Evaluation of the Clinical Relevance of the Anionic Glutathione-S-Transferase (GSTπ) and Multidrug Resistance (mdr-1) Gene Coexpression in Leukemias and Lymphomas

Russo, Domenico; Marie, Jean‐Pierre; Zhou, Da-Cheng; Faussat, Anne Marie; Melli, Cristina; Damiani, D. Doḿınguez; Michelutti, Angela; Michieli, Mariagrazia; Fanin, Renato; Baccarani, Michele; Zittoun, R

doi:10.3109/10428199409049749

Cited by 17 publications

(7 citation statements)

References 27 publications

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“…29 Fusion toxins bypass these drug resistance pathways due to their distinct molecular shape and mechanism of action. We have previously demonstrated the cytotoxic potency of the DTGM fusion toxin both for multi-drug resistant cell lines and fresh patient leukemic progenitors.…”

Section: Discussionmentioning

confidence: 99%

Diphtheria toxin fused to human interleukin-3 is toxic to blasts from patients with myeloid leukemias

et al. 2000

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Leukemic blasts from patients with acute phase chronic myeloid leukemic and refractory acute myeloid leukemia are highly resistant to a number of cytotoxic drugs. To overcome multi-drug resistance, we engineered a diphtheria fusion protein by fusing human interleukin-3 (IL3) to a truncated form of diphtheria toxin (DT) with a (G 4 S) 2 linker (L), expressed and purified the recombinant protein, and tested the cytotoxicity of the DTLIL3 molecule on human leukemias and normal progenitors. The DTLIL3 construct was more cytotoxic to interleukin-3 receptor (IL3R) bearing human myeloid leukemia cell lines than receptor-negative cell lines based on assays of cytotoxicity using thymidine incorporation, growth in semi-solid medium and induction of apoptosis. Exposure of mononuclear cells to 680 pM DTLIL3 for 48 h in culture reduced the number of cells capable of forming colonies in semi-solid medium (colony-forming units leukemia) у10-fold in 4/11 (36%) patients with myeloid acute phase chronic myeloid leukemia (CML) and 3/9 (33%) patients with acute myeloid leukemia (AML). Normal myeloid progenitors (colony-forming unit granulocytemacrophage) from five different donors treated and assayed under identical conditions showed intermediate sensitivity with three-to five-fold reductions in colonies. The sensitivity to DTLIL3 of leukemic progenitors from a number of acute phase CML patients suggests that this agent could have therapeutic potential for some patients with this disease. Leukemia (2000) 14, 576-585.

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Section: Discussionmentioning

confidence: 99%

Diphtheria toxin fused to human interleukin-3 is toxic to blasts from patients with myeloid leukemias

et al. 2000

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“…[6][7][8] Moreover, their concentration in leukemia blasts correlates with response to therapy and remission duration. [9][10][11] It has been proposed that cell-specific inhibitors of protein synthesis, such as targeted toxins, might exert their effects by down-regulating these drug-resistance proteins. [12][13][14][15] Targeted toxins or fusion toxins are recombinant polypeptides that consist of the catalytic and translocation domains of a toxin fused with a tumor-selective ligand such as an antibody or a growth factor.…”

Section: Introductionmentioning

confidence: 99%

Enhanced ceramide generation and induction of apoptosis in human leukemia cells exposed to DT388–granulocyte-macrophage colony-stimulating factor (GM-CSF), a truncated diphtheria toxin fused to human GM-CSF

Senchenkov

Han

Wang

et al. 2001

Blood

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, a targeted fusion toxin constructed by conjugation of human granulocyte-macrophage colony-stimulating factor (GM-CSF) with the catalytic and translocation domains of diphtheria toxin, is presently in phase I trials for patients with resistant acute myeloid leukemia. HL-60/VCR, a multidrug-resistant human myeloid leukemia cell line, and wild-type HL-60 cells were used to study the impact of DT 388 -GM-CSF on metabolism of ceramide, a modulator of apoptosis. After 48 hours with DT 388 -GM-CSF (10 nM), ceramide levels in HL-60/VCR cells rose 6-fold and viability fell to 10%, whereas GM-CSF alone was without influence.Similar results were obtained in HL-60 cells. Examination of the time course revealed that protein synthesis decreased by about 50% and cellular ceramide levels increased by about 80% between 4 and 6 hours after addition of DT 388 -GM-CSF. By 6 hours this was accompanied by activation of caspase-9, followed by activation of caspase-3, cleavage of caspase substrates, and chromatin fragmentation. Hygromycin B and emetine failed to elevate ceramide levels or induce apoptosis at concentrations that inhibited protein synthesis by 50%. Exposure to C 6 -ceramide inhibited protein synthesis (EC 50 ϳ5 M) and decreased viability (EC 50 ϳ6 M). Sphingomyelinase treatment depleted sphingomyelin by about 10%, while increasing ceramide levels and inhibiting protein synthesis. Diphtheria toxin increased ceramide and decreased sphingomyelin in U-937 cells, a cell line extremely sensitive to diphtheria toxin; exposure to DT 388 -GM-CSF showed sensitivity at less than 1.0 pM. Diphtheria toxin and conjugate trigger ceramide formation that contributes to apoptosis in human leukemia cells through caspase activation and inhibition of protein synthesis. (Blood. 2001; 98:1927-1934

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“…It is well known that GST P1 is overexpressed in some multidrug resistant tumor cells [42,43]. This might implicate resistance of tumor cells to chemotherapy, but also a cellular stress response.…”

Section: Gst P1mentioning

confidence: 99%

Suction blister fluid as potential body fluid for biomarker proteins

et al. 2007

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Early diagnosis is important for effective disease management. Measurement of biomarkers present at the local level of the skin could be advantageous in facilitating the diagnostic process. The analysis of the proteome of suction blister fluid, representative for the interstitial fluid of the skin, is therefore a desirable first step in the search for potential biomarkers involved in biological pathways of particular diseases. Here, we describe a global analysis of the suction blister fluid proteome as potential body fluid for biomarker proteins. The suction blister fluid proteome was compared with a serum proteome analyzed using identical protocols. By using stringent criteria allowing less than 1% false positive identifications, we were able to detect, using identical experimental conditions and amount of starting material, 401 proteins in suction blister fluid and 240 proteins in serum. As a major result of our analysis we construct a prejudiced list of 34 proteins, relatively highly and uniquely detected in suction blister fluid as compared to serum, with established and putative characteristics as biomarkers. We conclude that suction blister fluid might potentially serve as a good alternative biomarker body fluid for diseases that involve the skin.

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Evaluation of the Clinical Relevance of the Anionic Glutathione-S-Transferase (GSTπ) and Multidrug Resistance (mdr-1) Gene Coexpression in Leukemias and Lymphomas

Cited by 17 publications

References 27 publications

Diphtheria toxin fused to human interleukin-3 is toxic to blasts from patients with myeloid leukemias

Diphtheria toxin fused to human interleukin-3 is toxic to blasts from patients with myeloid leukemias

Enhanced ceramide generation and induction of apoptosis in human leukemia cells exposed to DT388–granulocyte-macrophage colony-stimulating factor (GM-CSF), a truncated diphtheria toxin fused to human GM-CSF

Suction blister fluid as potential body fluid for biomarker proteins

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