Fludarabine therapy in macroglobulinemic lymphoma.
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Fludarabine, a fluorinated analogue of adenine, was given to 11 patients with macroglobulinemic lymphoma, all but one having failed prior standard chemotherapy. Five patients (45%) responded with more than a 50% reduction of immunoglobulin M (IgM) tumor mass for a projected median duration of longer than 1 year. The onset of remission was usually slow, with a median tumor halving time of 5.2 months in responding patients, emphasizing the importance of repeated courses of treatment. Fludarabine is an important new agent effective against macroglobulinemic lymphoma, and should be evaluated further in combination with other active modalities. (+info)
Termination of DNA synthesis by 9-beta-D-arabinofuranosyl-2-fluoroadenine. A mechanism for cytotoxicity.
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The action of 9-beta-D-arabinofuranosyl-2-fluoroadenine (F-ara-A) on DNA synthesis was evaluated both in whole cells and in vitro. 9-beta-D-Arabinofuranosyl-2-fluoroadenine was converted to its 5'-triphosphate 9-beta-D-arabinofuranosyl-2-fluoroadenine 5'-triphosphate (F-ara-ATP) in cells and then incorporated into DNA in a self-limiting manner. More than 94% of the analogue was incorporated into DNA at the 3' termini, indicating a chain termination action. In vitro DNA primer extension experiments further revealed that F-ara-ATP compared with dATP for incorporation into the A site of the extending DNA strand. The incorporation of F-ara-AMP into DNA resulted in termination of DNA strand elongation. Human DNA polymerase alpha incorporated more F-ara-AMP into DNA than polymerase epsilon (proliferating cell nuclear antigen-independent DNA polymerase delta) and was more sensitive to inhibition by F-ara-ATP. On the other hand, DNA polymerase epsilon was able to excise the incorporated F-ara-AMP from DNA in vitro. The incorporation of F-ara-AMP into DNA was linearly correlated both with inhibition of DNA synthesis and with loss of clonogenicity; thus it may be the mechanism of cytotoxicity. (+info)
G-quadruplex induced stabilization by 2'-deoxy-2'-fluoro-D-arabinonucleic acids (2'F-ANA).
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The impact of 2'-deoxy-2'-fluoroarabinonucleotide residues (2'F-araN) on different G-quadruplexes derived from a thrombin-binding DNA aptamer d(G2T2G2TGTG2T2G2), an anti-HIV phosphorothioate aptamer PS-d(T2G4T2) and a DNA telomeric sequence d(G4T4G4) via UV thermal melting (T(m)) and circular dichroism (CD) experiments has been investigated. Generally, replacement of deoxyguanosines that adopt the anti conformation (anti-guanines) with 2'F-araG can stabilize G-quartets and maintain the quadruplex conformation, while replacement of syn-guanines with 2'F-araG is not favored and results in a dramatic switch to an alternative quadruplex conformation. It was found that incorporation of 2'F-araG or T residues into a thrombin-binding DNA G-quadruplex stabilizes the complex (DeltaT(m) up to approximately +3 degrees C/2'F-araN modification); 2'F-araN units also increased the half-life in 10% fetal bovine serum (FBS) up to 48-fold. Two modified thrombin-binding aptamers (PG13 and PG14) show an approximately 4-fold increase in binding affinity to thrombin, as assessed via a nitrocellulose filter binding assay, both with increased thermal stability (approximately 1 degrees C/2'F-ANA modification increase in T(m)) and nuclease resistance (4-7-fold) as well. Therefore, the 2'-deoxy-2'-fluoro-d-arabinonucleic acid (2'F-ANA) modification is well suited to tune (and improve) the physicochemical and biological properties of naturally occurring DNA G-quartets. (+info)
Characterization of a cyclodextrinoligonucleotide complex by capillary electrophoresis using laser-induced fluorescence.
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PURPOSE: Cyclodextrins (CDs) have been identified as a viable alternative to viral vectors for use in therapeutic applications. Here, the stability of the complex formed between the a multiply charged, cationic, fully substituted heptakis-(6-amino-2-galactosyl)cyclodextrin (BCDX12) with a multiply charged 12-mer hexachlorofluorescein tagged arabinopolynucleotide (Hex-PAH) have been evaluated. METHODS: The stability of complexes of Hex-PAH and BCD-X12 was studied with respect to mole ratio (1:1, 1:2, and 1:5 Hex-PAH:BCD-X12), pH, buffer concentration, temperature, and agitation using capillary electrophoresis with laser induced fluorescence detection (CE/LIF). Two neutral CDs and an additional cationic CD were also tested under the same analytical conditions to determine their ability to form complexes. RESULTS: Hex-PAH:BCDX12 complexes at mole ratios of 1:2 were stable in 10 mM (160 mM total borate concentration) sodium tetraborate buffer at pH 7.5 and at temperatures of 4 degrees C and 25 degrees C over 48 hours. However, the Hex-PAH:BCD-X12 complex was less stable at 37 degrees C and at higher buffer concentrations and pH values. Strong vortex mixing prior to analysis was found to disrupt the complex. Of the four CDs tested for their ability to complex with Hex-PAH, only BCDX12 formed stable complexes with Hex-PAH under the test conditions. CONCLUSIONS: Capillary electrophoresis was found to be well suited to test the stability of cyclodextrin-nucleotide complexes. CE/LIF indicated that only a single Hex- PAH:BCD-X12 complex was formed at all formulation ratios, and that the complexes were electrophoretically identical to each other, and increasing the molar ratio beyond 1:2 did not contribute measurably to complex stability. Storage temperature and agitation conditions were found to influence complex stability. Since no stable complexes were formed with neutral cyclodextrins, the results support the hypothesis of a 'charge associated' complex rather than an inclusion complex, although inclusion complexes cannot be excluded on the basis of these studies. (+info)
Phase I trial of nelarabine in indolent leukemias.
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