Pentostatin for the Treatment of Indolent Lymphoproliferative Disorders

Ho, Anthony D.; Hensel, Manfred

doi:10.1053/j.seminhematol.2005.12.005

Cited by 15 publications

(10 citation statements)

References 80 publications

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“…These analogues either incorporate into DNA and/or affect metabolic enzymes such as ribonucleotide reductase [2], purine nucleoside phosphorylase [3], and adenosine deaminase [4, 5] to perturb intracellular deoxynucleotide pools, resulting in decreased DNA synthesis in cells. In contrast, 8-chloroadenosine (8-Cl-Ado) contains a ribose sugar and is unique because it is RNA-directed.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of ATP synthase by chlorinated adenosine analogue

Chen

Nowak

Ayres

et al. 2009

Biochemical Pharmacology

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8-Chloroadenosine (8-Cl-Ado) is a ribonucleoside analogue that is currently in clinical trial for chronic lymphocytic leukemia. Based on the decline in cellular ATP pool following 8-Cl-Ado treatment, we hypothesized that 8-Cl-ADP and 8-Cl-ATP may interfere with ATP synthase, a key enzyme in ATP production. Mitochondrial ATP synthase is composed of two major parts; FO intermembrane base and F1 domain, containing α and β subunits. Crystal structures of both α and β subunits that bind to the substrate, ADP, are known in tight binding (αdpβdp) and loose binding (αtpβtp) states. Molecular docking demonstrated that 8-Cl-ADP/8-Cl-ATP occupied similar binding modes as ADP/ATP in the tight and loose binding sites of ATP synthase, respectively, suggesting that the chlorinated nucleotide metabolites may be functional substrates and inhibitors of the enzyme. The computational predictions were consistent with our whole cell biochemical results. Oligomycin, an established pharmacological inhibitor of ATP synthase, decreased both ATP and 8-Cl-ATP formation from exogenous substrates, however, did not affect pyrimidine nucleoside analogue triphosphate accumulation. Synthesis of ATP from ADP was inhibited in cells loaded with 8-Cl-ATP. These biochemical studies are in consent with the computational modeling; in the αtpβtp state 8-Cl-ATP occupies similar binding as ANP, a non-hydrolyzable ATP mimic that is a known inhibitor. Similarly, in the substrate binding site (αdpβdp) 8-Cl-ATP occupies a similar position as ATP mimic ADP-BeF3 −. Collectively, our current work suggests that 8-Cl-ADP may serve as a substrate and the 8-Cl-ATP may be an inhibitor of ATP synthase.

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Section: Introductionmentioning

confidence: 99%

Inhibition of ATP synthase by chlorinated adenosine analogue

Chen

Nowak

Ayres

et al. 2009

Biochemical Pharmacology

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“…P was combined with rituximab (R-P) with or without mitoxantrone (R-PM) in advancedstage indolent NHL patients. R-PM regimen appeared to be superior to R-P in terms of ORR (73 vs 84%), but equivalent in terms of response duration (10 months in both regimens) [87,88]. More intensive regimens including P (i.e., pentostatin, bleomycin, mitoxantrone and prednisone) conferred a longer median duration of remission (38 months) and OS (71% at 3 years) [76].…”

Section: Other Alkylating Agent-based Regimensmentioning

confidence: 95%

Chemotherapy and treatment algorithms for follicular lymphoma: a look at all options

Steffanoni

Ghielmini

Moccia

2015

Expert Review of Anticancer Therapy

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The outcome of patients with follicular lymphoma has substantially improved in recent years, mainly due to the widespread use of the monoclonal antibody rituximab and partially due to autologous and allogeneic transplantation, and the introduction of new drugs and to the improvement in diagnostic accuracy. The choice of therapy is still based on patient characteristics, extension of disease and clinical prognostic factors. The majority of patients in need of treatment are still treated with cytotoxic agents in combination with rituximab; nevertheless a number of new agents, which are active in this disease, have recently been developed. It has yet to be determined, whether they will partly or completely replace chemotherapy in the near future. This review focuses on the role and the choice of chemotherapy in different clinical situations of follicular lymphoma, in a time when chemotherapy-free treatment becomes more and more of a topic of discussion.

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“…Pentostatin is useful for patients who may benefit from high-dose chemotherapy with autologous stem cell transplantation. 93,116 Nonmyeloablative allogeneic peripheral blood stem cell transplantation may be a promising alternative in patients with refractory disease. 117 Splenectomy is rarely indicated, but limited case reports suggest that it may be helpful for managing symptomatic painful splenomegaly and hypersplenism.…”

Section: Treatment Optionsmentioning

confidence: 99%

Waldenström macroglobulinemia

Vijay

Gertz

2007

Blood

179

163

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IntroductionNearly 63 years have passed since Jan Gosta Waldenström first described 2 patients with oronasal bleeding, lymphadenopathy, anemia and thrombocytopenia, elevated erythrocyte sedimentation rate, high serum viscosity, normal bone radiographs, and bone marrow showing predominantly lymphoid cells. 1 At a time when paper electrophoresis was unheard of, he attributed hyperviscosity symptoms to an abnormal high-molecular-weight serum protein. These preliminary observations proved to be the cornerstones of the widely recognized but relatively uncommon diagnosis of Waldenström macroglobulinemia (WM). The abnormal high-molecular-weight serum protein subsequently was shown to be monoclonal immunoglobulin M (IgM). Definition and pathologyWM is a malignant lymphoplasmo-proliferative disorder with monoclonal pentameric IgM production. The most consistent feature of the bone marrow or lymph nodes of patients with WM is the presence of pleomorphic B-lineage cells at different stages of maturation, such as small lymphocytes, lymphoplasmacytoid cells (abundant basophilic cytoplasm but lymphocyte-like nuclei), and plasma cells. 2 Bone marrow is infiltrated in a predominantly intertrabecular pattern. A significant increase in the number of mast cells has been noted in bone marrow biopsies of WM patients. 3 Bone marrow mast cells of WM patients overexpress the CD40 ligand (CD154), which is a potent inducer of B-cell expansion. ClassificationWM was initially defined in broad terms with the Kiel classification 4 as a lymphoma of Ig-secreting cells, often associated with a paraproteinemia. Subsequently, WM was combined with lympho- IncidenceWM has an overall incidence of approximately 3 per million persons per year, accounting for approximately 1% to 2% of hematologic cancers. 8,9 The incidence of WM is higher among whites, with blacks representing only 5% of all patients. 10 In large series of patients, the median age varies between 63 and 68 years, with 55% to 70% men. 11 WM remains incurable, and most patients die of disease progression, with a median survival of 5 years. 12 Because of the late age of presentation of WM, half of the patients succumb to causes unrelated to WM. Etiology and predisposing factorsWM is believed to be predominantly a sporadic disease. Its cause is unknown, but various reports of multigenerational clustering and familial patterns indicate the possible role of a single genetic defect. 13 Treon et al 14 analyzed 257 consecutive and unrelated patients with WM: 48 (18.7%) had at least 1 first-degree relative with either WM or another B-cell disorder. Moreover, patients with a familial history of WM or a plasma cell disorder received the diagnosis at a younger age and with greater bone marrow involvement. Deletions in 6q21-22.1 were confirmed in most WM patients regardless of family history. In short, a high degree of clustering of For personal use only. on May 10, 2018. by guest www.bloodjournal.org From B-cell disorders was seen among first-degree relatives of patients with WM.The main risk facto...

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Pentostatin for the Treatment of Indolent Lymphoproliferative Disorders

Cited by 15 publications

References 80 publications

Inhibition of ATP synthase by chlorinated adenosine analogue

Inhibition of ATP synthase by chlorinated adenosine analogue

Chemotherapy and treatment algorithms for follicular lymphoma: a look at all options

Waldenström macroglobulinemia

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