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)

A limited number of biologically active materials were examined for their relative ability to selectively inhibit the replication of Gross or Rauscher murine leukemia virus (MLV) in Swiss mouse embryo cells by means of the UV-XC plaque-reduction assay. Among the compounds demonstrating significant antiviral activity against Gross MLV in vitro were 1-(4-fluorobenzyloxy) adenosine (FBAR), polyadenylic acid [poly(A)], the carbocyclic analogue of 6-methylthiopurine ribonucleoside (C-MeMPR), 3-(2,4-dinitrophenylhydrazonemethyl)rifamycin SV (AF/DNFI), and phosphonoacetic acid (PAA). Five compounds that exhibited significant antiviral activity against MLV in vitro were tested for similar activity against Rauscher MLV in vivo. Three of these selected compounds, pyrazofurin (pyrazomycin), ribavirin (Virazole), and 9-beta-D-arabinofuranosyladenine (ara-A), produced a significant (50%-100%) inhibition of virus-induced splenomegaly development in mice, whereas the other two candidate inhibitors, 3-deazauridine (deazaUR) and rifamycin SV, the other two candidate inhibitors, 3-deazauridine (deazaUR) and rifamycin SV, failed to demonstrate any in vivo activity in this 21-day leukemogenesis assay. The administration of an inhibitor of adenosine deaminase (Co-vidarabine) in combination with ara-A resulted in an enhanced antiviral response in both infected cell cultures and animals. Co-vidarabine also increased the potency of ara-AMP against Gross MLV in vitro, indicating the probable dephosphorylation of the compound to ara-A and its subsequent deamination to ara-H in this system.
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PMID:Selective inhibition of RNA tumor virus replication in vitro and evaluation of candidate antiviral agents in vivo. 28 Jan 46

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

Ara-C at very low dosage has been reported to decrease the host toxicity of ara-AMP or ara-A in combination with 2'-deoxycoformycin, a potent adenosine deaminase inhibitor, while increasing the toxicity to intracerebral L1210 leukemia. The possibility of increasing the selectivity of ara-A by prior administration of ara-C is explored. The importance of deoxynucleoside kinases, some of which may be cancer-induced, in obtaining selective anticancer effects is discussed. The possibility of a conformational basis for the differing degrees of selectivity and activity of various novel arabinosyl nucleosides is evaluated. The levels of cyclic nucleotides, which have opposing effects on leukemia, may possibly be manipulated to interfere with the growth of cancer cells. Approaches to minimizing major metabolic distortions, such as the progressive accumulation of dATP associated with the use of potent adenosine deaminase inhibitors and which limit the therapeutic effects of ara-A, are proposed.
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PMID:Biochemical and biophysical approaches to improving the anticancer effectiveness of Ara-adenine. 629 45