Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.5.1.4 (deaminase)
 5,113 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Thirteen experimental mouse neoplasms were tested by cytidine (CR)-deaminase and deoxycytidine (dCR)-kinase levels. Four neoplasms, Sarcoma T241, Adenocarcinoma E0771, Lewis lung carcinoma (LL), and Sarcoma 180 Japan (S180J), considered to have high deaminase and sufficient dCR-kinase activities, were tested in vivo for combination chemotherapy with cytosine arabinoside (ara-C) and the CR-deaminase inhibitor, tetrahydrouridine (THU). THU did not significantly improve the growth inhibition of ara-C in a wide range of combinations in T241, E0771, LL, and the solid form of S180J, but more than doubled the survival time of the S180J ascites-bearing animals. Toxicity in the form of weight loss and toxic deaths was observed in some but not all groups, especially at high dosages of ara-C and THU. Tissue distribution of [3H]-ara-C and [14C]-THU in T241-bearing mice revealed an accelerated clearance of ara-C-derived radioactivity under the influence of THU in the tumor and five host tissues, but not in the small intestines. With the exception of the small intestines, clearance of THU-derived radioactivity was faster in all tissues studied compared to the clearance of [3H]-ara-C-derived radioactivity. Intracellular CR-deaminase levels were inhibited significantly, ie, dose dependent, in tumor and host kidney after a single ip injection of THU to E0771--bearing mice. In the solid S180J, with or without simultaneous ip administration of THU, [3H]-ara-C was not converted to 5'-di- and tri-phosphates at all. In mice bearing the ascites form of S180J, [3H]-ara-C was extensively converted to ara-C 5'-di- and tri-phosphates. THU increased both overall ara-C-derived radioactivity and the relative amounts of ara-C 5'-di- and tri-phosphates.
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PMID:Combinations of tetrahydrouridine and cytosine arabinoside in mouse tumors. 58 1

The cellular metabolism of 3'-amino-2',3'-dideoxycytidine (3'-NH2-dCyd), a cytotoxic agent previously reported to be a poor substrate for purified Cyd/dCyd deaminase (dCydD), was compared with that of cytosine arabinoside (ara-C) in cells that displayed dCydD activity (HeLa) and in cells that did not (L1210). Growth inhibition induced by 3'-NH2-dCyd was dependent on the levels of anabolic enzymes, particularly dCyd kinase (dCydK), whereas cytotoxicity induced by ara-C was dependent on the expression of both anabolic and catabolic enzyme activities. Competition kinetics using purified enzyme revealed that the binding affinity of ara-C to dCydK was 5-fold that of the amino analog. However, this binding advantage is apparently offset in cells that contain high levels of dCydD, since the Ki values for this enzyme were 0.2 and 23 mM for ara-C and 3'-NH2-dCyd, respectively. This was reflected in the decrease in analog sensitivity observed between the two cell lines, whereby the concentrations of ara-C and 3'-NH2-dCyd required to inhibit growth by 50% were 200 and 7 times higher, respectively, in the dCydD-containing HeLa cells as compared with the dCydD-deficient L1210 cells. The metabolic stability and cytotoxicity of 3'-NH2-dCyd was independent of cell number. An unexpected finding was the extent to which the effectiveness of ara-C could be mitigated by the number of dCydD-containing cells. A completely cytotoxic concentration of ara-C was rendered nontoxic by a 10-fold increase in cell number. This observation was supported by an increase in I-beta-D-arabinofuranosyluracil (ara-U) formation, a decrease in ara-C 5'-triphosphate (ara-CTP) accumulation, and a rise in cell viability with increasing cell number. These findings indicate that unlike ara-C, the effectiveness of 3'-NH2-dCyd is independent of the level of deaminase, which suggests its possible utility in situations in which high levels of deaminase are manifest.
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PMID:The role of deoxycytidine-metabolizing enzymes in the cytotoxicity induced by 3'-amino-2',3'-dideoxycytidine and cytosine arabinoside. 131 70