Potentiation of Treosulfan Toxicity by the Glutathione-Depleting Agent Buthionine Sulfoximine in Human Malignant Glioma Cells

Reber, Ulrike; Wüllner, U.; Trepel, Martin; Baumgart, J.; Seyfried, Jan; Klockgether, Thomas; Dichgans, J.; Weller, Michael

doi:10.1016/s0006-2952(97)00480-2

Cited by 26 publications

(26 citation statements)

References 32 publications

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“…[8][9][10][11] It is approved for the treatment of ovarian carcinoma in a number of European countries. 12,13 Since the early 1980s, clinical studies with the i.v.…”

Section: Treosulfan: Clinical Pharmacologymentioning

confidence: 99%

Treosulfan-based conditioning before hematopoietic SCT: more than a BU look-alike

Danylesko

Shimoni

Nagler

2011

Bone Marrow Transplant

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Allogeneic hematopoietic SCT is a curative treatment for a variety of hematological malignancies and genetic diseases. There is a continuous search for novel conditioning regimens that will reduce SCT-related toxicity while retaining maximal antimalignancy effect. Treosulfan (L-threitol-1,4-bis-methanesulfonate; dihydroxybusulfan) was initially used in the treatment of certain solid tumors. Preclinical studies showed that it has a myeloablative effect on committed and non-committed stem cells. It has potent immunosuppressive characteristics, more prominent than its related chemotherapy agent BU, which makes it an attractive candidate for the use in conditioning regimens before allo-SCT. It is also associated with a favorable toxicity profile with little extramedullary toxicity. The combination of fludarabine and treosulfan was explored in several studies in patients not eligible for standard myeloablative conditioning, and data are rapidly emerging. This regimen is associated with consistent engraftment. A limited non-relapse mortality (NRM) rate in the range of 9-28% was observed. This rate is promising considering the patients selected and results from low rates of organ toxicity as well as acute and chronic GVHD. The regimen was also associated with low relapse rates of 5-30% depending on disease status at SCT. Together with low NRM rate, this resulted in favorable survival in the range of 40-80%. Promising results were seen in myelodysplastic syndrome (survival 36-70%) and leukemia in remission (60-70%). Randomized prospective studies will be needed to better define the role of treosulfan-based regimens in SCT.

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“…[8][9][10][11] It is approved for the treatment of ovarian carcinoma in a number of European countries. 12,13 Since the early 1980s, clinical studies with the i.v.…”

Section: Treosulfan: Clinical Pharmacologymentioning

confidence: 99%

Treosulfan-based conditioning before hematopoietic SCT: more than a BU look-alike

Danylesko

Shimoni

Nagler

2011

Bone Marrow Transplant

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“…As a control, the cells were treated with ethacrinic acid. 41 To assess the generation of free radicals, the cells were washed with PBS and incubated with H 2 -DCFDA (5 mM) for 15 min. The cells were washed with PBS again, trypsinized and harvested by centrifugation.…”

Section: Detection Of Intracellular Free Radicalsmentioning

confidence: 99%

Alkylphosphocholine-induced glioma cell death is BCL-XL-sensitive, caspase-independent and characterized by massive cytoplasmic vacuole formation

et al. 2004

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Alkylphosphocholines (APC) are candidate anticancer agents. We here report that APC induce the formation of large vacuoles and typical features of apoptosis in human glioma cell lines, but not in immortalized astrocytes. APC promote caspase activation, poly(ADP-ribose)-polymerase (PARP) processing and cytochrome c release from mitochondria. Adenoviral X-linked inhibitor of apoptosis (XIAP) gene transfer, or exposure to the caspase inhibitor, benzyloxycarbonyl-Val-Ala-DL-Asp-fluoro-methylketone zVAD-fmk, blocks caspase-7 and PARP processing, but not cell death, whereas BCL-X L blocks not only caspase-7 and PARP processing but also cell death. APC induce changes in DW m in sensitive glioma cells, but not in resistant astrocytes. The changes in DW m are unaffected by crm-A (cowpox serpin -cytokine response modifier protein A), XIAP or zVAD-fmk, but blocked by BCL-X L , and are thus a strong predictor of cell death in response to APC. Free radicals are induced, but not responsible for cell death. APC thus induce a characteristic morphological, BCL-X L -sensitive, apparently caspase-independent cell death involving mitochondrial alterations selectively in neoplastic astrocytic cells.

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“…The generation of reactive oxygen species was monitored using the fluorescent probe, DCF-H 2 (Reber et al, 1998). Immunoblot analysis was performed as described (Weller et al, 1994).…”

Section: Biochemical Studiesmentioning

confidence: 99%

“…AKBA did not induce the formation of reactive oxygen species (data not shown), and the antioxidants NAC, SOD and PBN did not block AKBA toxicity ( Figure 1F). Ethacrynic acid was used as a positive control for reactive oxygen species formation (Reber et al, 1998), and LN-229 cells were exposed to AKBA (20 µM) for 24 h or 48 h and processed for electron microscopy as described (Weller et al, 1994). (A) (× 2500) shows the appearance of untreated cells, (B) and (C) show different stages of apoptosis 24 h and 48 h after treatment with AKBA.…”

Section: Akba-induced Glioma Cell Apoptosis Requires New Protein Syntmentioning

confidence: 99%

Boswellic acids and malignant glioma: induction of apoptosis but no modulation of drug sensitivity

et al. 1999

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Steroids are essential for the control of oedema in human malignant glioma patients but may interfere with the efficacy of chemotherapy. Boswellic acids are phytotherapeutic anti-inflammatory agents that may be alternative drugs to corticosteroids in the treatment of cerebral oedema. Here, we report that boswellic acids are cytotoxic to malignant glioma cells at low micromolar concentrations. In-situ DNA end labelling and electron microscopy reveal that boswellic acids induce apoptosis. Boswellic acid-induced apoptosis requires protein, but not RNA synthesis, and is neither associated with free radical formation nor blocked by free radical scavengers. The levels of BAX and BCL-2 proteins remain unaltered during boswellic acid-induced apoptosis. p21 expression is induced by boswellic acids via a p53-independent pathway. Ectopic expression of wild-type p53 also induces p21, and facilitates boswellic acid-induced apoptosis. However, targeted disruption of the p21 genes in colon carcinoma cells enhances rather than decreases boswellic acid toxicity. Ectopic expression of neither BCL-2 nor the caspase inhibitor, CRM-A, is protective. In contrast to steroids, subtoxic concentrations of boswellic acids do not interfere with cancer drug toxicity of glioma cells in acute cytotoxicity or clonogenic cell death assays. Also, in contrast to steroids, boswellic acids synergize with the cytotoxic cytokine, CD95 ligand, in inducing glioma cell apoptosis. This effect is probably mediated by inhibition of RNA synthesis and is not associated with changes of CD95 expression at the cell surface. Further studies in laboratory animals and in human patients are required to determine whether boswellic acids may be a useful adjunct to the medical management of human malignant glioma. © 1999 Cancer Research Campaign

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Potentiation of Treosulfan Toxicity by the Glutathione-Depleting Agent Buthionine Sulfoximine in Human Malignant Glioma Cells

Cited by 26 publications

References 32 publications

Treosulfan-based conditioning before hematopoietic SCT: more than a BU look-alike

Treosulfan-based conditioning before hematopoietic SCT: more than a BU look-alike

Alkylphosphocholine-induced glioma cell death is BCL-XL-sensitive, caspase-independent and characterized by massive cytoplasmic vacuole formation

Boswellic acids and malignant glioma: induction of apoptosis but no modulation of drug sensitivity

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