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  • 1
    Online Resource
    Online Resource
    Differential Methotrexate Resistance in Childhood T- Versus Common/PreB-Acute Lymphoblastic Leukemia Can Be Measured by an In Situ Thymidylate Synthase Inhibition Assay, But Not by the MTT Assay
    American Society of Hematology ; 1999
    In:  Blood Vol. 93, No. 3 ( 1999-02-01), p. 1067-1074
    Details
    In: Blood, American Society of Hematology, Vol. 93, No. 3 ( 1999-02-01), p. 1067-1074
    Abstract: Methotrexate (MTX) is not cytotoxic to patient-derived acute lymphoblastic leukemia (ALL) cells in total-cell-kill assays, such as the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, putatively due to the rescue effects of hypoxanthine and thymidine released from dying cells. This was mimicked by a diminished methotrexate (MTX) cytotoxicity for the cell lines HL60 and U937 in the presence of hypoxanthine, thymidine, or lysed ALL cells. However, enzymatic depletion or inhibition of nucleoside membrane transport did not result in MTX dose-dependent cytotoxicity in patient samples. Alternatively, a thymidylate synthase inhibition assay (TSIA), based on inhibition of the TS-catalyzed conversion of 3H-dUMP to dTMP and 3H2O, correlated with the MTT assay for antifolate sensitivity in four human leukemia cell lines with different modes of MTX resistance. For 86 ALL patient samples, TSI50 values after 21 hours exposure to MTX were not different between T- and c/preB-ALL (P = .46). After 3 hours incubation with MTX followed by an 18-hour drug-free period, T-ALL samples were 3.4-fold more resistant to MTX compared with c/preB-ALL samples (P = .001) reflecting the clinical differences in MTX sensitivity. TSI50 values correlated with MTX accumulation (r = −.58, P & lt; .001). In conclusion, the TSIA, but not the MTT assay, can measure dose-response curves for MTX in patient-derived ALL cells and showed relative MTX resistance in T-ALL compared with c/preB-ALL.
    Type of Medium: Online Resource
    ISSN: 1528-0020 , 0006-4971
    URL: Article
    DOI: 10.1182/blood.V93.3.1067
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 1999
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
    Location Call Number Limitation Availability
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  • 2
    Online Resource
    Online Resource
    Differential Methotrexate Resistance in Childhood T- Versus Common/PreB-Acute Lymphoblastic Leukemia Can Be Measured by an In Situ Thymidylate Synthase Inhibition Assay, But Not by the MTT Assay
    American Society of Hematology ; 1999
    In:  Blood Vol. 93, No. 3 ( 1999-02-01), p. 1067-1074
    Details
    In: Blood, American Society of Hematology, Vol. 93, No. 3 ( 1999-02-01), p. 1067-1074
    Abstract: Methotrexate (MTX) is not cytotoxic to patient-derived acute lymphoblastic leukemia (ALL) cells in total-cell-kill assays, such as the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, putatively due to the rescue effects of hypoxanthine and thymidine released from dying cells. This was mimicked by a diminished methotrexate (MTX) cytotoxicity for the cell lines HL60 and U937 in the presence of hypoxanthine, thymidine, or lysed ALL cells. However, enzymatic depletion or inhibition of nucleoside membrane transport did not result in MTX dose-dependent cytotoxicity in patient samples. Alternatively, a thymidylate synthase inhibition assay (TSIA), based on inhibition of the TS-catalyzed conversion of 3H-dUMP to dTMP and 3H2O, correlated with the MTT assay for antifolate sensitivity in four human leukemia cell lines with different modes of MTX resistance. For 86 ALL patient samples, TSI50 values after 21 hours exposure to MTX were not different between T- and c/preB-ALL (P = .46). After 3 hours incubation with MTX followed by an 18-hour drug-free period, T-ALL samples were 3.4-fold more resistant to MTX compared with c/preB-ALL samples (P = .001) reflecting the clinical differences in MTX sensitivity. TSI50 values correlated with MTX accumulation (r = −.58, P 〈 .001). In conclusion, the TSIA, but not the MTT assay, can measure dose-response curves for MTX in patient-derived ALL cells and showed relative MTX resistance in T-ALL compared with c/preB-ALL.
    Type of Medium: Online Resource
    ISSN: 1528-0020 , 0006-4971
    URL: Article
    DOI: 10.1182/blood.V93.3.1067.403k01_1067_1074
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 1999
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
    Location Call Number Limitation Availability
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  • 3
    Online Resource
    Online Resource
    MiRNA Profiles in Acute Lymphoblastic Leukemia: Rather a Characteristic for the Leukemia Subtype Than a Reflection of Its Differentiation Status.
    American Society of Hematology ; 2007
    In:  Blood Vol. 110, No. 11 ( 2007-11-16), p. 4144-4144
    Details
    In: Blood, American Society of Hematology, Vol. 110, No. 11 ( 2007-11-16), p. 4144-4144
    Abstract: MicroRNAs (miRNAs) are noncoding RNAs that regulate processes involved in proliferation and differentiation. Since abnormal proliferation and differentiation is the hallmark of cancer, miRNAs may have a role in the pathogenesis of cancer. Here we examined the miRNA expression in various subtypes of Childhood Acute Lymphoblastic Leukemia (ALL) including MLL-rearranged ALL (n = 16), T-ALL (n = 10) and precursor B-ALL patients positive for TEL-AML1 (n = 10), BCR-ABL (n = 10), E2A-PBX (n = 8) or hyperdiploidy (more than 50 chromosomes, n = 10) and other precursor B-ALL patients that are negative for all major genetic abnormalities in ALL (n = 19). We have found that miR-196b is highly expressed only in MLL-rearranged ALL and its expression level is ∼400 to 700-fold (P 〈 0.05) higher than the levels in all other precursor B-ALL subtypes and T-ALL cases. Moreover, all precursor B-ALL subtypes including TEL-AML1, BCR-ABL, E2A-PBX and hyperdiploid positive cases have a 250- to 6500- fold upregulation (P ≤0.01) of miR-708 compared to MLL-rearranged ALL and T-ALL patients. Interestingly, it is known that MLL-translocated ALL arises in an earlier stage of B-lineage development compared to other precursor B-ALL subtypes negative for MLL rearrangements, thus subtype-specific expression of miR-196b and miR-708 could reflect a difference in maturation status. However, miR-196b and miR-708 expression levels do not seem to correlate with the differentiation status of the leukemia cells based on the immunoglobulin (Ig) and T-cell receptor (TCR) rearrangements in case of precursor B-ALL and EGIL classification in case of T-ALL. Furthermore, miR-196b is located between the HOXA9 and HOXA10 genes, which are known to be upregulated in MLL-translocated patients. Here we find a positive correlation between miR-196b expression and HOXA9/HOXA10 expression within MLL- rearranged and T-ALL patients. Further research has to reveal whether high expression of miR-196b actively contributes to leukemogenesis like HOX genes or whether it is an epiphenomenon of HOXA upregulation in MLL-rearranged ALL patients. All together, our present study suggests that the expression level of miR-196b and miR-708 reflects differences between genetic subtypes rather than differences in differentiation status and emphasizes the need to further investigate the role of these miRNAs in leukemogenesis.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V110.11.4144.4144
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2007
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
    Location Call Number Limitation Availability
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  • 4
    Online Resource
    Online Resource
    Effect of polymorphisms in folate-related genes on in vitro methotrexate sensitivity in pediatric acute lymphoblastic leukemia
    American Society of Hematology ; 2005
    In:  Blood Vol. 106, No. 2 ( 2005-07-15), p. 717-720
    Details
    In: Blood, American Society of Hematology, Vol. 106, No. 2 ( 2005-07-15), p. 717-720
    Abstract: We studied whether common polymorphisms in genes involved in folate metabolism affect methotrexate (MTX) sensitivity. Ex vivo MTX sensitivity of lymphoblasts obtained from pediatric patients with acute lymphoblastic leukemia (ALL; n = 157) was determined by the in situ thymidylate synthase inhibition assay after either continuous (21 hours; TSI50, cont) or short-term (3 hours; TSI50, short) MTX exposure. DNA was isolated from lymphoblasts obtained from cytospin slides. Polymorphisms in methylenetetrahydrofolate reductase (MTHFR 677C & gt;T, MTHFR 1298A & gt;C), methionine synthase (MTR 2756A & gt;G), methionine synthase reductase (MTRR 66A & gt;G), methylenetetrahydrofolate dehydrogenase (MTHFD1 1958G & gt;A), serine hydroxymethyl transferase (SHMT1 1420C & gt;T), thymidylate synthase (TS 2R3R), and the reduced folate carrier (RFC 80G & gt;A) were detected by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) or real-time PCR. Patients with the MTHFR 1298AC variant or the MTRR 66 G-allele showed decreased in vitro MTX sensitivity measured under both test conditions. SHMT1 1420TT homozygotes only showed decreased MTX sensitivity in the TSI50, cont. In conclusion, polymorphisms in the folate-related genes MTHFR, MTRR, and SHMT1 are related to MTX resistance in pediatric patients with ALL. (Blood. 2005;106:717-720)
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2004-12-4941
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2005
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
    Location Call Number Limitation Availability
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  • 5
    Online Resource
    Online Resource
    Polymorphisms in folate-related genes and risk of pediatric acute lymphoblastic leukemia
    American Society of Hematology ; 2009
    In:  Blood Vol. 113, No. 10 ( 2009-03-05), p. 2284-2289
    Details
    In: Blood, American Society of Hematology, Vol. 113, No. 10 ( 2009-03-05), p. 2284-2289
    Abstract: Polymorphisms in folate pathway genes may influence the susceptibility to acute lymphoblastic leukemia (ALL). DNA was isolated from 245 pediatric ALL patients (cases) and from 500 blood bank donors (controls). Polymorphisms in methylene-tetrahydrofolate reductase (MTHFR 677C 〉 T, 1298A 〉 C), methionine synthase (MTR 2756A 〉 G), methionine synthase reductase (MTRR 66A 〉 G), methylenetetrahydrofolate dehydrogenase (MTHFD1 1958G 〉 A), nicotinamide N-methyltransferase (NNMT IVS −151C 〉 T), serine hydroxymethyl transferase (SHMT1 1420C 〉 T), thymidylate synthase (TS 2R3R), and the reduced folate carrier (RFC1 80G 〉 A) were detected. In ALL patients, an increased occurrence was observed of the RFC1 80AA variant (odds ratio [OR] = 2.1; 95% confidence interval [CI] = 1.3-3.2; P = .002) and the RFC1 80A allele (OR = 1.5; 95% CI, 1.1-2.1; P = .02). Likewise, the NNMT IVS −151TT genotype showed a 2.2-fold increased ALL risk (OR = 2.2; 95% CI, 1.1-4.6; P = .04). A 1.4-fold reduction in ALL risk was observed for (heterozygous or homozygous) carriers of the TS 2R allele and the MTHFR 677T allele (OR = 0.7; 95% CI, 0.5-1.0; P 〈 .05). Furthermore, interactions between NNMT and MTHFR 677C 〉 T and RFC1 were observed. NNMT IVS −151CC/MTHFR 677CT + TT patients exhibited a 2-fold reduction in ALL risk whereas RFC1 80AA/NNMT IVS −151CT + TT subjects had a 4.2-fold increase in ALL risk (P = .001). For the first time, we associate the RFC1 80G 〉 A and NNMT IVS −151C 〉 T variants to an increased ALL susceptibility.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2008-07-165928
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2009
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
    Location Call Number Limitation Availability
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