Platelet‐derived growth factor (PDGF) in human acute myelogenous leukemia: PDGF receptor expression, endogenous PDGF release and responsiveness to exogenous PDGF isoforms by <i>in vitro</i> cultured acute myelogenous leukemia blasts

Foss, Brynjar; Ulvestad, Elling; Bruserud, Øystein

doi:10.1034/j.1600-0609.2001.066006365.x

Cited by 19 publications

(18 citation statements)

References 37 publications

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“…This close contact between AML blasts and platelets may thereby form a basis for functional interactions between these cells. 28,41,43,44,57 Various methods for detection of peripheral blood platelet activation and platelet-leukocyte adhesion have been described previously, 31,39,40,45,46 and most of these methods include platelet fixation to avoid ex vivo activation. Fixation procedures themselves may induce platelet activation, however, although this does not seem to occur when using low paraformaldehyde concentrations.…”

Section: Discussionmentioning

confidence: 99%

“…Autologous peripheral blood stem cell grafts contain increased levels of platelets, 43,54,55 and platelet adhesion with release of platelet-derived mediators may then affect the survival of contaminating AML cells and thereby influence the relapse risk in autografted patients. 43,44,56,57 It is not known whether local growth or hematogenous spread of malignant cells is affected by similar mechanisms in patients with other malignant disorders and normal levels of circulating platelets.…”

Section: Discussionmentioning

confidence: 99%

“…Our recent studies have demonstrated that the platelet-secreted mediators platelet-derived growth factor, platelet factor 4 and vascular endothelial growth factor can alter AML blast proliferation or constitutive cytokine secretion. 44,57 Additional clinical studies are definitely required, however, to clarify whether these mechanisms have any clinical impact in AML patients receiving conventional chemotherapy or autologous stem cell transplantation.…”

Section: Discussionmentioning

confidence: 99%

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Effects of cytarabine and various anthracyclins on platelet activation: Characterization of in vitro effects and their possible clinical relevance in acute myelogenous leukemia

Foss

Ulvestad

Hervig

et al. 2001

Intl Journal of Cancer

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Previous in vitro studies have demonstrated that normal platelets and platelet-released mediators can alter in vitro characteristics of human acute myelogenous leukemia (AML) blasts. To further investigate whether platelets can be expected to adhere to and thereby affect AML blasts through their release of soluble mediators into a common microenvironment, we investigated (i) the effects on platelet activation by cytotoxic drugs commonly used in AML therapy; (ii) the occurrence of circulating activated platelets in acute leukemia patients; and (iii) the in vivo and in vitro adherence of platelets to AML blasts. The anthracyclins daunorubicin and idarubicin increased the expression of activation-associated membrane molecules (GPIIb/IIIa, CD62P, CD63) by normal platelets, daunorubicin then having the strongest effect. In contrast, cytarabine, epirubicin, doxorubicin and mitoxantrone had no significant effects. Although AML patients did not show increased levels of activated platelets in the circulation, adhesion of platelets to AML blasts was demonstrated both in vivo and in vitro. These results suggest that platelets and AML blasts may locate to common in vivo microenvironments, and platelet-derived soluble mediators may thereby affect the functional characteristics of the leukemia cells. Key words: antracyclins; cytarabine; platelets; AML blastsAcute myelogenous leukemia (AML) is a malignant disorder characterized by a differentiation block and an accumulation of immature myeloid cells. 1 The overall AML-free survival after intensive chemotherapy is less than 50%. 1 Both cytarabine and anthracyclins (i.e., daunorubicin or idarubicin) are commonly used in AML therapy. 1 These drugs can be used both in induction therapy to achieve disease control, and in consolidation therapy to eradicate residual disease. Recent studies have also demonstrated that the combination of mitoxantrone plus cytarabine can be effective in AML. 1 Younger AML patients treated with conventional chemotherapy have a treatment-related mortality of approximately 5%, but the mortality risk can be considerably higher for elderly patients. 1 Severe hemorrhages due to thrombocytopenia contribute to the mortality. Although various platelet dysfunctions have also been described in AML patients, 2-5 it is not known whether these abnormalities are caused by the disease or the chemotherapy, and whether they contribute to the bleeding risk in these patients.Platelet activation can be induced by specific inducers including adenosine diphosphate (ADP), thrombin and collagen, 6 but it is also induced/affected by cytokines, 7-9 cytotoxic drugs 10 -17 and artificial surfaces. 18 -20 Activated platelets then release several soluble mediators 6,21 that may modulate functions. [22][23][24][25][26][27][28] Several observations, however, also suggest that platelets may affect AML blasts by ligation of membrane molecules leukocyte or through adhesion: 29 -35 (i) normal and malignant myeloid cells express common membrane molecules, and platelets can adhere to norm...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Effects of cytarabine and various anthracyclins on platelet activation: Characterization of in vitro effects and their possible clinical relevance in acute myelogenous leukemia

Foss

Ulvestad

Hervig

et al. 2001

Intl Journal of Cancer

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“…23,24 Sorafenib also has potent activity against kinases reported to potentially be contributing to AML physiopathology such as PDGFR, KIT and VEGFR. [25][26][27] Although the selective antiproliferative and proapoptotic effects of sorafenib in FLT3-dependent cells versus FLT3-independent cells as well as the potent inhibition of Stat5 phosphorylation, a major downstream target of FLT3-ITD, 28 argue for FLT3 as an important driver of the activities reported, it is likely that the inhibition of other kinases by sorafenib may also contribute to the observed antiproliferative effects. It is noteworthy that MV4-11 cell proliferation was inhibited with an IC 50 of 0.88 nM, 3-5-fold less than the IC 50 for inhibition of FLT3.…”

Section: Discussionmentioning

confidence: 99%

Antitumor activity of sorafenib in FLT3-driven leukemic cells

et al. 2007

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Activating internal tandem duplication (ITD) insertions in the juxtamembrane domain of the FLT3 tyrosine kinase are found in about one fourth of patients with acute myeloid leukemia and have been shown to be an independent negative prognostic factor for survival. We show that sorafenib (BAY 43-9006, Nexavar) potently inhibits FLT3 enzymatic and signaling activities. In HEK293 cells stably transfected with FLT3-WT or FLT3-ITD, sorafenib blocked basal and ligand dependent FLT3-mediated tyrosine autophosphorylation as well as extracellular signal-regulated kinase1/2 and Stat5 phosphorylation. In leukemia cell lines MV4-11 and EOL-1, sorafenib treatment resulted in decreased cell proliferation and inhibition of FLT3 signaling. The growth of the FLT3-independent RS4-11 cell line was only weakly inhibited by sorafenib. Cell cycle arrest and induction of apoptosis were observed upon treatment with sorafenib in MV4-11 and EOL-1 cells. The antitumor efficacy of sorafenib was evaluated against the MV4-11 leukemia grown subcutaneously in NCr nu/nu mice. Doses of 3 and 10 mg/kg administered orally for 14 days resulted in six and nine out of 10 animals with complete responses, respectively. The demonstration that sorafenib exhibits potent target inhibition and efficacy in FLT3-driven models suggests that this compound may have a therapeutic benefit for patients with FLT3-driven leukemias.

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“…PDGFRα and PDGFRβ are expressed in 45-55 % and 90 % of AML cases, respectively. 49 PDGFRβ is also frequently activated in chronic myelomonocytic leukemia (CMML), a myelodysplastic/myeloproliferative disorder that is characterized by an increased amount of monocytes in the blood and bone marrow, marrow dysplasia, organ involvement and eventually progression to AML. This aberrant activation is due to recurring chromosomal translocations in which the PDGFRβ gene is fused with a partner gene providing a dimerization domain essential for the constitutive activation of the PDGFRβ kinase domain.…”

Section: Hypothetical Up-stream Regulators Of Mtor In Amlmentioning

confidence: 99%