Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0023418 (leukemia)
93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

5-Azacytidine is more active when administered parenterally than orally in the treatment of L1210 leukemic mice. Oral coadministration of tetrahydrouridine, a pyrimidine nucleoside deaminase inhibitor with no intrinsic antitumor activity, greatly increases the oral activity of 5-azacytidine. 5-azacytidine (or cytotoxic equivalent) blood levels in BDF mice are much higher after oral administration of the 5-azacytidine-tetrahydrouridine combination than when 5-azacytidine is administered alone by the same route. The therapeutic results (L1210 leukemia) achieved with the oral combination are similar to those observed with parenteral 5-azacytidine alone.
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PMID:Enhancement by tetrahydrouridine (NSC-112907) of the oral activity of 5-azacytidine (NSC-102816) in L1210 leukemic mice. 5 11

The pyrimidine analog, 5-azacytidine (NSC 102816), was administered by continuous intravenous infusion in Ringer's lactate in increasing doses to sets of patients with metastatic cancer to establish a dose sufficient to produce mild toxicity. Twenty-one patients (23 trials) were treated with doses of 50-200 mg/sq/m/day for 5 days every 2-4 wk. Nausea and vomiting were moderate and easily preventable. Doses of 100-200 mg/sq/m for 5 days every 14 days produced granulocytopenia, usually after two courses. Less toxicity was observed when courses were given every 21-28 days. Forty-five patients with previously treated and refractory acute myeloblastic leukemia were treated. The majority received doses of 150 mg/sq m for 5 days every 2 wk. Eleven (24%) complete remissions and four partial remissions were observed. The number of courses to achieve remission averaged three and required an average of 59 days. Nine patients with blastic crisis of chronic myeloblastic leukemia and four with refractory acute lymphoblastic leukemia failed to respond. 5-Azacytidine administered by continuous infusion is well tolerated and is an active compound in acute myeloblastic leukemia.
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PMID:5-Azacytidine (NSC 102816): a new drug for the treatment of myeloblastic leukemia. 6 Jan 56

5-Azacytidine was applied to NMRI-mice (1-2 mg/kg) either on gestation day 12, 14, or 16. In the first case it mainly induced leukemias, while in the latter experiments leukemias, lung adenomas and soft tissue sarcomas represent the main effects. The experiments performed on gestation day 14 led to tumor rates below the spontaneously occurring tumor frequencies in NMRI-mice. There is a clear-cut inverse dose-response relationship in leukemia induction, as the higher dose principally shows a lower degree of effectiveness. This, as well as a reduction of tumor frequency below control levels after application of this drug on day 14, can be explained by an "overkill" effect. The cytotoxic and embryolethal efficacy of the agent thus surpasses the transformation effects at the cellular genome. While a negative correlation between the general embryotoxicity of azacytidine and the simultaneous tumor inducibility is to be observed, there is no correlation at the target organ level between the embryotoxic and the carcinogenic effects.
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PMID:Diaplacental carcinogenic effects of 5-azacytidine in NMRI-mice. 240 41

Several new cytostatic drugs have entered clinical Phase I-II studies for treatment of leukemia: most promising are pyrimidine analogues such as 5-Azacytosine arabinoside, 5-Aza-2-deoxycytidine, 5-Azacytidine, cyclocytidine, and 2'-2'-difluorodeoxycytidine. They act on different biochemical levels towards DNA-synthesis. Fludarabine is a purin analogue and seems very active in treating CLL. Tiazofurin is an antimetabolite counter-acting nicotinic acid with most promising activity in CML blast crisis. Other substances include deoxycoformycin, an adenosine analogue for treatment of T-cell neoplasias, 1, 25-dihydroxy vitamin D 3 as differentiation inducer, and homoharringtonine, an alkylating agent widely used for treating de novo AML in China. New anthracyclines are THP-adriamycin, fluoroadriamycin, and 4-demethoxydaunorubicin. Amsacrine (mAMSA) finally, is a synthetic aminoacridine with DNA-intercalating properties. The intact acridine ring appears essential for antitumor activity. The plasma clearance of both total amsacrine and unchanged parent species is biphasic. There is a considerable influence of hepatic and renal impairment on plasma clearance. Clinical toxicities include marked myelosuppression, gastrointestinal symptomes, phlebitis, mucocutaneous lesions, occasionally alopecia and neurotoxities. It is a very active drug, particularly in treating AML. Studies using mAMSA alone or in combination revealed comparable results to the anthracyclines. The E.O.R.T.C. Leukemia Cooperative Group has used successfully mAMSA in several trials: relapsed and refractory AML, intensive maintenance treatment during first remission in AML, and, still on-going, during intensive consolidation randomized against BMT in AML-patients under the age of 45 years, and randomized against standard consolidation between the age of 45 and 60 years.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:New drugs in the treatment of acute and chronic leukaemia: current role of mAMSA. 269 2

5-Azacytidine (5-aza-CR) and 5-aza-2'-deoxycytidine (5-aza-CdR), analogs of cytidine modified in position 5, were originally developed as antitumor agents, and have been useful in the treatment of both childhood and adult leukemias. These agents are cytotoxic per se, but also induce differentiation in several experimental systems, most notably the induction of muscle, adipocytes, and chondrocytes in cultures of drug-treated mouse embryo fibroblasts. The mechanisms underlying this drug-induced differentiation have been difficult to unravel, a fact which limits the rational design of differentiation therapy as a modulator of cancer using these agents. Induction of new developmental pathways in cultured cells involves stable, heritable changes, presumably of an epigenetic nature. Our early studies demonstrated that changes in methylation of cytosine in DNA occurred concurrently with changes in developmental potential, and that the presence of 5-azacytosine in DNA interfered with the action of DNA methyltransferase. Since DNA methylation is believed to be involved at some level in the regulation of gene expression, the hypothesis was developed that changes in methylation allowed the expression of new genes whose activity initiated new pathways of differentiation. The characterization of this drug-induced system of differentiation has therefore opened the way to identifying genes directly involved in the initiation or modification of pathways of differentiation. The first of these was MyoD, a member of a family of myogenic determination genes. Expression of MyoD in myogenic cell lines has been correlated with loss of methylation at specific sites in the genome, but the critical events leading to expression of MyoD and muscle differentiation are poorly understood. Recent developments in understanding this mechanism are discussed.
Leukemia 1993 May
PMID:5-Aza-2'-deoxycytidine: cell differentiation and DNA methylation. 768 53

Azacitidine is a new drug with a novel mechanism of action; it can correct abberant gene expression in patients with myelodysplastic syndrome. The drug improves symptoms, decreases the need for transfusions, reduced the rate of transformation to leukemia and probably improves survival.
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PMID:Azacitine (vidaza) for myelodysplastic syndrome. 1567 15

Hypermethylation of the MLH1 gene has been described in many kinds of human cancers with microsatellite instability (MSI). However, it is not clear whether the same mechanism occurs in hematological malignancies. Genomic DNA was extracted from 31 patients with adult T-cell leukemia/lymphoma (ATL), 9 patients with acute lymphoblastic leukemia (ALL) who had MSI, and 12 leukemia and lymphoma cell lines with MSI. Aberrant methylation of the MLH1 gene was found in 2/31 (6%) ATL patients, and in 1/12 (8%) cell lines with MSI. MLH1 promoter was not methylated in either of the twelve peripheral blood samples from normal individuals or ALL samples. The MLH1 gene was expressed in the normal peripheral blood samples, but not in the MLH1-methylated cell line KCL22. Demethylation with 5-Azacytidine treatment restored MLH1 expression in the KCL22 cell line. Methylation of the MSH2 gene was not found in any of the samples. Our data show that hypermethylation of the MLH1 gene is occasionally involved in the pathogenesis of hematological malignancies, but is not always associated with MSI.
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PMID:Methylation of the MLH1 gene in hematological malignancies. 1594 88

The class of DNA methyltransferase inhibitors is represented by azacitidine and decitabine. Azacitidine is approved for the treatment of patients in both low- and high-risk subtypes of myelodysplastic syndrome (MDS), and decitabine is currently under review by the FDA. Azacitidine phase III trial data, based upon the Cancer and Leukemia Group B (CALGB) study 9221, showed durable clinical and symptomatic improvement in bone marrow function, a reduction in the risk of leukemic transformation, and significant improvements in the quality of life of patients treated with azacitidine compared with supportive care alone. This study also provided data suggestive of improvement in survival in MDS patients. The experience with decitabine comprises a number of phase I/II studies and a phase III trial yet to be published. While there is a strong base of experience supporting the efficacy of DNA methyltransferase inhibitors in the treatment of MDS, a number of practical issues need to be explored further. These include the optimization of the timing and duration of treatment, and the prediction of response to therapy. Along with current experience, future studies will lead to the development of treatment algorithms, strategies for selecting patients (e.g. according to age, risk, classification, and cytogenetic profile), and the combination strategies, particularly with histone deacetylase inhibitors, in the management of MDS.
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PMID:Methylation inhibitor therapy in the treatment of myelodysplastic syndrome. 1634 Dec 36

5-Azacytidine, a DNA methyl transferase inhibitor, is effective in patients with myelodysplastic syndromes (MDS). Whether responses to 5-Azacytidine are achieved by demethylation of key genes or by cytotoxicity is unclear. Of 34 patients with MDS or acute myeloid leukaemia (AML) treated with 5-Azacytidine, 7 achieved complete remissions (CR) (21%) and 6 achieved haematological improvement. All six had less than 5% bone marrow (BM) blasts at the time of haematological improvements (HI) (2 had pre-existing refractory anaemia (RA), 4 had refractory anaemia with excess blasts (RAEB)). A further patient with RAEB had blast reduction to less than 5% without HI. Five of the seven (71%) complete responders had chromosome 7 abnormalities. BM CR predicted longer overall survival (OS) (median 23 versus 9 months, P=0.015). Bisulphite genomic sequencing (BGS) of the CDKN2B (p15(INK4b)) promoter showed low level, heterogeneous pretreatment methylation (mean 12.2%) in 14/17 (82%) patients analysed. Lower baseline methylation occurred in responders (9.8% versus 16.2% in non-responders P=0.07). No response was seen in patients with >24% methylation, in whom p15(INK4b) mRNA was not expressed. 5-Azacytidine reduced CDKN2B methylation by mean 6.8% in 8/17 (47%) patients, but this did not correlate with response. At 75 mg/m(2), cell death (reduced BM cellularity (P=0.001) and increased apoptosis (P=0.02)) rather than demethylation of CDKN2B correlates with response. Patients with >24% methylation may benefit from alternative dosing or combination strategies.
Leukemia 2007 Sep
PMID:CDKN2B methylation status and isolated chromosome 7 abnormalities predict responses to treatment with 5-azacytidine. 1761 69

Azacitidine and decitabine are cytidine analogues that inhibit DNA methylation, and are used to treat myeloid haematological malignancies. Hydroxycarbamide (HC) (also known as hydroxyurea), a ribonucleotide reductase (RR) inhibitor, blocks the conversion of ribonucleotides to deoxyribonucleotides, and is also used to treat leukaemia and sickle-cell disease. Azacitidine is a ribonucleoside and decitabine is a deoxyribonucleoside; therefore, we hypothesized that inhibition of RR by HC would be antagonistic to azacitidine and synergistic to decitabine. HL-60 and T24 cancer cell lines were treated with azacitidine or decitabine in combination with HC and DNA methylation of LRE1, MAGEA1 and CDKN2A was quantitatively measured by bisulphite-polymerase chain reaction pyrosequencing. Surprisingly, we found that HC blocked the ability of both azacitidine and decitabine to inhibit DNA methylation and this antagonistic effect was attributable to the arrest of the cell cycle induced by HC. However, this antagonism could be avoided with sequential treatment of HC followed by azacitidine or decitabine. This data suggest that concurrent combination of HC blocks the ability of azacitidine and decitabine to inhibit DNA methylation and therefore these drugs should be used sequentially.
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PMID:Hydroxycarbamide in combination with azacitidine or decitabine is antagonistic on DNA methylation inhibition. 1768 55


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