin translocation, and cell growth. (3) These effects were abolished by treatment with the tyrosine kinase inhibitor, genistein. (4) Treatment with IL-1alpha or EGF induced an invasive phenotype, i.e., membrane ruffling, and process formation. CONCLUSIONS: High expression and activation of ezrin appear to be related to OVCA metastatic behavior. Interleukin-1alpha and EGF may regulate OVCA invasive behavior by activating ezrin tyrosine phosphorylation, translocation, and cancer cell proliferation. The authors' results may partially explain why OVCA patients with positive macrophage colony stimulating factor (a chemoattractant of IL-1alpha secreting monocytes) or EGF receptors (c-erb B-2) have a poor prognosis.

Blotting, Western↗
PubMed2001

Effects of common polymorphisms on the properties of recombinant human methylenetetrahydrofolate reductase.

Methylenetetrahydrofolate reductase (MTHFR) catalyzes the conversion of methylenetetrahydrofolate to methyltetrahydrofolate, the major methyl donor for the conversion of homocysteine to methionine. Two common polymorphisms of the human enzyme have been identified: 677C>T, which leads to the substitution of Ala-222 by valine, and 1298A>C, which leads to the replacement of Glu-429 by alanine; the former polymorphism is the most frequent genetic cause of mild hyperhomocysteinemia, a risk factor for cardiovascular disease. By using a baculovirus expression system, recombinant human MTHFR has been expressed at high levels and purified to homogeneity in quantities suitable for biochemical characterization. The Glu429Ala protein has biochemical properties that are indistinguishable from the wild-type enzyme. The Ala222Val MTHFR, however, has an enhanced propensity to dissociate into monomers and to lose its FAD cofactor on dilution; the resulting loss of activity is slowed in the presence of methyltetrahydrofolate or adenosylmethionine. This biochemical phenotype is in good agreement with predictions made on the basis of studies comparing wild-type Escherichia coli MTHFR with a mutant, Ala177Val, homologous to the Ala222Val mutant human enzyme [Guenther, B. D., et al. (1999) Nat. Struct. Biol. 6, 359-365].

Animals↗
PubMed2001

Expression of proangiogenic chemokine Gro 1 in low and high metastatic variants of Pam murine squamous cell carcinoma is differentially regulated by IL-1alpha, EGF and TGF-beta1 through NF-kappaB dependent and independent mechanisms.

We previously reported that chemokine Growth Regulated Oncogene 1 (Gro 1) is over-expressed in murine squamous cell carcinoma (SCC) with metastatic tumor progression. The enhanced expression of Gro-1 gene by SCC is regulated by activation of nuclear factor-kappaB (NF-kappaB), leading to accelerated tumor growth, angiogenesis and metastasis in vivo. In our study, we investigated the effect of the regulatory cytokines, IL-1alpha, EGF and TGF-beta1 on activation of NF-kappaB and Gro1 in primary and metastatic sublines of the murine SCC Pam 212. We found that Gro 1 expression could be induced by IL-1alpha or EGF in the low cytokine producing Pam 212 cells, but no significant induction was observed in high cytokine producing and metastatic LY-2 cells. Conditioned medium from LY-2 containing functional IL-1alpha induced Gro 1 expression in Pam 212 cells, which can be blocked by IL-1 receptor antagonist (IL-1RA). IL-1RA, however, had a minimal effect on constitutive Gro 1 production by LY-2 cells. TGF-beta1 suppressed constitutive as well as IL-1alpha and EGF-inducible Gro 1 production in both Pam 212 and LY-2 cells. IL-1alpha and EGF, but not TGF-beta1, were found to activate NF-kappaB in Pam 212, whereas none of the stimulants showed a significant effect on constitutive activation of NF-kappaB in LY-2 cells. Overexpression of a super repressor IkappaBalphaM in Pam 212 inhibited NF-kappaB binding activity, which led to impaired Gro 1 induction by IL-1alpha and EGF. These results demonstrate that IL-1alpha, EGF, and TGF-beta1 are important modulators of Gro 1 expression in SCC. Different responses to these modulators observed along with SCC metastatic progression may suggest a transition mechanism(s) for Gro 1 expression from host factor dependent to an independent stage involving NF-kappaB activation. Published 2001 Wiley-Liss, Inc.

Animals↗
PubMed2001

C. elegans Rb, NuRD, and Ras regulate lin-39-mediated cell fusion during vulval fate specification.

The tumor suppressor Rb and the NuRD (nucleosome remodeling and histone deacetylation) complex have been implicated in transcriptional repression during cell cycle progression and cell fate specification. The Rb/E2F complex physically interacts with and thus recruits the NuRD complex to actively repress transcription. Caenorhabditis elegans counterparts of Rb, E2F/DP, and some NuRD complex components appear to function in a common class B synthetic Multivulva (synMuv) pathway to antagonize RTK/Ras signaling during vulval fate specification. Therefore, it has been suggested that they function together in a single complex to repress vulva-specific gene transcription. However, little is known about the in vivo interactions between these class B synMuv genes and their relationships with other pathways in specific cellular processes during vulval development. We show that C. elegans Rb/E2F and NuRD complexes antagonize Ras activity by controlling a lin-39 Hox-mediated cell fusion event that regulates the competence of vulval cells. Interestingly, Rb/E2F and NuRD complexes exhibit very different genetic properties. While the NuRD complex negatively regulates lin-39 Hox activity, likely by downregulating its expression, RB/E2F appears to play dual roles in regulating lin-39: a negative role in controlling its activity and a previously uncharacterized positive role in regulating its expression.

Animals↗
PubMed2001

Identification of negative and positive estrogen response elements in human GnRH upstream promoter in the placental JEG-3 cells.

Results from our previous studies have demonstrated regulatory effects of estradiol on human gonadotropin-releasing hormone (GnRH) gene expression in human placental cells. The present study was designed to determine the molecular mechanisms whereby estrogens regulate the human GnRH gene expression in the placenta. The effects of estradiol on human GnRH upstream promoter activity in JEG-3 cells depends on the amounts of estrogen receptor (ER) alpha expression vector co-transfected, with the maximal effect obtained at the amount of 1.0 microg of ER expression vector cotransfected. Estriol, an isoform of estradiol, also possesses a regulatory effect on the upstream promoter activity, while estrone, another isoform, does not. Serial deletion studies revealed two estrogen responsive elements in the GnRH upstream promoter region. One element (-987 to -968 bp, E4 element) confers a negative estradiol response, while another one (-827 to -730 bp) is responsible for a positive estradiol effect. Replacement of these two elements with unrelated DNA sequences could abolish the responsiveness to estradiol treatment. Furthermore, footprinting and gel shift assays demonstrated that nuclear protein from estradiol-treated JEG-3 cells, but not from control cells, could bind to a 41 bp DNA fragment (-824 to -784 bp) within the estrogen positive responsive element. Results of gel-shift assay demonstrated that other protein(s) might also be involved in interacting the E4 element to mediate the negative effect of estradiol on the hGnRH upstream promoter activity in JEG-3 cells.

Dose-Response Relationship, Drug↗
PubMed2001

DNA array and biological characterization of the impact of the maturation status of mouse dendritic cells on their phenotype and antitumor vaccination efficacy.

We systematically investigated the impact of the relative maturation levels of dendritic cells (DCs) on their cell surface phenotype, expression of cytokines and chemokines/chemokine receptors (by DNA array and RNase protection analyses), biological activities, and abilities to induce tumor immunity. Mature DCs expressed significantly heightened levels of their antigen-presenting machinery (e.g., CD54, CD80, CD86) and numerous cytokines and chemokines/chemokine receptors (i.e., Flt-3L, G-CSF, IL-1alpha and -1beta, IL-6, IL-12, CCL-2, -3, -4, -5, -17, and -22, MIP-2, and CCR7) and were significantly better at inducing effector T cell responses in vitro. Furthermore, mice vaccinated with tumor peptide-pulsed mature DCs better survived challenge with a weakly immunogenic tumor (8 of 8 survivors) than did mice vaccinated with less mature (3 of 8 survived) or immature (0 of 8 survivors) DCs. Nevertheless, intermediate-maturity DCs expressed substantial levels of Flt-3L, IGF-1, IL-1alpha and -1beta, IL-6, CCL-2, -3, -4, -9/10, -17, and -22, MIP-2, osteopontin, CCR-1, -2, -5, and -7, and CXCR-4. Taken together, our data clearly underscore the critical nature of employing DCs of full maturity for DC-based antitumor vaccination strategies.

Animals↗
PubMed2001

[Phenotypic and functional alterations of mesangial cells in patients with diabetic nephropathy].

OBJECTIVE: To explore the phenotypic and functional changes of glomerular mesangial cells (MC) in the development of diabetic nephropathy (DN). METHODS: Renal biopsy specimens were obtained from patients with type II DN. MC from microdissected glomeruli were cultured in vitro. Both the cells deriving from minute piece of renal biopsy specimen of type 2 DN with overt proteinuria and from transplanted donors' kidneys were investigated. Cell volume, RNA/DNA ratio and the production of fibronectin and glucose transporter 1 (GLUT1) was analyzed by flow ctrometry. Cell proliferation was determined by 3H-Tdr incorporation assay and doubling time. Immunofluorescence staining and flow ctrometry were used to examine the expression of alpha-smooth muscle actin and extracellular matrix. The mRNA expression of GLUT1 was determined by Northern blotting and flow cytometry. Glucose uptake rate by MC was detected using the [3H]-2-DG. The activity of glutamine: fructose-6-P aminotransferase (GFAT), the key enzyme of hexosamine pathway, was measured by spetrophotometry method. Specimens from transplanted kidneys were used a s controls. RESULTS: In specimens from patients with type II DN, increase in volume of MC (in arbitrary units) and RNA/DNA ratio (0.29 +/- 0.05 vs. 0.17 +/- 0.03, P < 0.01) accompanied with high 3H-Tdr incorporation rate (1,898 +/- 421 vs. 1,221 +/- 262, P < 0.05) and shorter doubling time (31.6 +/- 1.84 h vs. 35.0 +/- 5.37 h, P < 0.05) was found in comparison with the control. The synthesis of alpha-smooth muscle actin and extracellular matrix, including fibronectin and laminin, increased. Enhanced mRNA and protein expression of GLUT1 were verified in MC from DN. 2-DG uptake assay showed increased glucose uptake rate in MC from DN compared to the control(1,592 cpm x 10(5) cell-1 vs. 1,275 cpm x 10(5) cell-1, P < 0.05). Furthermore, MC from DN demonstrated a higher GFAT activity as compared to control. CONCLUSION: Dramatic phenotypic and functional changes, including cell hypertrophy, increased cell turnover, excessive formation of ECM, enhanced expression of GLUT1 as well as alterration in cell glucose uptake, excessive flux of glucose metabolism through the hexosamine pathway, occur in MC from type II DN. The above mentioned phenotypic and functional changes may be the basis of pathogenesis of MC in DN.

Actins↗
PubMed2001

Leukocyte integrin Mac-1 recruits toll/interleukin-1 receptor superfamily signaling intermediates to modulate NF-kappaB activity.

The leukocyte integrin Mac-1 (alphaMbeta2, CD11b/CD18) regulates important cell functions in inflammation, including adhesion, phagocytosis, and oxidative burst. Deficiency of Mac-1 reduces vessel wall inflammation and neointimal thickening after murine carotid artery injury. Although Mac-1 has been implicated in modulating AP-1 and NF-kappaB activity, the signal transduction pathways involved are undefined. cDNA array analysis of Mac-1-clustered compared with -nonclustered monocytic THP-1 cells showed increased expression of the signal transducer TRAF6 (TNF receptor-associated factor 6), leading us to consider the possibility that Mac-1 used a Toll/IL-1 receptor family-like signaling pathway. Mac-1-dependent activation of NF-kappaB was potentiated by wild-type, and attenuated by dominant negative, TRAF6- and TGF-beta-activated kinase (TAK1) constructs. IRAK1 (IL-1 receptor associated kinase), a kinase immediately upstream of TRAF6, coimmunoprecipitated with Mac-1. Taken together, these observations indicate that Mac-1 recruits a Toll/IL-1 receptor family-like cascade to modulate NF-kappaB activity. This represents a new pathway for integrin-dependent modulation of gene expression.

Adaptor Proteins, Signal Transducing↗
PubMed2001

Arsenic trioxide, a therapeutic agent for APL.

Acute promyelocytic leukemia (APL) is an interesting model in cancer research, because it can respond to the differentiation/apoptosis induction therapy using all-trans retinoic acid (ATRA) and arsenic trioxide (As(2)O(3)). Over the past 5 years, it has been well demonstrated that As(2)O(3) induces a high complete remission (CR) rate in both primary and relapsed APL patients (around 85 to 90%). The side effects are mild to moderate in relapsed patients, while severe hepatic lesions have been found in some primary cases. After CR obtained in relapsed patients, chemotherapy in combination with As(2)O(3) as post-remission therapy has given better survival than those treated with As(2)O(3) alone. The effect of As(2)O(3) has been shown to be related to the expression of APL-specific PML-RARalpha oncoprotein, and there is a synergistic effect between As(2)O(3) and ATRA in an APL mouse model. Cell biology studies have revealed that As(2)O(3) exerts dose-dependent dual effects on APL cells. Apoptosis is evident when cells are treated with 0.5 approximately 2.0 microM of As(2)O(3) while partial differentiation is observed using low concentrations (0.1 approximately 0.5 microM) of the drug. The apoptosis-inducing effect is associated with the collapse of mitochondrial transmembrane potentials in a thiol-dependent manner, whereas the mechanisms underlying APL cell differentiation induced by low dose arsenic remain to be explored. Interestingly, As(2)O(3) over a wide range of concentration (0.1 approximately 2.0 microM) induces degradation of a key leukemogenic protein, PML-RARalpha, as well as the wild-type PML, thus setting up a good example of targeting therapy for human cancers.

Animals↗