Disease relevance of Leustatin

• Lasting remissions in hairy-cell leukemia induced by a single infusion of 2-chlorodeoxyadenosine [1].
• 2-Chlorodeoxyadenosine therapy in chronic lymphocytic leukemia [2].
• Epstein-Barr virus-associated lymphoma after treatment of macroglobulinemia with cladribine [3].
• Treatment of systemic mast-cell disease with cladribine [4].
• The patients received 2-chlorodeoxyadenosine (0.1 mg per kilogram of body weight per day) by continuous infusion for seven days [1].

High impact information on Leustatin

• Tumor lysis syndrome after treatment of chronic lymphocytic leukemia with cladribine [5].
• We treated 28 patients with CLL refractory to fludarabine therapy with a continuous infusion of 2-chlorodeoxyadenosine at a daily dose of 4 mg per square meter of body-surface area for seven days [6].
• Although 20 percent of the patients have some response, thrombocytopenia and anemia are rarely corrected and may be made worse by 2-chlorodeoxyadenosine therapy [6].
• The median platelet count at the start of 2-chlorodeoxyadenosine therapy in these 10 patients was 24,000 per cubic millimeter, as compared with 109,000 per cubic millimeter in the other 18 patients [6].
• Brief report: tumor lysis syndrome following treatment with 2-chlorodeoxyadenosine for refractory chronic lymphocytic leukemia [7].

Chemical compound and disease context of Leustatin

• Fludarabine and 2-chlorodeoxyadenosine are nucleoside analogues that have proved effective in patients with chronic lymphocytic leukemia (CLL) [6].
• Mechanism of deoxyadenosine and 2-chlorodeoxyadenosine toxicity to nondividing human lymphocytes [8].
• Although the nucleoside analogs cladribine and pentostatin produce high response rates in patients with hairy cell leukemia (HCL), a significant number of patients eventually relapse [9].
• Cladribine alone and in combination with cyclophosphamide or cyclophosphamide plus mitoxantrone in the treatment of progressive chronic lymphocytic leukemia: report of a prospective, multicenter, randomized trial of the Polish Adult Leukemia Group (PALG CLL2) [10].
• Therapeutic and neurotoxic effects of 2-chlorodeoxyadenosine in adults with acute myeloid leukemia [11].

Biological context of Leustatin

• DATA SYNTHESIS: 2-Chlorodeoxyadenosine is unique compared with traditional antimetabolite drugs in that it is equally active against dividing and resting lymphocytes, which may be especially important in indolent lymphoid malignancies, such as chronic lymphocytic leukemia, because most cells in these disorders are in the resting phase [12].
• Adenine deoxynucleosides, such as 2-chloro-2'-deoxyadenosine (2CdA) induce apoptosis in quiescent lymphocytes, and are thus useful drugs for the treatment of indolent lymphoproliferative diseases [13].
• Despite expectations that 2-chlorodeoxyadenosine (2-CdA) would prove active primarily in lymphoproliferative diseases, early reports suggested unexpected high activity of this drug in heavily pretreated children with acute myeloblastic leukemia (AML) at a maximally tolerated dose of 8.9 mg/m2/day for 5 days [11].
• 2-Chlorodeoxyadenosine (2-CdA) induces more than 80% complete responses, but is associated with profound suppression of CD4+ lymphocyte counts [14].
• Flow cytometry of blood and bone marrow cells from patients with hairy cell leukemia: phenotype of hairy cells and lymphocyte subsets after treatment with 2-chlorodeoxyadenosine [15].

Anatomical context of Leustatin

• Response to 2-chlorodeoxyadenosine in patients with B-cell chronic lymphocytic leukemia resistant to fludarabine [16].
• Potent toxicity of 2-chlorodeoxyadenosine toward human monocytes in vitro and in vivo. A novel approach to immunosuppressive therapy [17].
• METHODS: Adenovirus encoding beta-galactosidase was injected intravenously in lethally irradiated B6D2F1 mice that had received syngeneic B6D2F1 bone marrow and spleen cell transplants, in athymic mice, in mice treated with 2-chlorodeoxyadenosine, or in normal mice [18].
• The present experiments demonstrate that the 2'-arabino-fluoro derivative of CdA, designated CAFdA, is also directly toxic to quiescent lymphocytes and macrophages [19].
• We treated 22 patients with mature T-cell lymphoproliferative diseases with 2-chlorodeoxyadenosine (2-CDA) administered as a continuous infusion at a daily dose of 4 mg/m2 over 7 days [20].

Associations of Leustatin with other chemical compounds

• OBJECTIVE: To review the structure, mechanism of action, pharmacologic features, and clinical trial results of the newer purine analog, 2-chlorodeoxyadenosine (2-CdA) [12].
• Twenty-three patients underwent primary splenectomy, 65 received interferon alpha, 24 deoxycoformycin, and 67 cladribine (2-chlorodeoxyadenosine) [21].
• PKC412 inhibits in vitro growth of neoplastic human mast cells expressing the D816V-mutated variant of KIT: comparison with AMN107, imatinib, and cladribine (2CdA) and evaluation of cooperative drug effects [22].
• Apoptosis was induced by the 2'-deoxyadenosine analogue, 2-chloro-2'-deoxyadenosine (Cl-dA), with the concentration for apoptosis in one-half of the cells at 24 hours (LD(50)) being 10 microM for 697 cells and 120 microM for 697/Bcl 2 cells [23].
• There was no excess of malignancy among patients treated with interferon alfa (IFN-alpha; P = .27), 2-chlorodeoxyadenosine (2CDA; P = .37), or deoxycoformycin (DCF; P = .7) [24].

Gene context of Leustatin

• Adenine deoxynucleotides fludarabine and cladribine induce apoptosis in a CD95/Fas receptor, FADD and caspase-8-independent manner by activation of the mitochondrial cell death pathway [25].
• Apart from low-level MRP4-mediated cladribine resistance, the cytotoxicity of clinically used anticancer nucleosides was not influenced by overexpression of MRP4 or MRP5 [26].
• In addition, CdA augmented release of IL-8 from whole blood cultures [27].
• Cladribine induced currents in oocytes expressing rSPNT (K(0.5) = 57 +/- 12 microM) but not hSPNT1 [28].
• Pharmacological inhibition of the MAPK/ERK pathway increases sensitivity to 2-chloro-2'-deoxyadenosine (CdA) in the B-cell leukemia cell line EHEB [29].

Analytical, diagnostic and therapeutic context of Leustatin

• 2-Chlorodeoxyadenosine may induce a complete remission in chronic lymphocytic leukemia that is highly resistant to chemotherapy, and it deserves wider clinical evaluation in patients with this condition [16].
• INTERVENTION: 2-Chlorodeoxyadenosine was administered as a continuous intravenous infusion at a dose of 0.1 mg/kg body weight per day for 7 days [30].
• A 2-year, placebo-controlled, double-blind, crossover study was started in 1992 to evaluate cladribine, an immunosuppressive drug, in the treatment of chronic progressive multiple sclerosis [31].
• As is typical for patients in CR after treatment with CdA, minimal residual disease was detectable by flow cytometry of the bone marrow aspirate [32].
• All 4 HCL patients were resistant to standard and salvage therapies for HCL, including 2-chlorodeoxyadenosine (CdA) and interferon alpha, and all patients responded to LMB-2 after a single cycle [32].

References