Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.5.4.4 (adenosine deaminase)
 5,136 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We determined the activity of adenosine deaminase in normal lymphocytes from peripheral blood, leukemic cells from patients with various hematologic malignancies, and mononuclear cells from kidney-transplant patients, by adapting the method of Hopkinson et al. [Ann. Hum. Genet. 32, 361 (1969)] to the centrifugal analyzer. Normal lymphocytes separated on Ficoll-Hypaque from peripheral blood had a mean activity of 1.42 U/10(9) cells (SD = 0.57; N = 33). Cells similarly isolated from patients with acute lymphoproliferative and myeloproliferative disease generally showed greater values, but the ranges overlapped. Cells from patients with chronic lymphocytic leukemia had activities that were within or below the normal range. Mononuclear cells isolated from the peripheral blood of 15 stable renal allograft recipients showed a mean activity of 1.90 U/10(9) cells (SD = 0.59), not significantly different from normal. In contrast, cells from five patients with biopsy-proven allograft rejection showed a mean activity of 12.84 U/10(9) cells (SD = 10.10), which was significantly different from that of the stable patients.
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PMID:Adenosine deaminase activity in lymphocytes of normal persons, leukemic patients, and kidney-transplant recipients. 33 94

Fludara I.V. (fludarabine phosphate) (9-beta-D-arabinosyl-2-fluoroadenine, F-ara-A) is an adenine nucleoside analogue resistant to adenosine deaminase that shows promising therapeutic activity in the clinical treatment of lymphocytic hematologic malignancies. F-ara-A is transported into cells, where it is converted to its 5'-triphosphate (F-ara-ATP), the principal active metabolite. Deoxycytidine kinase is the enzyme responsible for the initial step of this activation metabolism. The differential transport and phosphorylation of F-ara-A and accumulation of F-ara-ATP by normal and cancer cells may constitute the metabolic basis of its positive therapeutic index. The major action of F-ara-A is the inhibition of DNA synthesis. F-ara-ATP competes with deoxyadenosine triphosphate for incorporation into the A sites of the elongating DNA strand by DNA polymerases and terminates DNA synthesis at the incorporation sites. That action is potentiated by the decrease of cellular dATP that results from inhibition of ribonucleotide reductase by F-ara-ATP. In vitro experiments demonstrated that DNA polymerase delta is able to excise the incorporated F-ara-AMP residues from DNA with its 3' to 5' exonuclease activity. The terminal incorporation of F-ara-AMP into DNA results in deletion of genetic material. That mechanism may be responsible for the observed mutagenicity of Fludara I.V., and ultimately its cytotoxic action.
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PMID:Metabolism and action of fludarabine phosphate. 169 80

Pentostatin, a novel inhibitor of adenosine deaminase, has shown activity in various lymphoid malignancies of both the T and B cell lineage. This agent has unique side effects and in general myelosuppression has been mild. Interferon has both antiviral and antineoplastic properties. This agent has shown activity in hairy cell leukemia, chronic granulocytic leukemia, low grade lymphoma, and myeloma. Side effects from interferon are in general dissimilar to those that have been seen with pentostatin and in particular myelosuppression has not been a major toxicity with low doses of interferon. This current trial explored the combination of pentostatin and interferon in hematologic malignancies. Fifteen patients were enrolled in this phase I trial at a fixed dose of pentostatin of 4 mg/m2 biweekly and interferon at doses of 0.5, 1, 2, or 4 million units/m2 of interferon. At the first three dose levels of interferon nausea and vomiting were the predominant toxicity and appeared to worsen with time on study. Fatigue also was seen at the lowest level of interferon and was severe enough to cause two individuals to discontinue the study medications. At higher dose levels of interferon, myelosuppression, nausea and vomiting, and fatigue were the predominant toxicities. One patient with hairy cell leukemia had a complete response and a second patient with T cell cutaneous lymphoma had a partial response which lasted for 6 to 7 weeks. The maximum tolerated dose of interferon with pentostatin in this patient population was four million units/m2.
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PMID:A phase I trial of alpha-interferon in combination with pentostatin in hematologic malignancies. 205 72

Hairy cell leukemia (HCL) is a rare chronic lymphoproliferative disorder which has been extensively studied over the past decade. Much has been learned regarding the diagnosis, natural history, biology, and treatment of this unique neoplasm. The disease most commonly affects middle aged men and characteristic clinical features include splenomegaly, cytopenias, and usually the presence in the peripheral blood of distinctive 'hairy cells' with irregular cytoplasmic projections. Diagnosis can usually be confirmed by bone marrow biopsy. Although the natural history can be extremely variable among patients, complications are usually referable to the cytopenias, with anemia and infection being most frequent. In addition to pyogenic infections, patients are susceptible to unusual organisms including atypical mycobacterium, legionella, and fungi. The requirement of red blood cell transfusion, severe granulocytopenia or thrombocytopenia, frequent infections, or painful splenomegaly are all indications for treatment. Splenectomy is the standard initial treatment of choice. However, in the past few years there have been exciting major advances in the therapeutic modalities for HCL. Recombinant alpha-interferon is highly effective, with beneficial responses occurring in close to 90% of patients. The Food and Drug Administration has recently approved the use of interferon for HCL. This represents the first time a biological response modifier has been approved for the treatment of human disease. In addition, preliminary results with the adenosine deaminase inhibitor, 2'deoxycoformycin (dcf), have been encouraging. Further clinical trials are required in order to determine the optimal sequential treatment strategy for HCL. The exact mechanisms of action of both interferon and dcf in HCL remain to be elucidated. A better understanding of the unusual features of the hairy cell and the underlying biological effect of these two agents in HCL may have important applications in other hematologic and non-hematologic malignancies.
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PMID:Hairy cell leukemia: clinical features and therapeutic advances. 244 91

The adenosine deaminase-resistant purine deoxynucleoside 2-chloro-2'-deoxyadenosine (CdA) is markedly toxic in vitro to nondividing and proliferating normal human lymphocytes and to many leukemia cell specimens. The CdA is also effective against mouse L1210 leukemia in vivo. The present investigations have examined the pharmacology, chemotherapeutic activity, and toxicity of CdA in nine patients with advanced hematologic malignancies refractory to conventional therapy. When administered by continuous intravenous infusion, the deoxyadenosine analog was well tolerated. As monitored by radioimmunoassay, plasma CdA levels rose gradually during the infusions. The CdA was not deaminated significantly. In all patients with leukemia, the CdA lowered the blast count by at least 50%. In one patient with a T-cell leukemia-lymphoma, and in another patient with chronic myelogenous leukemia in blast crisis, the CdA infusion eliminated all detectable blasts from the blood and bone marrow. In a patient with a diffuse lymphoma complicated by severe autoimmune hemolytic anemia, CdA treatment quickly terminated the hemolytic process. Bone marrow suppression represented the dose-limiting toxicity, and was related to plasma CdA levels, cumulative drug dosage, and the rapid release of CdA that accompanied tumor cell lysis.
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PMID:Antileukemic and immunosuppressive activity of 2-chloro-2'-deoxyadenosine. 658 95

A deficiency of adenosine deaminase, an enzyme important in purine nucleoside catabolism, is associated with a severe combined immunodeficiency disease in children. Inhibition of this enzyme in vitro and in vivo results in an impairment in lymphoblast proliferation. We have investigated the pharmacologic inhibition of this enzyme by 2'-deoxycoformycin in 15 patients with hematologic malignancies. Biochemical consequences of the administration of this agent were closely monitored in erythrocytes, nucleated peripheral blood and bone marrow cells, serum, and urine. A marked rise in erythrocyte dATP was accompanied by a depletion of ATP in those patients exhibiting toxicity. Most patients excreted large amounts of deoxyadenosine but not adenosine in the urine. Serum deoxyadenosine rose in patients demonstrating a marked decrease in cell mass. The biochemical disturbances and clinical toxicity, including hepatic, renal, and conjunctival abnormalities, were usually reversible. Central nervous system toxicity, which potentially was the most serious consequence, was associated with high erythrocyte dATP/ATP ratios and high levels of cerebrospinal fluid deoxyadenosine. In patients with lymphoma and leukemia, objective responses were observed but were short-lived. Patients with chronic lymphocytic leukemia receiving weekly low doses of the drug demonstrated minimal toxicity and some efficacy. The chemotherapeutic potential o 2'-deoxycoformycin, as either a single agent or in combination with Ara-A, merits further exploration.
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PMID:The biochemical and clinical consequences of 2'-deoxycoformycin in refractory lymphoproliferative malignancy. 697 50

2-Chlorodeoxyadenosine (2-CDA) is an adenosine deaminase resistant analogue of deoxyadenosine which has shown clinical activity in human hematologic neoplasms. The exact mode of action of this drug remains the subject of investigation. We applied the Differential Staining Cytotoxicity (DiSC) assay to 50 human tumour specimens obtained from patients with a variety of hematologic malignancies to characterise the activity spectrum of 2-CDA. We evaluated the disease-specific activity of this agent in vitro and compared its relative cytotoxicity with that of other antineoplastic agents in current clinical use. Comparisons were conducted against nitrogen mustard, doxorubicin, vincristine and cytosine arabinoside. Our results indicate that 2-CDA has activity in myeloid and many lymphoid neoplasms but that multiple myeloma specimens reveal significant resistance. Cross resistance studies reveal a correlation between 2-CDA and the alkylator nitrogen mustard but no correlation between 2-CDA and doxorubicin, vincristine nor cytosine arabinoside. The results suggest 2-CDA activity in many human hematologic neoplasms with the clear exception of multiple myeloma and further suggest a relationship between this agent and alkylators of the mustard class. The DiSC assay may provide useful insights in the pre-clinical evaluation of new antineoplastic drugs and may help to elucidate drug activities and mechanisms of action.
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PMID:2 chlorodeoxyadenosine activity and cross resistance patterns in primary cultures of human hematologic neoplasms. 809 2

Cladribine is an adenosine deaminase-resistant deoxyadenosine analog with a unique mechanism of action. It is directly toxic towards both resting and proliferating human lymphocytes and monocytes. The development of this compound into clinical practice best exemplifies rational drug development and the success of translational research. Cladribine is well established as first-line treatment for hairy cell leukemia, inducing an overall response rate of 75-100%, with the majority being complete responses following only a single 7-day treatment course. The 9-year overall survival for hairy cell leukemia is currently 97%. Cladribine has also proven useful in the treatment of a variety of other hematologic malignancies, and its current place in the oncologic therapeutic armamentarium, as well as in potential areas of development, are outlined.
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PMID:Cladribine: from the bench to the bedside--focus on hairy cell leukemia. 1548 11

Cladribine was synthesized as a purine analogue drug that inhibited adenosine deaminase. It received FDA approval in the 1980s for treatment of hairy cell leukemia. Given its toxicity towards lymphocytes and its corresponding immunosuppressive effects, it has been studied and found efficacious in a variety of hematologic malignancies and autoimmune conditions, most recently multiple sclerosis. This review highlights pharmacological, toxicological and clinical data for the use of cladribine. It also discusses existing and new mechanisms that may contribute to its unique clinical activity. Emerging data show that in addition to its known purine nucleoside analogue activity, cladribine possesses epigenetic properties, inhibiting S-adenosylhomocysteine hydrolase and DNA methylation. This may contribute to its efficacy and highlights the importance of studying combination therapy with other epigenetic or targeted agents. Clinical trials are underway in a variety of malignant and nonmalignant conditions.
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PMID:Cladribine: not just another purine analogue? 1960 18

Nelarabine is the prodrug of 9-beta-arabinofuranosylguanine (ara-G) and is therapeutically classified as a purine nucleoside analog. Nelarabine is converted to ara-G by adenosine deaminase and transported into cells by a nucleoside transporter. Ara-G is subsequently phosphorylated to ara-G triphosphate (ara-GTP), thereby initiating the therapeutic effect by inhibiting DNA synthesis. Nelarabine has been extensively studied in regards to its pharmacokinetics, and the data have demonstrated that ara-GTP preferentially accumulates in malignant T-cells. Clinical responses to nelarabine have been demonstrated in various T-cell malignancies and appear to correlate with a relatively high intracellular concentration of ara-GTP compared to nonresponders. Therefore, this unique drug feature of nelarabine accounts for clinical utilization in treating adult and pediatric patients with relapsed or refractory T-cell acute lymphoblastic leukemia or T-cell lymphoblastic lymphoma. Neuropathy is the most predominant adverse effect associated with nelarabine and the incidence correlates with the dose administered. Myelosuppression has been observed, with thrombocytopenia and neutropenia as the most common hematologic complications. This article reviews the pharmacology, mechanism of action, and pharmacokinetic properties of nelarabine, as well as nelarabine's clinical efficacy in T-ALL, T-LBL, and other hematologic malignancies. The toxicity profile, dosage, and administration, and areas of ongoing and future research, are also presented.
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PMID:Profile of nelarabine: use in the treatment of T-cell acute lymphoblastic leukemia. 2061 9


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