GM-CSF receptor targeted treatment of primary AML in SCID mice using Diphtheria toxin fused to huGM-CSF

Rozemuller, Henk; Terpstra, Wim; Rombouts, Elwin; Lawler, Mark; Byrne, Christopher; FitzGerald, DJ; Kreitman, R. J.; Wielenga, Jenne J.; Löwenberg, Bob; Touw, Ivo P.; Hagenbeek, Anton; Martens, Anton C.

doi:10.1038/sj.leu.2401205

Cited by 9 publications

(7 citation statements)

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“…In addition, dose effect titration experiments using the AML/SCID leukemia model indicated that efficient elimination of AML cells was achieved at dose levels as low as 6.25 g/kg/day. 8 However, a comparative evaluation of the systemic toxicity, the bone marrow-specific toxicity and the antileukemic efficacy of DT-mGM-CSF treatment in vivo would enable us to derive a therapeutic ratio. We compared the continuous administration scheme by means of osmotic pumps placed i.p.…”

Section: Discussionmentioning

confidence: 99%

“…The ADP ribosylation assay showed a comparable dose-dependent activity for DT-huGM-CSF, DTmGM-CSF and DT 388 proteins. 8 Murine GM-CSF was radiolabeled using the method of Bolton and Hunter 29 and the binding characteristics were determined as previous described. 5,30 In vitro cytotoxicity assays 3 H-thymidine ( 3 H-TdR) incorporation assays were performed as described.…”

Section: Growth Factor Toxinsmentioning

confidence: 99%

“…5,6 We have previously reported that human AML cells with long-term leukemia initiating potential in severe combined immunodeficient (SCID) mice could be eliminated by in vitro or in vivo targeting. 7,8 The absence of toxicity to the normal progenitor cell compartment, when exposed to the DT-huGM-CSF under similar conditions, suggested an exploitable therapeutic window. Since DT-huGM-CSF used in these studies reacts with human but not with murine cells, 9 the murine tissues were not at risk.…”

Section: Introductionmentioning

confidence: 99%

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In vivo targeting of leukemic cells using diphtheria toxin fused to murine GM-CSF

et al. 1998

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We have previously demonstrated that diphtheria toxin (DT) fused to human GM-CSF effectively eliminates human longterm leukemia initiating cells in SCID mice. However, because huGM-CSF does not react with the murine GM-CSF receptor possible side-effects to nonleukemic tissues could not be analyzed in the AML/SCID model. To overcome this problem, we used murine GM-CSF fused to DT and studied the therapeutic index in the rat leukemia model BNML/LT12. In DT-mGM-CSF dose escalation experiments, severe dose-dependent toxicity to organs such as liver, kidney and lung was observed. Therefore, the antileukemic effects were evaluated with the lower doses. Daily intraperitoneal bolus injections of 75 g/kg/day for 7 days induced a 3 log leukemic cell kill. The dose of 75 g/kg/day had no effect on the hemopoietic progenitor cell subsets. These in vivo studies show that the DT-GM-CSF fusion protein can be used for specifically targeting leukemic cells and thus has potential as a therapeutic agent in the treatment of AML.

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Section: Discussionmentioning

confidence: 99%

Section: Growth Factor Toxinsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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In vivo targeting of leukemic cells using diphtheria toxin fused to murine GM-CSF

et al. 1998

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“…3). Another concept targeting cell-surface molecules is the use of recombinant GM-CSF/diphtheria toxin or recombinant IL-3/diphtheria toxin fusion proteins [94,96]. In this regard it is noteworthy that leukemic stem cells differ from normal hematopoietic stem cells in aberrant expression of the IL-3 receptor alpha chain (CD123) (Fig.…”

Section: New Drugs Targeting Specific Cell-surface Markers On Aml (Stmentioning

confidence: 99%

Treatment concepts for elderly patients with acute myeloid leukemia

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Hauswirth

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et al. 2003

Wien Klin Wochenschr

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The majority of patients with acute myeloid leukemia (AML) are over 60 years of age at diagnosis. Unlike treatment options for younger adults, those for older patients are limited to non-myeloablative therapy, and many patients are not treatable because of poor performance status. In those who are treatable, long-term survival can be achieved using intensive induction and consolidation chemotherapy. Such curative treatment can be administered in about 70% of elderly patients with AML. In responding patients (up to 60%) the disease-free survival may be almost comparable to that of younger adults. However, treatment-related toxicity results in a higher mortality rate in the elderly patients. Moreover, aggressive chemotherapy cannot be used for 30% of the patients, due to their poor performance status. Currently, palliative cytoreductive treatment and supportive care are considered appropriate for these patients. Recently, however, targeting antileukemic antibodies and inhibitors of signal transduction have been introduced as promising new treatment options. The therapeutic efficiency and toxicity-profiles of these novel drugs are currently under investigation in clinical trials.

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“…These chimeric proteins have shown promise in their ability to kill certain tumors by binding the receptors and then initiating cell lysis. [113][114][115][116][117][118][119][120] Although this approach is designed to kill tumors expressing the receptors for a particular cytokine, it could be easily modified to treat autocrine tumors which express a given cytokine as well as the cognate receptor.…”

Section: Therapy Directed At Cytokine Gene Expressionmentioning

confidence: 99%

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1999

Leukemia

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Over the past decade, there has been an exponential increase in our knowledge of how cytokines regulate signal transduction, cell cycle progression, differentiation and apoptosis. Research has focused on different biochemical and genetic aspects of these processes. Initially, cytokines were identified by clonogenic assays and purified by biochemical techniques. This soon led to the molecular cloning of the genes encoding the cytokines and their cognate receptors. Determining the structure and regulation of these genes in normal and malignant hematopoietic cells has furthered our understanding of neoplastic transformation. Furthermore, this has allowed the design of modified cytokines which are able to stimulate multiple receptors and be more effective in stimulating the repopulation of hematopoietic cells after myelosuppressive chemotherapy. The mechanisms by which cytokines transduce their regulatory signals have been evaluated by identifying the involvement of specific protein kinase cascades and their downstream transcription factor targets. The effects of cytokines on cell cycle regulatory molecules, which either promote or arrest cell cycle progression, have been more recently examined. In addition, the mechanisms by which cytokines regulate apoptotic proteins, which mediate survival vs death, are being elucidated. Identification and characterization of these complex, interconnected pathways has expanded our knowledge of leukemogenesis substantially. This information has the potential to guide the development of therapeutic drugs designed to target key intermediates in these pathways and effectively treat patients with leukemias and lymphomas. This review focuses on the current understanding of how hematopoietic cytokines such as IL-3, as well as its cognate receptor, are expressed and the mechanisms by which they transmit their growth regulatory signals. The effects of aberrant regulation of these molecules on signal transduction, cell cycle regulatory and apoptotic pathways in transformed hematopoietic cells are discussed. Finally, anti-neoplastic drugs that target crucial constituents in these pathways are evaluated.

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GM-CSF receptor targeted treatment of primary AML in SCID mice using Diphtheria toxin fused to huGM-CSF

Cited by 9 publications

References 36 publications

In vivo targeting of leukemic cells using diphtheria toxin fused to murine GM-CSF

In vivo targeting of leukemic cells using diphtheria toxin fused to murine GM-CSF

Treatment concepts for elderly patients with acute myeloid leukemia

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