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PubMed2001

Telomerase activity is repressed during differentiation along the hepatocytic and biliary epithelial lineages: verification on immortal cell lines from the same origin.

Recent investigations indicate that telomerase activity regulates the life span of cells by compensating for telomere shortening during DNA replication. In addition, as differentiation progresses, telomerase activity is reduced in several different cell lineages. These findings lend support to the theory that more immature cells have greater remaining proliferative capacity and longer life span. However, it has not been directly demonstrated that the differentiation along a hepatocytic or a bile ductal lineage is accompanied by reduction of telomerase activity. In this study, we present direct evidence that telomerase activity is reduced during hepatocytic and biliary epithelial differentiation by using our unique cell lines including a stem-like cell line, ETK-1. When hepatocytic differentiation was induced in ETK-1 by 5-azacytidine, telomerase activity decreased significantly. Similarly, when we compared the telomerase activity on SSP-25 and RBE cell lines from the same origin but representing different maturation stages of cholangiocarcinoma, more mature cells were found to possess significantly lower activity. These results indicate that the generally accepted relationship between telomerase activity and differentiation stage also applies in the hepatocytic and biliary epithelial lineages.

Azacitidine↗
PubMed2003

Long-term follow-up of a phase I study of high-dose decitabine, busulfan, and cyclophosphamide plus allogeneic transplantation for the treatment of patients with leukemias.

BACKGROUND: Decitabine is a hypomethylating agent that has activity in patients with leukemia. The authors combined decitabine with busulfan and cyclophosphamide as a conditioning regimen prior to allogeneic hematopoietic stem cell transplantation. METHODS: Patients with high-risk acute myeloid leukemia (AML) (n = 12 patients); chronic myelomonocytic leukemia (CMML) (n = 1 patient); acute lymphocytic leukemia (ALL) (n = 1 patient); or late chronic phase, accelerated, or blastic phase chronic myelogenous leukemia (n = 9 patients) were eligible for the study. The treatment plan was comprised of busulfan, 12 mg/kg orally; cyclophosphamide, 100 mg/kg (n = 4 patients) or 120 mg/kg (n = 19 patients); and decitabine, intravenously at 3 dose levels: 400 mg/m(2) (n = 10 patients), 600 mg/m(2) (n = 8 patients), and 800 mg/m(2) (n = 5 patients). Donors were human leukocyte antigen-identical siblings in all cases, and all but one patient received peripheral blood stem cells. Graft-versus-host disease (GVHD) prophylaxis was tacrolimus based in all but one patient. RESULTS: The median time to neutrophil and platelet engraftment was 12.5 days and 17.5 days, respectively. Twenty-one patients were engrafted and achieved disease remission. At a median of 3.3 years posttransplantation, 26% of patients (40% of patients with AML) were alive and disease free. The median survival for the group was 17.2 months, and the disease free survival for the group was 8.9 months. Causes of death were disease recurrence (nine patients), chronic GVHD (four patients), infections (three patients), and acute GVHD (one patient). The 100-day mortality rate was 9%. No decitabine dose-limiting toxicity was documented. The treatment-related mortality rate at 3 years was 35%. Responders were treated at all three decitabine dose levels, and no dose-response correlation was observed. CONCLUSIONS: There was a high response rate with low treatment-related mortality, with 26% of patients alive in remission 3.3 years after transplantation.

Adolescent↗
PubMed2003

Results of decitabine (5-aza-2'deoxycytidine) therapy in 130 patients with chronic myelogenous leukemia.

BACKGROUND: General and site-specific DNA methylation is associated with tumor progression and resistance in several cancers, including chronic myelogenous leukemia (CML). Decitabine is a hypomethylating agent that has shown encouraging preliminary anti-CML activity. This study evaluated the activity and toxicity of decitabine in different phases of CML. METHODS: One hundred and thirty patients with CML were treated: 123 with Philadelphia chromosome (Ph)-positive CML (64 blastic, 51 accelerated, 8 chronic) and 7 with Ph-negative CML. Decitabine was given at 100 mg/m(2) over 6 hours every 12 hours x 5 days (1000 mg/m(2) per course) in the first 13 patients, 75 mg/m(2) in the subsequent 33 patients, and 50 mg/m(2) in the remaining 84 patients. RESULTS: A total of 552 courses were given to the 130 patients. Only four patients (3%) died during the first course from myelosuppressive complications (three patients) or progressive disease (one patient). Of 64 patients in the CML blastic phase, 18 patients (28%) achieved objective responses. Of these 18 patients, 6 achieved complete hematologic responses (CHR), 2 achieved partial hematologic responses (PHR), 7 achieved hematologic improvements (HI), and 3 returned to the second chronic phase (second CP). Five patients (8%) had cytogenetic responses. Among 51 patients in the accelerated phase, 28 patients (55%) achieved objective responses (12 CHR, 10 PHR, 3 HI, and 3 second CP). Seven patients (14%) had cytogenetic responses. Among eight patients treated in the chronic phase, five (63%) had objective responses. Of seven patients treated for Ph-negative CML, four (57%) had objective responses. There was no evidence of a dose-response effect. The estimated 3-year survival rate was less than 5% in the blastic phase and 27% in the accelerated phase. The only significant toxicity reported was severe myelosuppression, which was delayed, prolonged, and dose dependent. With decitabine 50-75 mg/m(2), the median time to granulocyte recovery above 0.5 x 10(9)/L was about 4 weeks. Myelosuppression-associated complications included febrile episodes in 37% and documented infections in 34%. CONCLUSIONS: Decitabine appears to have significant anti-CML activity. Future studies should evaluate lower-dose, longer-exposure decitabine schedules alone in imatinib-resistant CML, as well as combinations of decitabine and imatinib in different CML phases.

Adolescent↗
PubMed2005

CpG methylation at promoter site -140 inactivates TGFbeta2 receptor gene in prostate cancer.

BACKGROUND: The action of transforming growth factor beta (TGF-beta) is mediated through type 1 (TbetaRI) and type 2 (TbetaRII) receptors. Prostate cancer cells are often resistant to TGF-beta signaling due to loss of TbetaRII expression. The authors of the current study hypothesized that CpG methylation of the TbetaRII promoter at the Sp1 binding site -140 mediates this loss of TbetaRII expression in prostate cancer. METHODS: Sixty-seven prostate cancer (PC) samples, 8 benign prostatic hyperplasia (BPH) samples, and 4 prostate cancer cell lines (DUPro, LNCaP, ND-1 and PC-3) were analyzed for 1) TbetaRII mRNA expression by semiquantitative RT-PCR, 2) TbetaRII protein expression by immunohistochemistry, and 3) TGFbetaRII promoter methylation at CpG site -140 by methylation specific PCR and bisulfite DNA sequencing. Prostate cancer cell lines were treated with the demethylating agent 5aza2'deoxycytidine to determine if TbetaRII gene expression could be increased by blocking promoter methylation. RESULTS: mRNA and protein expression of TbetaRII was lower in the PC samples than in the BPH samples. CpG methylation at site -140 was higher in PC than in BPH (P < 0.01). Promoter methylation was inversely correlated with TbetaRII mRNA expression in the PC and BPH samples (P < 0.0001). PC3, ND1, and DUPro TbetaRII mRNA expression increased following treatment of cells with 5-aza-2'-deoxycytidine. CONCLUSION: CpG methylation of the TbetaRII promoter at CPG site -140 leads to functional loss of the TbetaRII gene in prostate cancer. Treatment with 5-aza-2' deoxycytidine can restore gene expression. The current study results report the first association between prostate cancer and loss of the TGF- beta signaling pathway by TbetaRII DNA promoter methylation.

Azacitidine↗
PubMed2005

DNA methylation of genes linked with retinoid signaling in gastric carcinoma: expression of the retinoid acid receptor beta, cellular retinol-binding protein 1, and tazarotene-induced gene 1 genes is associated with DNA methylation.

BACKGROUND: Hypermethylation of CpG islands has been associated with silencing of various tumor suppressor genes, and the retinoid acid receptor beta (RARbeta), cellular retinol-binding protein 1 (CRBP1), and tazarotene-induced gene 1 (TIG1) genes have been associated with retinoic acid signaling. To the authors' knowledge, little is known regarding the involvement of these three genes in gastric carcinoma (GC). In this study, the authors investigated the methylation status of these genes and analyzed the role of their DNA methylation in GC. METHODS: DNA methylation of 3 retinoic acid-associated genes was analyzed in 42 samples of GC from 42 patients and in 8 GC cell lines by methylation-specific polymerase chain reaction (PCR) analysis. The mRNA expression levels for these three genes were measured by quantitative reverse transcription-PCR. RESULTS: In 7 of 8 GC cell lines, the CRBP1 gene was hypermethylated, and CRBP1 transcription was inactive. In 6 of 8 GC cell lines, the TIG1 gene was hypermethylated, and TIG1 transcription was inactive. Treatment with demethylating agent 5-aza-2'-deoxycytidine restored both CRBP1 and TIG1 transcription. DNA methylation of the RARbeta, CRBP1, and TIG1 genes was detected in 15 of 42 GC samples (36%), 14 of 42 GC samples (33%), and 4 of 42 GC samples (10%), respectively, and in 6 of 30 samples (20%), 0 of 30 samples (0%), and 1 of 30 samples (3%) of corresponding nonneoplastic mucosa. None of the 10 normal gastric mucosa samples from young, healthy individuals demonstrated hypermethylation of any of these genes. DNA methylation of each gene was associated significantly with low mRNA expression of the respective gene. Twenty-four of 42 GC samples (57%) demonstrated hypermethylation of at least 1 of the 3 genes. However, no significant, concordant hypermethylation of these genes was observed. CONCLUSIONS: The results suggested that gastric carcinogenesis involves transcriptional inactivation by aberrant DNA methylation of genes related to retinoid signaling.

Adenocarcinoma↗
PubMed2005

The epigenome as a molecular marker and target.

Tumor cell proliferation, de-differentiation, and progression depend on a complex combination of altered cell cycle regulation, excessive growth factor pathway activation, and decreased apoptosis. The understanding of these complex mechanisms should lead to the identification of potential molecular markers, targets, and molecular profiles that should eventually expand and improve therapeutic intervention. It now appears clear that methylation plays a central role in transformation, both in vitro and in vivo. However, the exact targets and mechanism(s) are not yet fully understood. This is partly due to the significant number of genes altered by changes in intracellular methyltransferase activity and the chemical agents used to modulate gene expression. The complex nature of methylation's role in regulating gene expression suggests that in addition to investigating individual genes, researchers should develop more comprehensive methods to examine gene expression patterns and their predictive value as this will likely be necessary in the future. If methylation plays a role in transformation, then it seems logical that genes regulating intracellular methylation status may be used as molecular markers to profile tumors by any new methods currently being developed. Perhaps more noteworthy is that DNMT genes may be found to be novel molecular targets for new factor-specific anticancer agents. This idea will be addressed.

Azacitidine↗
PubMed2006

Decitabine improves patient outcomes in myelodysplastic syndromes: results of a phase III randomized study.

BACKGROUND: Aberrant DNA methylation, which results in leukemogenesis, is frequent in patients with myelodysplastic syndromes (MDS) and is a potential target for pharmacologic therapy. Decitabine indirectly depletes methylcytosine and causes hypomethylation of target gene promoters. METHODS: A total of 170 patients with MDS were randomized to receive either decitabine at a dose of 15 mg/m2 given intravenously over 3 hours every 8 hours for 3 days (at a dose of 135 mg/m2 per course) and repeated every 6 weeks, or best supportive care. Response was assessed using the International Working Group criteria and required that response criteria be met for at least 8 weeks. RESULTS: Patients who were treated with decitabine achieved a significantly higher overall response rate (17%), including 9% complete responses, compared with supportive care (0%) (P < .001). An additional 12 patients who were treated with decitabine (13%) achieved hematologic improvement. Responses were durable (median, 10.3 mos) and were associated with transfusion independence. Patients treated with decitabine had a trend toward a longer median time to acute myelogenous leukemia (AML) progression or death compared with patients who received supportive care alone (all patients, 12.1 mos vs. 7.8 mos [P = 0.16]; those with International Prognostic Scoring System intermediate-2/high-risk disease, 12.0 mos vs. 6.8 mos [P = 0.03]; those with de novo disease, 12.6 mos vs. 9.4 mos [P = 0.04]; and treatment-naive patients, 12.3 mos vs. 7.3 mos [P = 0.08]). CONCLUSIONS: Decitabine was found to be clinically effective in the treatment of patients with MDS, provided durable responses, and improved time to AML transformation or death. The duration of decitabine therapy may improve these results further.

Acute Disease↗
PubMed2006

Superiority of prolonged low-dose azanucleoside administration? Results of 5-aza-2'-deoxycytidine retreatment in high-risk myelodysplasia patients.

BACKGROUND: The optimal treatment duration with decitabine (DAC) in patients with myelodysplastic syndromes (MDS) remains a matter of debate. Although at least 2 consolidating courses after best response usually are performed, the response to treatment after disease recurrence has not been systematically studied to date. METHODS: In the current study, the authors report on 22 of 108 patients with MDS (20%) treated with low-dose DAC in 3 Phase II trials who received DAC as retreatment at the time of disease recurrence. RESULTS: According to the International Prognostic Scoring System (IPSS) at the time of initial treatment, 5 of 22 patients (23%) had a score of intermediate-1 (Int-1), 4 patients (18%) had a score of Int-2, and 13 patients (59%) were scored as high-risk. Patients initially received a median of 6 courses of DAC (range, 2 courses-6 courses), which resulted in a complete remission (complete response [CR]) in 12 of the 22 patients (55%). Retreatment with DAC at the time of disease recurrence was initiated at a median of 11 months (range, 3 mos-27 mos) after the last course of initial treatment. With regard to DAC retreatment, patients received a median of 3 courses (range, 1 courses-6 courses), with 10 of 22 patients (45%) responding (1 with a CR and 2 with partial remissions [partial response (PR)]; all 3 patients achieved a CR at the time of initial treatment) and 7 patients demonstrating a hematologic improvement (HI) (at the time of initial treatment there were 2 CRs, 4 PRs, and 1 HI). Twelve of the 22 patients (55%) did not demonstrate any objective responses to retreatment, including 4 patients with primary resistance to the first course of retreatment. The median survival of all patients from the initiation of the first DAC course was 27.5 months (range, 15 mos-50+ mos). The median survival of 43 patients who also had achieved a response to the initial treatment with DAC but who received best supportive care (n = 33 patients) or induction chemotherapy (n = 10 patients) was 18 months (range, 5 mos-72 mos). Second responders to DAC retreatment were found less frequently in the IPSS high-risk group compared with nonresponders (40% vs. 83%). Age, French-American-British classification subtype, serum lactate dehydrogenase level at retreatment, and previous response to DAC were not found to strongly differ between the groups; however, the subgroups were too small to perform a statistical analysis. CONCLUSIONS: Retreatment with DAC was found to result in objective responses in 45% of previously DAC-responsive patients. However, the quality and duration of the second disease remissions were found to be inferior. Therefore, DAC-responsive patients might derive more clinical benefit from continuation of the initial treatment.

Aged↗
PubMed2006

Sequential gene expression changes in cancer cell lines after treatment with the demethylation agent 5-Aza-2'-deoxycytidine.

BACKGROUND: 5-Aza-2'-deoxycytidine (5-AzaC) is known well for its demethylation effect and is a promising anticancer agent. However, to the authors' knowledge, serial changes in gene expression over time after 5-AzaC treatment have not been studied to date. To clarify the categories of genes that are up-regulated or down-regulated after 5-AzaC treatment, the authors surveyed the genes that had expression levels changed by 5-AzaC treatment in 6 hepatoma cell lines (Hep3B, HLE, Huh7, HepG2, PLC/PRF/5, and Huh6). METHODS: Cell lines were grown in medium that contained 1 microM of 5-AzaC. Changes in messenger RNA levels were monitored from 24 hours up to 120 hours after 5-AzaC treatment using an in-house microarray that consisted of 4608 combinational DNAs. Using clustering analysis to identify the genes that had gradually changed expression levels and to exclude the substantial experimental noise by microarray analysis, the authors focused on 206 up-regulated genes and 248 down-regulated genes. RESULTS: According to their functional characterization, genes that were involved in the cytoskeleton and the extracellular matrix were enriched significantly in the up-regulated genes. Conversely, genes that were involved in metabolism were enriched significantly in the down-regulated genes. CONCLUSIONS: The current results demonstrated that 5-AzaC can regulate the expression of groups of genes with characteristic functions.

Azacitidine↗
PubMed2006

RIZ1 is epigenetically inactivated by promoter hypermethylation in thyroid carcinoma.

BACKGROUND: Allelotype studies have suggested that chromosome 1p is frequently lost in thyroid cancers, thus suggesting that there is an important tumor suppressor at this location. RIZ1 (PRDM2), located on 1p36, is a recently described tumor suppressor gene and is a member of the protein methyltransferase superfamily. RIZ1 expression is lost in a variety of tumors, primarily by means of epigenetic mechanisms that involve promoter hypermethylation. METHODS: RIZ1 expression was examined in a panel of thyroid tumor cell lines and primary thyroid tissues (14 normal, 19 benign, and 31 cancerous) by using real-time polymerase chain reaction (PCR). Methylation status of the RIZ1 promoter was studied using bisulfite sequencing and methylation-specific PCR. RESULTS: The authors demonstrated that RIZ1 expression is lost in thyroid tumor cell lines and is also significantly reduced in thyroid carcinomas, when compared with normal thyroid tissues (P < .0001) and benign tumors (P = .0003). The current study results also showed that loss of RIZ1 is mediated by aberrant cytosine methylation of the RIZ1 promoter. One hundred percent of carcinomas were methylated, compared with 33% of normal thyroid tissues (P = .001). RIZ1 mRNA expression was significantly higher (P = .02) in unmethylated (1.22 +/- 1.2, mean +/- standard deviation [SD]), compared with methylated tissues (0.37 +/- 0.42, mean +/- SD). Last, treatment with a DNA methyltransferase inhibitor led to reactivation of RIZ1 expression in cell lines that had negligible RIZ1 expression at baseline. CONCLUSIONS: The current study suggested an important role for RIZ1 expression in thyroid tumorigenesis and identified a potential novel therapeutic target for tumors unresponsive to other therapies.

Antimetabolites, Antineoplastic↗
PubMed2007

Activity of decitabine, a hypomethylating agent, in chronic myelomonocytic leukemia.

BACKGROUND: Hypomethylating agents have activity in myelodysplastic syndrome (MDS) and have received approval for the treatment of both MDS and chronic myelomonocytic leukemia (CMML). The specific efficacy in CMML has not been detailed in a large number of patients. The aim of the study was to evaluate the activity and safety of decitabine in CMML. METHODS: Nineteen adults with a diagnosis of CMML treated on decitabine studies were analyzed. Decitabine was given at 100 mg/m(2) per course every 4 weeks. The median number of courses given was 9 (range, 1-18). RESULTS: Overall, 11 patients (58%) achieved complete response (CR) and 2 (11%) had hematologic improvement (HI), for an overall response rate of 69% according to the modified International Working Group (IWG) criteria. Median survival was 19 months. Severe (grade 3-4) extramedullary side effects were rare. CONCLUSIONS: Decitabine is active in CMML. Studies of combinations of decitabine with topoisomerase I inhibitors or other active anti-CMML agents are indicated.

Adult↗
PubMed1981

Rapid analysis of drug effects on the cell cycle.

Using a flow cytometric technique to analyse DNA content and chromatin structure simultaneously, the following parameters of cell cycle progression were estimated in control and drug-treated L1210 cell cultures: (a) the kinetics of cell exit from the G1 phase; (b) the probability of cell exit from the indeterminate portion of the G1 phase, measured as the half-time of cell residence in that state; (c) the duration of the deterministic portion of G1 phase; (d) the rates of cell transit through selected "windows" in S phase; (e) the rate of cell entrance into mitosis; (f) the mean duration of the cell cycle (Tc). These parameters are obtained in a single stathmokinetic experiment from measurements of individual samples withdrawn at 30 min-1 hr intervals from Vinblasatine-treated cultures. In the same experiment mitotic indices are obtained with high statistical accuracy, and may be used to determine the terminal point of drug action. In addition to cell cycle analysis the method makes it possible to detect drug-induced changes in nuclear chromatin that are manifested by varying sensitivity of DNA in situ to denaturation by acid. Such changes were found to be associated with defective chromatin condensation, altered histone modifications or intercalation of the drugs into DNA. Using this technique the effects of sodium n-butyrate and two new antitumor drugs on L1210 cells were investigated.

Animals↗
PubMed1989

5-azacytidine-induced tumorous transformation and DNA hypomethylation in Nicotiana tissue cultures.

The phenomenon of habituation is considered in plant tissue cultures to be a real process of chemical tumorogenesis; the cultures acquire the capacity of autonomous growth in a hormone-free medium under the influence of a variety of chemical and physical agents. Treatments with 5-azacytidine (AzaC) of in vitro cultured cells of the Nicotiana glauca x N. langsdorffii nontumorous hybrid (NNT) during the culture cycle led to the induction of a habituated phenotype. The repetitive DNA sequences showed a significant lower level of endogenous methylation in the treated cells in comparison with the normal ones. It is worth noting that it was impossible until now to habituate this strain by conventional methods and that the treatments were effective only in the first 5 days of subculturing; various evidence (cytological and biochemical) pointed out a phenomenon of DNA amplification, occurring in the same period. Moreover, analysis of DNA from control and treated cells shows the induction of variations in the endogenous methylation pattern by AzaC in a critical period of cell culture. These results suggest that demethylation can act as a switch from hormone-dependent to autonomous proliferation by activation of genes coding for or regulating the synthesis of growth factors.

5-Methylcytosine↗
PubMed1986

Azacytidine-induced reactivation of adenosine deaminase in a murine cytotoxic T cell line.

In C57BL/6 mice, cytotoxic T lymphocyte (CTL) lines have previously been found to exhibit low (less than 150 U/mg) or undetectable (less than 20 U/mg) adenosine deaminase (ADA) levels (Minkowski, Castellazzi and Buttin, J. Immunol. 1984. 133: 52) in contrast to what has been seen in T helper lines (1770 +/- 340 U/mg; Minkowski and Bandeira, Cell. Immunol. 1985. 95: 380). Treatment of one of these CTL ADA- lines with the demethylating agent 5-azacytidine gave rise to an ADA+ population. Subsequent cloning allowed the recovery of pure ADA+ clones showing a rather narrow range of activity with an average value of 2030 +/- 504 U/mg. The restored ADA+ activity is stable over several months of continuous growth. It is identical to the activity of C57BL/6 thymic cells or C57BL/6 T tumor lines regarding its sensitivity to ADA inhibitors 2-deoxycoformycin and erythro-9-(2-hydroxyl-3-nonyl)adenine, and its electrophoretic mobility under nondenaturing conditions (starch gel and isoelectric focusing). An ADA-specific, 1.4-kb mRNA is present in the reactivated clones but is undetectable in the CTL ADA- parental line. These results demonstrate that the ADA- phenotype is due to an extinction of the corresponding gene. They suggest that the extinction of the ADA gene which appears to be specific for CTL and to take place in vivo during T cell differentiation may result from increased methylation in or near the ADA gene. This extinction seems to affect specifically ADA since nucleoside phosphorylase, the enzyme which follows ADA in the purine salvage pathway, is present at equivalent levels in the ADA- and ADA+ CTL clones.

Adenosine Deaminase↗
PubMed1989

Induction of class II major histocompatibility complex antigens in murine placenta by 5-azacytidine and interferon-gamma involves different cell populations.

Class II MHC antigen expression is required for recognition of an alloantigen and generation of immune response. In rodents as well as in humans primary trophoblasts do not express class II MHC antigens. In this study we focused our interest on the mechanism(s) of class II antigen suppression on murine trophoblasts. First, we examined the possibility of gene inactivation by methylation and second the possibility of lymphokine regulation of the class II genes. The first possibility was tested by treatment of placental cells with 5-azacytidine (5-AzaC), a cytidine analog which upon incorporation into the DNA inhibits further methylation, thus leading to gene activation. In order to test the second possibility we treated placental cells with interferon-gamma (IFN-gamma) or interleukin 4 (IL4) which are known to induce class II antigen expression in many systems. We showed that treatment with 5-AzaC or IFN-gamma but not IL4 significantly increased class II expression on cytokeratin-positive and vimentin-negative adherent placental cells. Following placental cell fractionation we distinguished three cell subsets with different responsiveness to 5-AzaC and IFN-gamma. The first, characterized as placental macrophages, were induced to express class II MHC antigens only after IFN-gamma treatment. The other two subsets, characterized as trophoblasts, were isolated from the labyrinthine- and spongio-trophoblast layer of the placenta and showed class II inducibility to 5-AzaC and IFN-gamma, respectively. The results show that depending on the anatomical localization of trophoblasts within the placenta, various regulatory elements control gene expression, so that the placental barrier provides fetal protection at different levels.

Animals↗
PubMed1990

5-Azacytidine inhibits the lpr gene-induced lymphadenopathy and acceleration of lupus-like syndrome in MRL/MpJ-lpr/lpr mice.

MRL/MpJ-lpr/lpr mice spontaneously develop a lupus-like autoimmune disorder characterized by massive proliferation of T cells and rapidly fatal immune complex glomerulonephritis. We evaluated the therapeutic effect of 5-azacytidine (5AC), a cytidine analogue known as an inhibitor of DNA methylation, in MRL/MpJ-lpr/lpr mice. Intraperitoneal injection of 5AC (50 micrograms, twice a week) starting from 6 weeks of age retarded the development of lymphadenopathy and autoimmune syndrome. Its beneficial effects included: (a) increased life-span, (b) diminution of lymphadenopathy and splenomegaly, (c) reduction in circulating levels of autoantibodies such as anti-DNA and rheumatoid factors, and (d) suppression of lupus glomerulonephritis. However, similar treatment in BALB/c mice did not affect the development of IgG anti-human IgG antibody responses. These results suggest that the protective effect of 5AC is related to the inhibition of the lpr gene-induced T cell proliferation, thereby suppressing the autoimmunity-accelerating effect mediated by the lpr gene.

Animals↗