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

Abstract

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...

Platelets Promote Mitochondrial Uncoupling and Resistance to Apoptosis in Leukemia Cells: A Novel Paradigm for the Bone Marrow Microenvironment

“…The results presented here, demonstrate that leukemia cell lines promote platelet activation, supporting the notion that the leukemic bone marrow may possibly activate newly formed platelets, perhaps contributing to leukemic thrombocytopenia [31]. This notion is also congruent with the observation by Foss B and colleagues [32] that platelets can adhere to acute myeloid leukemia blasts, and their hypothesis that platelets and leukemic blasts share in vivo microenvironments. In addition, contrary to what has been reported for solid tumor cell lines, MSC [16,17] and leukemic blasts [18], platelet contents did not affect the proliferation of OCI-AML3 or MOLT cells, suggesting that the proliferative and the chemoprotective effects of platelets may be mediated by different mechanisms in a cell context dependent manner.…”

Serum levels of angiogenin, basic fibroblast growth factor and endostatin in patients receiving intensive chemotherapy for acute myelogenous leukemia

“…48,61 It is not possible to judge whether these variations reflect altered bone marrow vessel density because bone marrow biopsies for examination of vessel density after chemotherapy were not available, but the hypothesis is supported by a previous work describing an association between response to induction therapy and reduction of microvessel density in the bone marrow. 62 We recently reported that AML chemotherapy can activate platelets and increase platelet adhesion to AML blasts, 63 and these events may modulate the direct effects of cytotoxic drugs on malignant cells. Our results describing an effect of intensive chemotherapy on systemic angiogenic regulation is another example of indirect chemotherapy effects that may be clinically important.…”

The role of platelets in the tumor microenvironment: From solid tumors to leukemia

“…Platelets derived from acute and chronic myeloid leukemia (AML and CML) patients tend to have impaired platelet responsiveness to physiological agonists [76], may have platelet storage pool deficiency [77]; and commonly for AML, disease and treatment-induced thrombocytopenia [78,79]. Nonetheless, TPO has been shown to induce aggregation of CML platelets from chronic phase patients with cytogenic remission [80], and AML blasts have been shown to bind platelets and induce PDGF secretion [79,81] to provide protection from chemotherapy-induced apoptosis to adenocarcinomas [28].…”