The Clinical and Cellular Pharmacology Of Vincristine, Corticosteroids, <scp>l</scp>‐Asparaginase, Anthracyclines and Cyclophosphamide In Relation To Childhood Acute Lymphoblastic Leukaemia

Estlin, Edward J.; Ronghe, Milind; Burke, G A Amos; Yule, S. M.

doi:10.1046/j.1365-2141.2000.t01-1-02153.x

Cited by 35 publications

(25 citation statements)

References 87 publications

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“…All the enzymes were less effective in inducing the death of CCRF-CEM cells. This is in line with earlier studies,that have shown that CCRF-CEM cells are poorly sensitive 10 and SUP-B15 cells highly sensitive 11 to L-asparaginase therapy. Our results show that this applies to glycosylasparaginase therapy in vitro as well.…”

Section: Depletion Of L-asparagine Supply and Apoptosis Of Leukemia Csupporting

confidence: 81%

Depletion of L-asparagine supply and apoptosis of leukemia cells induced by human glycosylasparaginase

2009

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ReferencesA lysosomal enzyme glycosylasparaginase (GA; aspartylglucosaminidase; EC 3.5.1.26) hydrolyzes the N-glycosidic carbohydrate-to-protein linkage region, aspartylglucosamine, to L-aspartic acid and l-amino-N-acetylglucosamine through a reaction mechanism similar to L-asparaginase. 3 Glycosylasparaginase is transported in active form into various non-neuronal cell types, including Epstein-Barr virus-transformed (EBV) glycosylasparaginase-deficient lymphoblasts, and it effectively corrects the metabolic defects in glycosylasparaginase-deficient cell lines 4 and mice. 5 The finding that human glycosylasparaginase also hydrolyzes L-asparagine to L-aspartic acid and ammonia-like bacterial L-asparaginases 6 without any L-glutaminase activity 3 led us to investigate its potential cytotoxic activity toward leukemia cells that are dependent on their external supply of L-asparagine. We investigated the ability of human recombinant GA to deplete the intra-and extracellular Asn reservoirs in vitro using EBVtransformed glycosylasparaginase-deficient lymphoblasts from an Letters to the Editor 1167 Leukemia aspartylglycosaminuria patient. 4 Lymphoblasts were continuously grown in an RPMI-1640 (HyClone, Logan, Utah, USA) medium supplemented with 15% of fetal calf serum (BioClear, Wiltshire, UK), 2 mM L-glutamine (HyClone) and 1.5-2.0 mM L-asparagine (Fluka Chemie AG, Buchs, Switzerland) and various concentrations of either GA or Erwinia L-asparaginase (Erwinase, ErAII) for 24 h. The kinetic parameters of the enzymes for the hydrolysis of L-asparagine were determined by a spectrophotometric method as described. 7,8 At pH 7.5, the K m of glycosylasparaginase, Erwinia L-asparaginase and Escherichia coli L-asparaginase was 538, 90 and 130 mM and V max 1.49, 16 and 23 mM/min, respectively. One unit of enzyme causes hydrolysis of 1 mmol of L-asparagine per minute under standard conditions.The depletion of the extracellular Asn concentration in the culture medium from 2.3 to 0.2 mmol/l in the presence of 10 or 40 U/l of glycosylasparaginase or 10 U/l of ErAII took 18, 4 and 4 h, respectively. In the presence of 1500 U/l of ErAII, similar Asn concentration decrease occurred within 5 min. The Asn level in the cell culture medium remained unchanged at approximately 2 mmol/l in the absence of either glycosylasparaginase or ErAII (Figure 1a).To determine whether the enzymes can deplete the intracellular Asn reservoirs of EBV-transformed lymphoblasts, we analyzed both the Asn concentration and the enzyme activity inside the cells during the incubation. In the presence of 10 or 40 U/l of glycosylasparaginase or 10 U/l of ErAII in the cell culture medium, the Asn concentration inside the GA-deficient cells first increased within the first 2 h of incubation from the initial approximately 80 nmol/mg protein and then decreased below 6 nmol/mg protein during the next 16-18, 6 or 10-12 h, respectively (Figure 1b). In the presence of 1500 U/l of ErAII in the culture medium, the intracellular Asn concentration decreased from 89 to 14 nmol/m...

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Section: Depletion Of L-asparagine Supply and Apoptosis Of Leukemia Csupporting

confidence: 81%

Depletion of L-asparagine supply and apoptosis of leukemia cells induced by human glycosylasparaginase

2009

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“…12,13 Curcumin also disrupted the cytoskeleton of HCW-2 cells as shown by microtubule staining and confocal microscopy analysis (Fig. 8a).…”

Section: Curcumin Disrupts Mitotic Spindle In Hcw-2 Cellsmentioning

confidence: 99%

“…12,13 Both factors were effective in inducing typical apoptosis with caspase 3 activity, oligonucleosomal DNA degradation and apoptotic bodies formation in HL-60 cells ( Fig. 1), from which HCW-2 cells are derived.…”

Section: Curcumin and Vincristine Induce Cell Death In Hcw-2 Cellsmentioning

confidence: 99%

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Resistance to apoptosis of HCW‐2 cells can be overcome by curcumin‐ or vincristine‐induced mitotic catastrophe

Magalska

Śliwińska

Szczepanowska

et al. 2006

Intl Journal of Cancer

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The term mitotic catastrophe has recently become widely used to describe a form of death affecting many cancer cells, which, because of severe DNA or mitotic spindle damage, are not able to bypass mitosis. We show here that cells of the HL-60-derived HCW-2 line highly resistant to apoptosis, upon treatment with curcumin or vincristine, undergo mitotic catastrophe that is finalized by caspase 3 activation and oligonucleosomal DNA degradation. Curcumin is a natural dye, derived from Curcuma longa that has been shown to induce cell death in many cancer cells. Both treatments decrease cell proliferation and cell survival, arrest cells in G 2 /M phase of cell cycle and induce morphological changes characterized by cell enlargement and micronucleation. ''Catastrophic'' cells comprise a separate subpopulation with less than 4 C DNA, as evidenced by flow and scanning cytometry. This subpopulation is MPM-2 positive. Thymidine block increased the number of cell arrested in the G 2 /M phase of cell cycle and curcumin effectiveness as an inducer of mitotic catastrophe. Curcumin, but not vincristine, acts on HCW-2 cells by inhibiting the expression of survivin, a modulator of cell division and apoptosis in cancer. Altogether our results show that apoptosis resistance can be overcome by inducing mitotic catastrophe in HCW-2 cells. ' 2006 Wiley-Liss, Inc.

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“…15 Although it is conventional clinical medicament for cancer therapy, the neurotoxicity limited its application. 16 In chemotherapy, combination of two or more drugs with different mechanisms is generally available to bring about their synergistic effect and reduce their toxicity.…”

Section: Introductionmentioning

confidence: 99%

Suppression of N-Ras by shRNA-expressing plasmid increases sensitivity of HepG2 cells to vincristine-induced growth inhibition

et al. 2009

Cancer Gene Ther

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Oncogenic ras genes relate to the development of human cancers. In this study, we used a plasmid-mediated short-hairpin RNA (shRNA) targeting N-ras gene to combine with clinical drug vincristine (VCR) for the treatment of human hepatoma cells. Our results showed that anti-N-Ras shRNA expression vector (pCSH1-shNR) knocked down the target mRNA and protein. Higher efficacy on growth inhibition was observed when pCSH1-shNR was combined with VCR. This synergistic effect was associated with abrogation of VCR-induced overexpressions of P-glycoprotein and multidrug resistance-associated protein 1 by pCSH1-shNR through downregulations of N-Ras and total Ras. Western blot analysis showed that pCSH1-shNR-induced downregulations of N-Ras and total Ras were potentiated by VCR. Following Ras downregulation, phosphorylations of ERK1/2 and Akt were dramatically inhibited by combinatory treatment. The data showed that pCSH1-shNR-induced inhibition of nuclear factor-kB was enhanced by VCR. In addition, the combination of pCSH1-shNR and VCR synergistically inhibited the growth of human hepatoma HepG2 in vivo. Our findings suggested that combination of gene-specific therapeutics and appropriate chemotherapeutic agents might be a promising approach for the treatment of human hepatocellular carcinoma.

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The Clinical and Cellular Pharmacology Of Vincristine, Corticosteroids, l‐Asparaginase, Anthracyclines and Cyclophosphamide In Relation To Childhood Acute Lymphoblastic Leukaemia

Cited by 35 publications

References 87 publications

Depletion of L-asparagine supply and apoptosis of leukemia cells induced by human glycosylasparaginase

Depletion of L-asparagine supply and apoptosis of leukemia cells induced by human glycosylasparaginase

Resistance to apoptosis of HCW‐2 cells can be overcome by curcumin‐ or vincristine‐induced mitotic catastrophe

Suppression of N-Ras by shRNA-expressing plasmid increases sensitivity of HepG2 cells to vincristine-induced growth inhibition

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