pyrophosphate and Leukemia--Myeloid--Acute

Topics: Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Diphosphates; Drug Resistance, Neoplasm; Drug Synergism; Feasibility Studies; Female; Fibrin Fibrinogen Degradation Products; Hemorrhage; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Myelodysplastic Syndromes; Prodrugs; Respiratory Distress Syndrome; Salvage Therapy; Stilbenes; Treatment Outcome; Young Adult

Acute myelogenous leukemias (AMLs) and endothelial cells depend on each other for survival and proliferation. Monotherapy antivascular strategies such as targeting vascular endothelial growth factor (VEGF) has limited efficacy in treating AML. Thus, in search of a multitarget antivascular treatment strategy for AML, we tested a novel vascular disrupting agent, OXi4503, alone and in combination with the anti-VEGF antibody, bevacizumab. Using xenotransplant animal models, OXi4503 treatment of human AML chloromas led to vascular disruption in leukemia cores that displayed increased leukemia cell apoptosis. However, viable rims of leukemia cells remained and were richly vascular with increased VEGF-A expression. To target this peripheral reactive angiogenesis, bevacizumab was combined with OXi4503 and abrogated viable vascular rims, thereby leading to enhanced leukemia regression. In a systemic model of primary human AML, OXi4503 regressed leukemia engraftment alone and in combination with bevacizumab. Differences in blood vessel density alone could not account for the observed regression, suggesting that OXi4503 also exhibited direct cytotoxic effects on leukemia cells. In vitro analyses confirmed this targeted effect, which was mediated by the production of reactive oxygen species and resulted in apoptosis. Together, these data show that OXi4503 alone is capable of regressing AML by a multitargeted mechanism and that the addition of bevacizumab mitigates reactive angiogenesis.

Topics: Aged; Angiogenesis Inhibitors; Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Bevacizumab; Blotting, Western; Cell Proliferation; Diphosphates; Humans; Immunoenzyme Techniques; Interleukin Receptor Common gamma Subunit; Leukemia, Myeloid, Acute; Mice; Mice, Inbred NOD; Mice, Knockout; Mice, SCID; Middle Aged; Neovascularization, Pathologic; Reactive Oxygen Species; Remission Induction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Sarcoma, Myeloid; Stilbenes; Tumor Cells, Cultured; Vascular Endothelial Growth Factor A; Xenograft Model Antitumor Assays

High levels of terminal deoxynucleotidyl transferase have been observed in leukocytes of 7 out of 20 patients with chronic myelogenous leukemia in acute blast phase of the disease. These levels are comparable to the levels observed in human and calf thymus gland and cell lines with some T cell characteristics (Molt 4 and 8402). Negligible levels of this activity were observed in chronic myelogenous leukemia not in an acute blast phase of the disease, chronic lymphocytic leukemia, human B cells, mature T cells, and the mixed population of lymphocytes present in normal human blood. The detection of this enzyme in some patients with chronic myelogenous leukemia in acute blast phase of the disease suggests that the blast proliferation may involve primitive stem cells which have more lymphoid than myelogenous characteristics. This enzyme assay may be of use as a biological marker for following patients during treatment and in remission.

Topics: Cations, Divalent; Cell Line; Deoxyribonucleotides; Diphosphates; Ethylmaleimide; Humans; Hydrogen-Ion Concentration; Leukemia, Lymphoid; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Leukocytes; Lymphocytes; Nucleotidyltransferases; Oligonucleotides