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)

Fludarabine phosphate is the 2-fluoro, 5'-monophosphate derivative of vidarabine (ara-A) with the advantages of resistance to deamination by adenosine deaminase (ADA) and improved solubility. The mechanism of cytotoxic action of the compound appears to involve metabolic conversion to the active triphosphate. Fludarabine phosphate has substantial activity against lymphoid malignancies, particularly chronic lymphocytic leukemia (CLL) and low-grade non-Hodgkin's lymphoma (NHL). Its single-agent activity in CLL appears at least comparable to those of other conventional combination regimens. Its activity in Hodgkin's disease, mycosis fungoides, and macroglobulinemia, although suggestive, needs to be further defined and clinical trials are warranted in hairy cell leukemia, prolymphocytic leukemia, and previously untreated myeloma. The compound does not appear active against most common solid tumors. Early clinical trials indicated significant myelosuppression and the potential for severe neurotoxicity. Toxicity on the currently used low-dose schedules includes transient and reversible myelosuppression, nausea and vomiting, diarrhea, somnolence/fatigue, and elevations of liver enzymes and/or serum creatinine. Possible pulmonary toxicity has been suggested in several patients. The currently used low-doses of fludarabine phosphate, even with repeated administration, are well tolerated and appear safe with a negligible risk for severe neurotoxicity. Based on its single-agent activity and tolerability, the Food and Drug Administration recently granted group C designation of the drug for the treatment of patients with refractory CLL outside the clinical trials setting. The use of fludarabine phosphate in combination regimens and its impact on the natural history of the lymphoid malignancies is yet to be determined. Fludarabine phosphate may well occupy a pivotal role in the management of CLL and low-grade NHL.
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PMID:Fludarabine phosphate: a synthetic purine antimetabolite with significant activity against lymphoid malignancies. 170 43

The new fluorinated adenine analog, fludarabine, has been tested for efficacy in many tumor types over the past ten years. Two other similar nucleoside analogs are currently available for commercial use. Cytarabine is used principally as an antileukemic agent, and vidarabine as an antiviral. Unlike vidarabine, fludarabine is resistant to deactivation by adenosine deaminase. Data from Phase I and II trials suggest that fludarabine is potentially effective in a number of leukemias, including acute lymphocytic leukemia, acute nonlymphocytic leukemia, and chronic lymphocytic leukemia (CLL). Unfortunately, the doses required to achieve adequate response in the acute leukemias (greater than 75 mg/m2) were above the maximum tolerated dose, resulting in intolerable granulocytopenia, thrombocytopenia, and a life-threatening neurotoxic syndrome. In CLL: however, the dose required to achieve a satisfactory response is well within tolerated limits. Long-term survival statistics are not yet available, but historical perspective strongly correlates response to other agents with increased survival times. Toxicities seen at dose regimens of 15-40 mg/m2/d for five consecutive days include somnolence, metabolic acidosis, confusion, fatigue, nausea, vomiting, increase in serum creatinine and aminotransferase concentrations, and pulmonary and hepatic abnormalities. Mild to severe hematologic toxicity has been observed at all dose levels.
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PMID:Fludarabine: a review. 206 37

We evaluated the ability of three enzymes--N-acetyl-beta-D-glucosaminidase (NAG; EC 3.2.1.30), alanine aminopeptidase (AAP; microsomal aminopeptidase, EC 3.4.11.2), and gamma-glutamyltransferase (GGT; EC 2.3.2.2)--and adenosine deaminase binding protein (ABP) in urine to predict or confirm renal-transplant rejection in patients treated with cyclosporine. We measured the enzymes daily during the early post-transplant hospital stay of 104 renal-transplant recipients (72 men and 32 women). We also measured ABP in 32 of these patients. We analyzed the data by calculating the activity ratio of each day's test value to the previous day's result and optimized the sensitivity (SN) and specificity (SP) to determine the optimal ratio for each test. The results indicate that cyclosporine treatment reduces the optimal sensitivity and specificity of these tests. Three comparable tests (ABP, GGT, and AAP) yield the best optimal values (SN = 0.77, 0.69, 0.77; and SP = 0.71, 0.74, 0.63, respectively), and the NAG test yields the lowest combination of sensitivity and specificity (SN = 0.62, SP = 0.66). All four tests were less sensitive and specific than the plasma creatinine test (optimal day-to-day difference = 5 mg/L). However, the ABP and AAP tests gave indications of rejection at least 24 h before clinical diagnosis for 50% of the patients experiencing rejection, while early plasma creatinine increases of 5 mg/L occurred in only 19% of this group.
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PMID:Indicators of acute renal-transplant rejection in patients treated with cyclosporine. 233 86

We measured urinary levels of total protein, N-acetyl-beta-D-glucosaminidase (NAG), alanine aminopeptidase, and adenosine deaminase-binding protein in ten children with osteogenic sarcoma who were receiving combination chemotherapy that included 12 doses of methotrexate (12 g/m2). Analysis of the changes in these sensitive markers of renal tubular damage permitted detection of subclinical methotrexate-induced nephrotoxicity. In the absence of cisplatin, methotrexate therapy was associated with significant but transient increases in each of the four markers. Irreversible nephrotoxicity, indicated by persistent rises in NAG and alanine aminopeptidase as well as increased serum creatinine levels, was associated with doses of methotrexate that followed the administration of cisplatin (400 mg/m2). The biphasic pattern of total protein and NAG excretion observed in all patients suggests more than one mechanism of methotrexate-induced nephrotoxicity. Monitoring renal tubular damage in patients who are receiving methotrexate in combined-drug regimens would provide useful information for scheduling nephrotoxic drugs in clinical trials.
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PMID:Enhancement of methotrexate nephrotoxicity after cisplatin therapy. 287 29

The authors evaluated measurements of adenosine deaminase binding protein (ADB), a proximal renal tubular cell antigen, for detection of drug-induced tubular nephrotoxicity. Concentrations of ADB were determined immunochemically in serial urine specimens from 12 children who were receiving chemotherapy for malignant solid tumors. There was no indication of increased ADB excretion after administration of two nonnephrotoxic drugs, etoposide and doxorubicin, but in patients given the recognized nephrotoxins, cisplatin and methotrexate, or an investigational drug, ifosfamide, urinary concentrations of ADB increased greater than fivefold relative to baseline values. Increased ADB concentrations preceded cisplatin- or ifosfamide-induced elevations of serum creatinine. Results of the ADB assay correlated well with those obtained by enzymatic assays for N-acetyl-beta-D-glucosaminidase and alanine aminopeptidase (r = 0.76 and 0.53; n = 142, P less than 0.001) and marginally with total proteinuria (r = 0.21; P less than 0.02). Hence, serial ADB measurements may be useful in screening investigational drugs for acute subclinical nephrotoxicity.
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PMID:Cancer chemotherapy-induced tubular nephrotoxicity evaluated by immunochemical determination of urinary adenosine deaminase binding protein. 287 4

We have identified seven adenine nucleosides in urines of untreated adenosine deaminase (ADA) deficient patients, four of which (adenosine, 2'-deoxyadenosine, 1-methyladenosine and N6-methyladenosine) have been previously identified in urines of normals and/or ADA deficient patients. We confirm that ADA deficient patients excrete markedly increased amounts of 2'-deoxyadenosine (582 +/- 363 versus normal of less than 0.1 nmoles/mg creatinine) and increased amounts of adenosine (29.4 +/- 5.7 versus normal of 4.12 +/- 1.0 nmoles/mg creatinine). We have found three modified adenine nucleosides previously undetected in human urine. These three compounds are 2'-O-methyladenosine, N6, 2'-O-dimethyladenosine and an as yet incompletely characterized modified adenine nucleoside, R-adenosine. Only ADA deficient patients excrete detectable amounts of 2'-O-methyladenosine (2.1 +/- 1.1 versus normal of less than 0.1 nmoles/ mg creatinine), whereas both normals and ADA deficient children excrete N6, 2'-O-dimethyladenosine and R-adenosine. However, ADA deficient patients do excrete increased amounts of R-adenosine (5.5 +/- 1.0 versus normal of 1.4 +/- 0.4 nmoles/mg creatinine).
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PMID:Increased excretion of modified adenine nucleosides by children with adenosine deaminase deficiency. 698 Mar 97

In a child lacking adenosine deaminase and in patients treated with deoxycoformycin (a potent inhibitor of the enzyme), apparent renal secretion of 2'-deoxyadenosine (dAdo) and reabsorption of adenosine (Ado) were observed. The renal clearance of dAdo in humans was approximately five-fold that of creatinine, whereas the renal clearance of Ado was only one-fifth that of creatinine. In mice treated with deoxycoformycin, a similar paradigm was observed. Specifically, plasma levels of Ado and dAdo were elevated to detectable levels and apparent renal secretion and reabsorption of these purine nucleosides became manifest. Thus, the mouse may serve as a suitable model to study the renal handling of these two compounds. The active renal secretion of dAdo may occur because the compound has not been appreciably synthesized by mouse kidney in situ, and 'ion-trapping' of dAdo in acid urine could not explain the net secretion. The differential transport of these similar purine nucleosides suggests a very selective transport system in mammalian kidney. Although carrier-mediated, facilitated diffusion of purine nucleosides across cell membranes is a well-known ph enomenon, the present data indicate the existence of (an) active transport system(s) for the transepithelial secretion of dAdo, and possibly for the reabsorption of Ado.
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PMID:Renal handling of 2'-deoxyadenosine and adenosine in humans and mice. 698 Jul 41

To delineate the extent to which bone marrow transplantation provides "enzyme replacement therapy", we have determined metabolite concentrations in two patients with adenosine deaminase (ADA) deficiency treated with bone marrow transplants and rendered immunologically normal. 10 yr after engraftment of lymphoid cells, erythrocyte deoxy ATP was markedly decreased compared to the marked elevations of deoxy ATP observed in untreated patients, but was still significantly elevated (62 and 90 vs. normal of 6.0 +/- 6.0 nmol/ml packed erythrocytes). Similarly, deoxyadenosine and adenosine excretion were both markedly diminished compared to that of untreated patients but deoxyadenosine excretion was still clearly increased (20.1 and 38.6 vs. normal of less than 0.2 nmol/mg creatinine) while adenosine excretion was in the upper range of normal (7.0 and 8.1 vs. normal of 5.6 +/- 3.6 nmol/mg creatinine). Mononuclear cell deoxy ATP content was also elevated compared to normal (5.25 and 14.4 vs. 1.2 +/- 0.3). Separated mononuclear cells of bone marrow transplanted patients contain both donor lymphocytes and recipient monocytes. When mononuclear cells were depleted of the cells enriched for donor lymphocytes (i.e. monocyte depleted) was lower than that of the mixed mononuclear cells (2.2 vs. 5.26). Surprisingly, plasma adenosine was as high as in untreated ADA-deficient patients (3.2 and 1.5 vs. untreated of 0.3-3 microM). Consistent with the elevated plasma adenosine and urinary deoxyadenosine, erythrocyte S-adenosyl homocysteine hydrolase activity was diminished (0.88 and 1.02 vs. normal of 5.64 +/- 0.25). Thus, bone marrow transplantation of ADA-deficient patients not only provides lymphoid stem cells, but also partially, albeit incompletely, clears abnormally increased metabolites from nonlymphoid body compartments.
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PMID:Bone marrow transplantation only partially restores purine metabolites to normal in adenosine deaminase-deficient patients. 703 81

Markers of renal tubular injury were examined in 21 patients (16 male, 5 female, mean age 57.4 years) undergoing cardiac surgery utilising cardiopulmonary bypass. Postoperative urine outputs were very high (200-250 ml/h at 1-2 h), decreasing to 100 ml/h by 6 h. Although creatinine clearances did not vary significantly in the postoperative period (P = 0.16), significant changes were noted in the urinary concentrations of three tubular markers relative to creatinine concentration (P < 0.001). Urinary beta 2-microglobulin increased from negligible levels (median 0.01 mg/mmol creatinine) to peak at 4 h (median 4.55 mg/mmol), in part due to interference with its reabsorption by the plasma volume expander Haemaccel. Concentrations of the brush border antigen adenosine deaminase binding protein increased 6-fold, from a median of 5.03 arbitrary units (AU)/mumol to 31.2 AU/mumol at 48 h. The lysosomal enzyme N-acetyl-beta-D-glucosaminidase increased nearly 4-fold, from 0.68 units/mmol to 2.64 units/mmol at 48 h. Our results suggest that cardiac surgery utilising cardiopulmonary bypass is associated with acute tubular injury which can occur in the absence of overt changes in creatinine clearance.
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PMID:Tubular nephrotoxicity after cardiac surgery utilising cardiopulmonary bypass. 798 29

The means of measurement of adenosine and deoxyadenosine in urine was developed by separating adenosine and deoxyadenosine from other compounds using high-performance liquid chromatography with column switchings. This method is simple and convenient since no pretreatment of the urine is needed. Using this method, it could be demonstrated that urinary adenosine was higher in an adenosine deaminase (ADA) deficient patient who had a bone marrow transplant treatment (1.97 micromol/mmol creatinine) and in a heterozygote who had a markedly low erythrocyte ADA activity (1% of control ADA activity) (1.33 micromol/mmol creatinine) as compared to normal subjects (0.22+/-0.09 micromol/mmol creatinine, n=11). It was also noted that urinary deoxyadenosine was below the detection limits in the ADA-deficient bone marrow transplant patient, but it was detected in the heterozygote (3.7 micromol/mmol creatinine). Furthermore, it was also demonstrated that a fructose infusion increased the urinary concentration of adenosine from 0.21+/-0.03 to 2.66+/-1.21 micromol/mmol creatinine in five normal subjects.
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PMID:Determination of adenosine and deoxyadenosine in urine by high-performance liquid chromatography with column switching. 986 64


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