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

This review establishes the pharmacokinetic characteristics of the major nucleoside analogues with cytotoxic activity. Cytarabine, pentostatin, fludarabine, cladribine and gemcitabine are all prodrugs whose plasma pharmacokinetics do not fully reflect their therapeutic activity; after cellular uptake, these compounds undergo phosphorylation by deoxycytidine kinase before their incorporation into DNA results in cell death. Cytarabine is principally active in the S phase of the cell cycle and is most toxic to replicating cells, whereas pentostatin, fludarabine and cladribine are incorporated into DNA during the process in which strand breaks are repaired and are therefore cytotoxic to slowly replicating cells (although the action of pentostatin results from its inhibition of adenosine deaminase). Gemcitabine is unusual in being highly metabolised in solid tumour cells. The cytotoxic activity of pentostatin, fludarabine and cladribine against the clonal cells of lymphoproliferative disorders is accompanied by damage to normal lymphoid cells, which results in significant and long-lasting immunosuppression. Useful interactions between nucleoside analogues have been defined. Cells that are primed by exposure to fludarabine or cladribine exhibit enhanced accumulation of cytarabine triphosphate (the cytotoxic nucleotide of cytarabine) and an improved therapeutic effect against acute myeloid leukaemia and chronic lymphocytic leukaemia can be achieved by clinical schedules that exploit this effect. Combinations of alkylating agents and fludarabine or cladribine are also synergistic in producing significantly enhanced activity against refractory lymphoid malignancies, but at the cost of increased haematological toxicity. Developments in the clinical administration of gemcitabine are concentrating on efforts to extend the duration of exposure to the drug as a means of counteracting its rapid catabolism in the circulation. Future developments with this group of agents will further explore the use of fludarabine-based combination therapies to produce a transient period of myelosuppression and immunosuppression that is sufficient to permit the engraftment of allogeneic haemopoietic stem cells and also exploit the immunological benefits of graft-versus-tumour reactions. In addition, the clinical spectrum of activity of gemcitabine is also being extended by combining the drug with other active chemotherapeutic agents, such as cisplatin, and by early studies of its role as a radiosensitiser.
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PMID:Clinical pharmacokinetics of nucleoside analogues: focus on haematological malignancies. 1092 48

Cladribine (2-chlorodeoxyadenosine, 2-CdA) is a nucleoside analog with substituted halogen atom at position 2 in its purine ring that makes it resistant to deamination by adenosine deaminase (ADA). 2-CdA is the drug of choice in the treatment of hairy cell leukemia, but it is also highly active in other low grade lymphoid malignancies including chronic lymphocytic leukemia (CLL). The results of the studies presented so far have shown that 2-CdA gives similar complete response (CR) rate and overall response (OR) rate to fludarabine but the influence of both agents on survival times of the patients with CLL is still uncertain. CR rate induced with 2-CdA is significantly higher than in the patients treated with conventional chemotherapy. In refractory or relapsed patients 2-CdA induces 31 to 68% of overall responses including CR in 4 to 31%. In previously untreated patients overall remission rates of about 56-82% have been achieved with 2-CdA alone. When 2-CdA was used as primary therapy the CR rate was also significantly higher and ranged from 10% to 47%. Patients who received 2-CdA as their initial therapy and experienced a response lasting at least a year may be successfully treated subsequently with the same agent. A second response has been achieved in 35 to 100% patients treated with this agent for the second time. Despite the fact that 2-CdA gives higher CR and OR rates than conventional chemotherapy, it has not been established whether it has any influence on survival time. However, cross resistance between 2-CdA and FAMP in CLL patients is evident in the majority of studies. Bone marrow suppression with anemia neutropenia and thrombocytopenia are the dose limiting factors for 2-CdA use. These side effects are pronounced in heavily pretreated patients and after multiple courses of therapy. Treatment with this agent also leads to the decrease of the CD4+/CD8+ ratio for an extensive period of time exceeding 12, even up to 24 months. In consequence, infections including opportunistic type, are frequently observed. We suggest, that in patients with CLL, 2-CdA should be used as second line treatment rather than the first line therapy until the final results of ongoing randomized clinical trials are available.
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PMID:Cladribine in the treatment of chronic lymphocytic leukemia. 1142 28

Pentostatin (2prime prime or minute-deoxycoformycin, dCF) is a product of the fermentation of Streptomyces antibioticus. It is a tight-binding inhibitor of adenosine deaminase (ADA), an enzyme essential in cellular metabolism of purines. Children with congenital absence of ADA suffer from atrophy of lymphoid tissues and severe combined immune deficiency (SCID) syndrome. It was speculated that pentostatin would be lymphocytotoxic, and this proved to be the case, promoting its investigation in lymphoid neoplasms. It was anticipated that pentostatin would be most active in neoplasms with high intracellular concentrations of ADA---e.g., acute lymphocytic leukemia (ALL), particularly its T cell variety. Although pentostatin proved to be active in ALL, large doses were required and toxic effects outweighted therapeutic benefits. By contrast, pentostatin proved to be exceptionally active in hairy cell leukemia (HCL), a B cell neoplasm with low intracellular concentrations of ADA. Pentostatin has since been shown to possess activity in chronic lymphocytic leukemia, prolymphocytic leukemia, cutaneous T cell lymphomas, adult T cell lymphoma-leukemia, and low-grade non-Hodgkin's lymphomas. It potentiates the activity of vidarabine against viruses and against the cells of acute myeloid leukemia. Pentostatin is inactive in melanoma and renal carcinoma, but has not been adequately evaluated in other solid tumors. The toxic effects of pentostatin include renal failure, central nervous system (CNS) depression, immunosuppression, keratoconjunctivitis, and opportunistic infections. In the absence of pre-existing bone marrow compromise, pentostatin produces only mild myelosuppression. Aside from its use as an antineoplastic agent, pentostatin has potential applications as an immunosuppresive drug, as an antiviral agent, as an antimalarial compound, and in the protection of cells of the CNS from damage induced by ischemia and anoxia.
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PMID:Pentostatin (2prime prime or minute-Deoxycoformycin): Clinical Pharmacology, Role In Cancer Chemotherapy, and Future Prospects. 1184 52

Cladribine, an adenosine deaminase inhibitor, has been developed and launched by Ortho Biotech in collaboration with The Scripps Research Institute for the treatment of several neoplasms, including acute myelogenous leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, cutaneos T-cell lymphoma, hairy-cell leukemia and non-Hodgkin's lymphoma. It was first launched in the US in February 1993. Ortho Biotech and The Scripps Research Institute have since been developing the compound for its potential use in multiple sclerosis (MS). In 1997, Ortho filed air NDA in the US for the use of cladribine in the treatment of relapsing-remitting and secondary progressive MS. An FDA drug advisory committee was planning to meet in January 1999 to discuss the NDA. However, Ortho cancelled the meeting. Following an FDA inspection during December 1998 and January 1999, the Scripps Clinic received a warning letter from the FDA in April 1999 regarding violations in the clinical studies of cladribine for MS, and Ortho withdrew the NDA after concluding that further clinical studies would be necessary. Cladribine has been known since the 1960s as an intermediate for the synthesis of 2-deoxynucleotides and its potential for the treatment of leukemia was disclosed in 1984. The Scripps Research Institute and the Johnson & Johnson group hold several patents claiming preparation methods (US 05208327), and additional indications, such as multiple sclerosis (WO-09316706) and rheumatoid arthritis (US-05310732). The associated patent, WO-09323508, is the only one among those patents that claims the use of unmodified cladribine for the treatment of leukemia, but it focuses particularly on a specific form of the disease, chronic myelogenous leukemia. Analysts at UBS Warburg predicted in October 2001, that the product would make US sales of $50 million in 2004 for its MS indication.
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PMID:Cladribine. Ortho Biotech Inc. 1189 41

Adenosine deaminase inhibitors have proven superior to alkylating agent-based therapies in inducing clinical and hematologic remissions in treated and previously untreated chronic lymphocytic leukemia (CLL) patients, and they have become increasingly accepted as a standard for therapy. We report the case of a 66-year-old patient with a 7-year history of CLL who had been previously treated with alkylating agents. Upon presentation with abdominal lymphadenopathy, a 5-day course of the nucleoside analogue, fludarabine, was administered. Two days after completion, the patient developed acute tumor lysis syndrome (TLS) that induced renal failure with hyperkalemia and hyperuricemia. This resulted in critical, life-threatening complications requiring hospitalization, aggressive hemodialysis and fluid replacement therapy. While only 5 other cases of TLS associated with fludarabine therapy have been reported since 1989, we recommend that adenosine deaminase inhibitor therapy be initiated with the addition of allopurinol, and that hydration with copious amounts of oral fluids during therapy be encouraged in order to help protect against the renal effects of potential TLS induced by these agents.
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PMID:Tumor lysis syndrome (TLS) following fludarabine therapy for chronic lymphocytic leukemia (CLL): case report and review of the literature. 1260 95

Pentostatin (2'-deoxycoformycin, dCF) is a purine nucleoside analog and a product of the fermentation of Streptomyces antibioticus. It is a tight-binding inhibitor of adenosine deaminase (ADA), an enzyme essential in the cellular metabolism of purines. Children with congenital absence of ADA suffer from atrophy of lymphoid tissues and severe combined immune deficiency (SCID) syndrome. It was hypothesized that pentostatin would be lymphocytotoxic and this proved to be true; this finding prompted its investigation in lymphoid neoplasms. It was anticipated that pentostatin would be most active in neoplasms with high intracellular concentrations of ADA, e.g. acute lymphocytic leukemia (ALL), particularly of the T-cell variety. Although pentostatin proved to be active in ALL, large doses were required and major toxic effects outweighed therapeutic benefits. By contrast, pentostatin proved to be exceptionally active in hairy cell leukemia (HCL), a B-cell neoplasm with low intracellular concentrations of ADA. Pentostatin has since been shown to possess activity in chronic lymphocytic leukemia, prolymphocytic leukemia, cutaneous T-cell lymphomas, adult T-cell lymphoma-leukemia, and low grade non-Hodgkin's lymphomas. It potentiates the activity of vidarabine against viruses and against the cells of acute myeloid leukemia. Pentostatin is inactive in melanoma and renal carcinoma, but has not been adequately evaluated in other solid tumors. The toxic effects of pentostatin include renal failure, central nervous system (CNS) depression, immunosuppresion, keratoconjunctivitis, and opportunistic infections. In the absence of pre-existing bone marrow compromise, pentostatin produces only mild myelosuppression. Aside from its use as an antineoplastic agent, pentostatin has potential applications as an immunosuppressive drug, as an antiviral agent, as an antimalarial compound, and in the protection of cells of the CNS from damage induced by ischemia and anoxia. Clinical studies with pentostatin are ongoing, and its roles in the management of neoplastic and non-neoplastic diseases have yet to be fully defined.
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PMID:Deoxycoformycin (pentostatin): clinical pharmacology, role in the chemotherapy of cancer, and use in other diseases. 1465 Dec 24

Hairy cell leukemia (HCL) was once considered an untreatable form of chronic lymphoid malignancy. Based upon the recognition of the importance of adenosine deaminase to the normal B cell survival and proliferation, a hypothesis was developed that temporary inhibition of this enzyme might be therapeutically successful in treating chronic B cell leukemias. Pentostatin was initially explored in patients with refractory chronic lymphocytic leukemia (CLL). Both pentostatin and cladribine, purine nucleoside analogs, have been utilized to successfully treat HCL. The high degree of complete and durable remission observed with either agent resulted in many believing that the treatment of this rare disease had been fully optimized. However, a considerable number of patients will relapse. While tremendous progress has been made in initial management, the issues related to optimal therapy, timing of initiation of treatment, and discovery of novel agents that may be effective in those who have relapsed are important. Investigational agents currently being explored in chronic lymphocytic leukemia may also have benefit for those patients who have relapsed or are resistant to therapy of hairy cell leukemia. Many important questions remain (e.g. importance of minimal residual disease) and will require international collaboration to fully address these unanswered questions. The Hairy Cell Leukemia Consortium was established to address these unanswered questions.
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PMID:Hairy cell leukemia: a successful model for experimental therapeutics--pentostatin and new ideas. 2159 4

Hereditary adenosine deaminase deficiency results in failure of the lymphocyte development. This occurs because of the accumulation of deoxyadenine nucleotides in cells with high deoxycytidine kinase and low 5'-nucleotidase activity. 2-Chlorodeoxyadenosine (2-CdA) resists the action of adenosine deaminase and accumulates in cells with high deoxycytidine kinase and low 5'-nucleotidase activity. It is equally toxic to dividing and nondividing cells and may act by preventing repair of DNA single-strand breaks. In doses of 0.1 mg/kg/day given for seven days 2-CdA manifests low toxicity. It has been found to be effective in the treatment of patients with lymphoid neoplasms, including advanced cutaneous T-cell lymphomas, chronic lymphocytic leukemia, non-Hodgkin lymphomas, and hairy cell leukemia. In the latter disorder it appears to be as or more effective than the tight-binding adenosine deaminase inhibitor, deoxycoformycin, and is probably less toxic. 2-CdA also appears to be effective in controlling autoimmune hemolytic anemia and shows promise in the treatment of other autoimmune diseases.
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PMID:2-Chlorodeoxyadenosine (2-CdA): A Potent Chemotherapeutic and Immunosuppressive Nucleoside. 2746 4


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