Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Neplanocin A and aristeromycin are carbocyclic adenosine analogs that differ only in that neplanocin A contains a double bond in the carbocyclic ring, whereas this ring in aristeromycin is saturated. We have compared the metabolism and some of the metabolic effects of neplanocin A and synthetic (+/-)-aristeromycin (C-Ado) in murine leukemia L1210 cells in culture. C-Ado, as shown earlier, was not only converted to its own phosphates but also was metabolized to phosphates of carbocyclic guanosine. Both rapidly proliferating and slowly proliferating or resting cells phosphorylated C-Ado, but C-Ado was not converted to phosphates of carbocyclic guanosine in detectable amounts in cells whose growth had reached a plateau. When the metabolism of neplanocin and C-Ado was examined in the same experiment, both analogs were converted to the triphosphate analogs of ATP; no conversion of neplanocin A to the corresponding carbocyclic analogs of guanine nucleotides was detected, whereas C-Ado was converted to the carbocyclic analog of GTP in amounts that approximated the GTP pool. This difference in metabolism was associated with a marked difference in effects of the two analogs on the utilization of hypoxanthine and guanine which was inhibited by C-Ado but not by neplanocin. The failure of neplanocin A to be converted to analogs of guanine nucleotides apparently is the result of poor capacity of its monophosphate to serve as a substrate for AMP deaminase; the Vmax for deamination of neplanocin-5'-monophosphate by this enzyme was only 5% of that for C-Ado monophosphate. In contrast, neplanocin A was a better substrate than C-Ado for adenosine deaminase.
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PMID:Differences in the metabolism and metabolic effects of the carbocyclic adenosine analogs, neplanocin A and aristeromycin. 370 57

Neplanocin A, a novel antitumor antibiotic, was investigated to determine the biochemical mode(s) of its cytotoxic action. The molecule is an adenosine analogue with a unique cyclopentane structure in its ribose moiety. Both sublines of L1210 and P388 leukemia resistant to neplanocin A were cross-resistant in vitro to bredinin and 9-beta-D-arabinofuranosyladenine, which have been reported to be activated by adenosine kinase. The adenosine kinase activity was markedly reduced in the resistant sublines as compared with that of the respective sensitive lines. Furthermore, neplanocin A competitively inhibited the phosphorylation reaction of adenosine in a cell-free system. The results indicate that neplanocin A is activated by adenosine kinase. Regarding the target site for neplanocin A, the antibiotic suppressed RNA synthesis to a significantly greater extent than DNA synthesis. This RNA-preferential effect is unique among common antimetabolic antitumor agents.
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PMID:Biochemical mode of cytotoxic action of neplanocin A in L1210 leukemic cells. 394 84

Neplanocin A, a novel cyclopentenyl analog of adenosine, is a naturally occurring antibiotic which exhibits significant antitumor activity against L1210 leukemia in mice (Yaginuma, S., Muto, N., Tsujino, M., Sudate, Y., Hayashi, M., and Otani, M. (1981) J. Antibiot. 34, 359-366). In the present study we demonstrate that neplanocin A is also a potent inhibitor of S-adenosylhomocysteine (AdoHcy) hydrolase (EC 3.3.1.1) having a Ki of 8.39 nM for the purified bovine liver enzyme. Analysis of the apparent irreversible inactivation of AdoHcy hydrolase by neplanocin A indicates that the drug is a tight binding inhibitor, exhibiting a stoichiometry of one molecule of inhibitor to one molecule (tetramer) of enzyme. In addition, we show that neplanocin A is a potent inhibitor of vaccinia virus (WR) multiplication in monolayer cultures of mouse L-cells. Concentrations of the drug as low as 0.5 and 1.0 microM in the culture medium produce 84 and 95% inhibition of plaque formation, respectively, while exhibiting little toxicity to the host cells. The inhibition of virus multiplication by neplanocin A coincides with a rapid inhibition of AdoHcy hydrolase activity in the infected cells and a subsequent 10-fold increase in the intracellular AdoHcy/S-adenosylmethionine ratio. These findings suggest that the antiviral actions of this compound may be related to an inhibition of S-adenosylmethionine-dependent macromolecular methylation reactions which are essential to the production of new virus particles (e.g. viral messenger RNA).
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PMID:Neplanocin A. A potent inhibitor of S-adenosylhomocysteine hydrolase and of vaccinia virus multiplication in mouse L929 cells. 670 8

Neplanocin A. C11H13N5O3, is a novel carbocyclic analog of adenosine with cyclopentene. It was isolated from the culture filtrate of Ampullariella regularis A11079 by means of ion-exchange, carbon, silica gel adsorption, or partition chromatography. Neplanocin A forms crystals, and is stable at acidic or alkaline pH. Neplanocin A has cytotoxicity against L5178Y cells in culture and showed a remarkable effect on the life prolongation of mice infected with L1210 leukemia.
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PMID:Studies on neplanocin A, new antitumor antibiotic. I. Producing organism, isolation and characterization. 727 15

Several neplanocin A analogs were synthesized and their growth-inhibiting and differentiation-inducing activities on myelogenous leukemia cells were examined. An adenosine kinase-ineffective analog of neplanocin A was effective in inducing differentiation, suggesting that phosphorylation of the nucleoside is not essential for inducing the differentiation of leukemia cells. Neplanocin A induced functional and morphological differentiation of HL-60 cells, but did not effectively induce differentiation of NB4, a cell line derived from a leukemia patient with t(15;17). However, these cells have been known to undergo granulocytic differentiation upon treatment with all-trans retinoic acid (ATRA), and are used as a model for differentiation therapy in acute promyelocytic leukemia. Preexposure of NB4 cells to low concentrations of neplanocin A greatly enhanced the ATRA-induced differentiation of the cells, whereas representative antileukemic drugs such as cytosine arabinoside and daunomycin did not enhance this differentiation. A clinical strategy that combines intermittent treatment with neplanocin A analogs and a low dose of ATRA may increase the clinical response and decrease the adverse effects of ATRA.
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PMID:Neplanocin A, a potent inhibitor of S-adenosylhomocysteine hydrolase, potentiates granulocytic differentiation of acute promyelocytic leukemia cells induced by all-trans retinoic acid. 935 74

Several adenosine analogs induce the functional and morphological differentiation of myelomonocytic leukemia cells. They can be classified into two types; i.e., those that do/do not require phosphorylation to induce the differentiation of leukemia cells. Neplanocin A, a potent S-adenosylhomocysteine hydrolase inhibitor, induces the differentiation of some leukemia cells without phosphorylation. On the other hand, deoxycoformycin (dCF), a potent adenosine deaminase inhibitor, also induces the myelomonocytic differentiation of leukemia cells when it is treated with deoxyadenosine (dAdo). This differentiation is inhibited by 5'-amino-deoxyadenosine, an inhibitor of (deoxy)adenosine kinase, suggesting that kinase-dependent phosphorylation is involved in the differentiation-inducing effect of dCF plus dAdo. Retinoids induce the differentiation of NB4 cells, a cell line derived from human promyelocytic leukemia. When used in combination with all-trans retinoic acid (ATRA), both NPA and dCF plus dAdo greatly enhance the granulocytic differentiation of NB4 cells. This enhancing effect is greatest when the cells are pretreated with NPA and then with ATRA. On the other hand, pre-exposure of NB4 cells to ATRA greatly potentiates the differentiation induced by dCF plus dAdo, while pretreatment with dCF plus dAdo before exposure to ATRA is less effective. The ATRA-induced differentiation of NB4 cells is effectively augmented by clinically applicable concentrations of these analogs. A clinical strategy that combines intermittent treatment with these analogs and a low dose of ATRA may increase the clinical response and decrease the adverse effects of ATRA.
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PMID:Adenosine analogs as possible differentiation-inducing agents against acute myeloid leukemia. 1043 63