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David O'Connor,
Keith Sibson,
Mark Caswell,
Philip Connor,
Michelle Cummins,
Chris Mitchell,
Jayashree Motwani,
Mary Taj,
Ajay Vora,
Robert Wynn, Pamela R Kearns
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ABSTRACT: Clofarabine is a second-generation purine nucleoside analogue, which has shown promising activity in relapsed and refractory paediatric acute lymphoblastic leukaemia (ALL). This report summarizes the early United Kingdom experience of clofarabine for the treatment of paediatric ALL in 23 patients, outside of the context of a clinical trial. Our results demonstrated that clofarabine-based chemotherapy regimes were effective and well-tolerated in this heavily pre-treated group, with an overall response rate of 67% when used in combination regimes. Responses were seen in both B and T cell disease and in patients with adverse cytogenetics.
British Journal of Haematology 06/2011; 154(4):482-5. · 4.94 Impact Factor
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David O’Connor,
Keith Sibson,
Mark Caswell,
Philip Connor,
Michelle Cummins,
Chris Mitchell,
Jayashree Motwani,
Mary Taj,
Ajay Vora,
Robert Wynn, Pamela R. Kearns
[show abstract]
[hide abstract]
ABSTRACT: Clofarabine is a second-generation purine nucleoside analogue, which has shown promising activity in relapsed and refractory paediatric acute lymphoblastic leukaemia (ALL). This report summarizes the early United Kingdom experience of clofarabine for the treatment of paediatric ALL in 23 patients, outside of the context of a clinical trial. Our results demonstrated that clofarabine-based chemotherapy regimes were effective and well-tolerated in this heavily pre-treated group, with an overall response rate of 67% when used in combination regimes. Responses were seen in both B and T cell disease and in patients with adverse cytogenetics.
British Journal of Haematology 06/2011; 154(4):482 - 485. · 4.94 Impact Factor
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[hide abstract]
ABSTRACT: Optimization of therapy for childhood acute lymphoblastic leukemia (ALL) requires a greater understanding of the cells that proliferate to maintain this malignancy because a significant number of cases relapse, resulting from failure to eradicate the disease. Putative ALL stem cells may be resistant to therapy and subsequent relapses may arise from these cells. We investigated expression of CD133, CD19, and CD38 in pediatric B-ALL. Cytogenetic and molecular analyses demonstrated that karyotypically aberrant cells were present in both CD133(+)/CD19(+) and CD133(+)/CD19(-) subfractions, as were most of the antigen receptor gene rearrangements. However, ALL cells capable of long-term proliferation in vitro and in vivo were derived from the CD133(+)/CD19(-) subfraction. Moreover, these CD133(+)/CD19(-) cells could self-renew to engraft serial nonobese diabetic-severe combined immunodeficient recipients and differentiate in vivo to produce leukemias with similar immunophenotypes and karyotypes to the diagnostic samples. Furthermore, these CD133(+)/CD19(-) ALL cells were more resistant to treatment with dexamethasone and vincristine, key components in childhood ALL therapy, than the bulk leukemia population. Similar results were obtained using cells sorted for CD133 and CD38, with only the CD133(+)/CD38(-) subfraction demonstrating xenograft repopulating capacity. These data suggest that leukemia-initiating cells in childhood B-ALL have a primitive CD133(+)/CD19(-) and CD38(-) phenotype.
Blood 02/2009; 113(14):3287-96. · 9.90 Impact Factor
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ABSTRACT: Glutathione is an intracellular, nonprotein thiol that appears to play an important role in protection of the cell against
cytotoxic drugs (1) and has been implicated in the control of cell cycling (2,3) and apoptosis (4,5). It can exist in an oxidized (disulfide, [GSSG]) and a reduced (sulphydryl, [GSH]) form. In general, GSSG comprises less
than 1% of the total intracellular glutathione. In circumstances of oxidative stress, GSH dimerizes to form glutathione disulfide
(GSSG), making protons available to neutralize reactive oxygen species (Reaction 1). In vivo, reduction of GSSG is catalysed by glutathione reductase, efficiently regenerating high intracellular GSH levels
(Reaction 2)
01/2008: pages 83-90;
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ABSTRACT: A significant proportion of children with T-cell acute lymphoblastic leukemia (T-ALL) continue to fail therapy. Consequently, characterization of the cells that proliferate to maintain the disease should provide valuable information on the most relevant therapeutic targets. We have used in vitro suspension culture (SC) and nonobese diabetic-severe combined immune deficient (NOD/SCID) mouse assays to phenotypically characterize and purify T-ALL progenitor cells. Cells from 13 pediatric cases were maintained in vitro for at least 4 weeks and expanded in 8 cases. To characterize the progenitors, cells were sorted for expression of CD34 and CD4 or CD7 and the subfractions were evaluated in vitro and in vivo. The majority of cells capable of long-term proliferation in vitro were derived from the CD34+/CD4- and CD34+/CD7- subfractions. Moreover, the CD34+/CD4- or CD7- cells were the only subfractions capable of NOD/SCID engraftment. These T-ALL cells successfully repopulated secondary and tertiary recipients with equivalent levels of engraftment, demonstrating self-renewal ability. The immunophenotype and genotype of the original leukemia cells were preserved with serial passage in the NOD/SCID mice. These data demonstrate the long-term repopulating ability of the CD34+/CD4- and CD34+/CD7- subfractions in T-ALL and suggest that a cell with a more primitive phenotype was the target for leukemic transformation in these cases.
Blood 02/2007; 109(2):674-82. · 9.90 Impact Factor
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ABSTRACT: Glutathione S-transferases (GSTs) are implicated in cytotoxic drug resistance in leukaemia. In a previous study, expression of mu class GST (GSTM) was associated with poor prognosis in childhood acute lymphoblastic leukaemia (ALL), however, that study did not differentiate between individual GSTM isoforms. This study, therefore, investigated individual GSTM isoform expression in ALL blasts at the mRNA level. Leukaemic blasts from 21 children with ALL were studied. Interindividual variation in the pattern of GSTM mRNA isoform expression was demonstrated. GSTM2 transcript was expressed in all patients in contradistinction to GSTM5, which was not detected in any sample. GSTM3 and GSTM4 expression varied between individuals, with GSTM3 expressed in 62% and GSTM4 in 24% of patients. Lymphoblast expression of GSTM3 was positively related to good prognosis whereas expression of GSTM4 was not related to clinical outcome in this small cohort. No relationship was demonstrated with established indicators of prognosis, including sex, age, immunophenotype and presenting white cell count. The results suggest that expression of GSTM3 may play a role in determining prognosis in childhood ALL and could provide more information for accurate stratification of treatment. Further studies are required to determine whether there is a causal relationship between GSTM3 expression and clinical outcome.
British Journal of Haematology 02/2003; 120(1):80-8. · 4.94 Impact Factor
