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)

The combination of 2'-deoxyadenosine and deoxycoformycin is known to be markedly toxic to T-lymphocyte cell lines relative to B-cell lines, and this difference appears to be related to the capacity of the cells to accumulate deoxyadenosine triphosphate (dATP). In the presence of dipyridamole and 2'-deoxyadenosine and when adenosine deaminase was inhibited with deoxycoformycin, the L1210 leukemia cell which is a non-T-, non-B-cell type accumulated dATP like a T-cell type. The intracellular L1210 concentration of dATP using the triple combination (1.1 microM deoxycoformycin-40 microM deoxyadenosine-10 microM dipyridamole) reached 400 microM at which concentration ribonucleotide reductase specific activity was reduced by 80%. While this degree of enzyme may be significant, complete inhibition might have been expected, since 400 microM dATP is approximately 40 times the concentration to give 50% inhibition in some purified systems.
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PMID:Dipyridamole enhancement of toxicity to L1210 cells by deoxyadenosine and deoxycoformycin combinations in vitro. 636 51

gamma-L-glutaminyl-4-hydroxybenzene, a stable phenol found in high concentrations in the gill tissue of the common mushroom, Agaricus bisporus, was shown to be capable of selectively inhibiting DNA synthesis in L1210 leukemia cells. Studies with isolated enzymes and permeabilized L1210 cells revealed that this compound inhibits ribonucleotide reductase ( RNR ) but has no effect on DNA polymerase. The results indicated a good correlation between the inhibition of DNA synthesis and the ability of this compound to inhibit RNR . The concentration of glutaminyl-4-hydroxybenzene required to elicit these inhibitory effects has physiological relevance to the gill tissue during the prodromal period of sporulation.
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PMID:Inhibition of ribonucleotide reductase by naturally occurring quinols from spores of Agaricus bisporus. 637 59

Experiments were carried out to test for the presence of "channeling" in L1210 cells. L1210 cells were incubated in culture in the presence of labeled cytidine and "cold" deoxycytidine and conversely, in the presence of labeled deoxycytidine and "cold" cytidine. Cytidine did not inhibit the incorporation of [14C]deoxycytidine into DNA while deoxycytidine decreased the incorporation of [14C]cytidine into DNA. Further, in L1210 cells there was not a coordinate inhibition of thymidylate synthetase when either DNA polymerase was inhibited (aphidicolin) or ribonucleotide reductase was inhibited (hydroxyurea). These data indicate that leukemia L1210 cells do not selectively channel ribonucleotides to DNA through a tightly coupled enzyme complex.
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PMID:Studies directed toward testing the "channeling" hypothesis--ribonucleotides----DNA in leukemia L1210 cells. 643 17

A series of forty 5'-ester derivatives of 5-ethyl-2'-deoxyuridine (EDU) have been evaluated for their inhibitory effects on the growth and metabolism of murine leukemia L1210 cells. Several EDU esters proved as potent as EDU in their inhibitory effects on L1210 cell growth (inhibitory dose-50:5-10 micrograms/ml), suggesting that these esters were readily hydrolyzed to release the parent compound EDU. That the EDU esters had to be hydrolyzed first to EDU was further suggested by the dependence of their antiproliferative action on the thymidine kinase activity of the cells. It was further ascertained that EDU and its esters acquired their antiproliferative effects by an interaction with dCTP biosynthesis, possibly at the CDP ribonucleotide reductase step. Under conditions where thymidine was readily incorporated, we were unable to demonstrate any incorporation of EDU into L1210 cell DNA.
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PMID:Antitumor cell and antimetabolic effects of 5-ethyl-2'-deoxyuridine and 5'-substituted 5-ethyl-2'-deoxyuridine derivatives. 646 97

In four patients with Thy-acute lymphoblastic leukaemia changes in blast cell deoxynucleoside triphosphate concentrations and, in three, changes in blast cell S-adenosyl homocysteine hydrolase activity were measured during treatment with 2' deoxycoformycin, a potent inhibitor of adenosine deaminase. These studies were aimed at identifying the molecular basis of cell killing by this drug. In three patients an increase in blast deoxyadenosine triphosphate (dATP) concentration occurred which was found to be temporally related to cell killing and was accompanied by decreased concentrations of the other three deoxyribonucleoside triphosphates. In the one patient with Thy-ALL who responded poorly to treatment, the increase in dATP concentration was delayed and was not accompanied by a fall in the concentrations of the other deoxyribonucleoside triphosphates. Progressive inactivation of blast cell S-adenosyl homocysteine hydrolase was found to occur in the three patients tested but was maximal only after a substantial reduction of peripheral blast cell count. These results show that 2' deoxycoformycin has a potent cytoreductive effect in Thy-ALL and suggest that the molecular basis of this toxicity is related both to the intracellular accumulation of dATP with inhibition of ribonucleotide reductase. Inactivation of S-adenosyl homocysteine hydrolase may be of importance as an additional mechanism.
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PMID:Studies on the biochemical sequelae of therapy in Thy-acute lymphoblastic leukaemia with the adenosine deaminase inhibitor 2' deoxycoformycin. 697 3

2,3-Dihydro-1H-imidazo[1,2-b]pyrazole (IMPY) is an inhibitor of ribonucleotide reductase and of DNA synthesis selected for clinical trials because of its activity against L1210 leukemia variants resistant to other inhibitors of this enzyme. A phase I trial designated to allow in-depth pharmacologic evaluation has recently been completed and the clinical results and preliminary pharmacokinetic data are reported here. Each patient received IMPY by three different schedules. A single iv bolus, intermittent 5-day bolus, and 5-day continuous infusion were given at 3-week intervals. The major dose-limiting toxic effects were vomiting, rbc hemolysis, confusion, and somnolence. All toxic effects seemed to be dose- and schedule-dependent and were readily reversible. IMPY enters the cerebrospinal fluid and is highly concentrated in gastric secretions. Clearance of IMPY is impaired in the presence of hepatic insufficiency. Eighteen of 26 patients entered are evaluable for response, including one patient with colon cancer with minimal response and three patients with stable disease.
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PMID:Clinical toxic effects of 2,3-dihydro-1H-imidazo[1,2-b]pyrazole (IMPY) with relevant pharmacokinetic parameters. 740 59

Inhibition of cellular DNA synthesis is the major action of gemcitabine. In cells, this drug is converted to its triphosphate (dFdCTP), which is incorporated into DNA and terminates DNA strand elongation. After incorporation of gemcitabine nucleotide into the DNA strand, one more deoxynucleotide is incorporated, and thereafter the DNA polymerases are unable to proceed ("masked chain termination"). Gemcitabine also inhibits DNA synthesis indirectly by decreasing cellular dNTP pools via inhibition of ribonucleotide reductase. Incubation of human leukemia cells (CEM) with gemcitabine leads to apoptotic cell death. Two types of DNA fragmentation were observed in the gemcitabine-treated cells: (1) large-sized double-stranded DNA fragments range from 5 kb to 500 kb with the majority of the fragments located at 50 kb, and (2) nucleosomal-sized DNA fragments. Both types of drug-induced DNA fragmentation were detected in exponentially growing cells and were much more prominent in cells synchronized at S phase. The gemcitabine-induced DNA fragmentation in either synchronized or nonsynchronized cells was inhibited by the DNA synthesis inhibitor, aphidicolin. Thus, incorporation of gemcitabine into DNA is essential to induce DNA fragmentation. The intracellular calcium chelator BAPTA-AM inhibited the drug-induced nucleosomal DNA fragmentation but did not prevent the large-sized DNA fragmentation, suggesting that the nucleosomal DNA fragmentation is a calcium-dependent event, whereas the large-sized DNA fragmentation is independent of calcium. Furthermore, BAPTA-AM did not prevent the morphologic appearance of apoptotic bodies in cells incubated with gemcitabine, indicating that degradation of DNA to nucleosomal fragments is not an essential element of the apoptotic process. Phorbol 12-myristate 13-acetate also inhibited drug-induced nucleosomal DNA fragmentation, but prevented neither large-sized DNA fragmentation nor formation of apoptotic bodies. In contrast, aphidicolin inhibited both types of DNA fragmentation and blocked the formation of apoptotic bodies in the presence of gemcitabine. These data suggest that the generation of large-sized DNA fragments caused by incorporated gemcitabine monophosphate in DNA is critical in gemcitabine-induced apoptosis, whereas nucleosomal DNA fragmentation is not a requirement in this cell death process.
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PMID:Induction of apoptosis by gemcitabine. 748 40

The success of gemcitabine (2',2'-difluorodeoxycytidine; dFdC) resulted in new interest in its purine congeners. Based on the structure-activity relationship studies of catabolism and anabolism, 2',2'-difluorodeoxyguanosine (dFdG) emerged as a lead candidate among the difluoropurine analogs. The cytotoxicity, metabolism, and actions of dFdG on DNA synthesis were studied in the human leukemia lymphoblastoid line CCRF-CEM. The IC50 values of dFdG after a 72-hour continuous incubation were 0.01, 0.03, and 0.28 mumol/L for CCRF-CEM, K562, and HL-60 cells, respectively. A cell line deficient in dCyd kinase was equally sensitive to dFdG, suggesting that, in contrast to dFdC, dFdG may be activated by other deoxynucleoside kinase(s). Consistent with these data, coincubation with dGuo spared the dFdG-mediated toxicity; however, up to 500 mumol/L dCyd failed to reverse the toxicity of dFdG. These observations indicated that dGuo kinase, which phosphorylates arabinosylguanine, also appears to play a major role in activating dFdG. CCRF-CEM cells incubated with varying concentrations of [3H]dFdG accumulated dFdGTP in a dose-dependent manner; a 3-hour incubation with 1 mmol/L dFdG resulted in more than 600 mumol/L intracellular dFdGTP. This is in contrast to the gemcitabine triphosphate accumulation, which is saturated at 10 to 20 mumol/L of exogenous dFdC. dFdG metabolites affected ribonucleotide reductase, resulting in a lowering of the dCTP pool; this is in agreement with the effect of dFdC on dNTP pools in leukemia cell lines. The major effect of dFdG on macromolecular synthesis was inhibition of DNA synthesis. DNA primer extension over a defined template revealed that dFdGTP was a good substrate for DNA polymerase alpha and incorporated opposite C sites of the template. Unlike arabinosyl analogs, but similar to gemcitabine triphosphate, dFdGTP incorporation caused DNA polymerase to pause after one normal deoxynucleotide was incorporated beyond the analog. The unique activation requirements of dFdG, its novel mode of inhibition of DNA synthesis, and its potent toxicity to human leukemia cells make it a promising new antimetabolite.
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PMID:Difluorodeoxyguanosine: cytotoxicity, metabolism, and actions on DNA synthesis in human leukemia cells. 748 47

2-Chloro-9-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)adenine (Cl-F-ara-A) is a new deoxyadenosine analogue that is resistant to phosphorolytic cleavage and deamination. Studies with a variety of cell lines demonstrated that Cl-F-ara-A is a potent cytotoxic agent; in cell-free systems, its triphosphate (Cl-F-ara-ATP) inhibited DNA polymerase alpha and ribonucleotide reductase. To further characterize its mechanism of cytotoxicity, the present study investigated the cellular metabolism of Cl-F-ara-A and the actions of its nucleotide metabolites in human T-lymphoblast leukemia CCRF-CEM cells. The mono-, di-, and triphosphates of Cl-F-ara-A accumulated in cells, with the monophosphate as its major metabolite. After washing cells into drug-free medium, the elimination of each Cl-F-ara-A nucleotide was nonlinear with a prolonged terminal phase. Incubation of CCRF-CEM cells with Cl-F-ara-A resulted in the incorporation of Cl-F-ara-AMP into DNA; a much lesser amount was associated with RNA, suggesting that Cl-F-ara-A is a more DNA-directed compound. The site of Cl-F-ara-AMP in DNA was related to the ratio of the cellular concentrations of the analogue triphosphate and the natural substrate dATP. At low Cl-F-ara-ATP:dATP values, incorporation was mainly in phosphodiester linkages at internal sites, whereas at higher Cl-F-ara-ATP:dATP values, Cl-F-ara-AMP was principally detected at terminal sites. Clonogenicity assays showed a strong inverse correlation between cell survival and Cl-F-ara-AMP incorporation into DNA. These results suggest that the incorporation of Cl-F-ara-A monophosphate into DNA is critical for the cytotoxicity of Cl-F-ara-A.
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PMID:Metabolism and actions of 2-chloro-9-(2-deoxy-2-fluoro-beta-D- arabinofuranosyl)-adenine in human lymphoblastoid cells. 754 Sep 50

The synthesis of a new series of pyridine-2-carboxaldehyde thiosemicarbazones (HCTs) that have amino groups in the 3- and 5-positions has allowed the comparison of the structure/function relationships with regard to inhibition of ribonucleotide reductase activity, L1210 cell growth in culture and L1210 leukemia in vivo. 3-Aminopyridine-2-carboxaldehyde thiosemicarbazones are more active than the corresponding 3-hydroxy-derivatives. The 3-amino-2-pyridine carboxaldehyde thiosemicarbazones were also more active then the 5-amino-2-carboxaldehyde thiosemicarbazones in inhibiting ribonucleotide reductase activity and L1210 cell growth in culture and in vivo. N-Acetylation of the 3-amino derivative resulted in a compound that was much less active both in vitro and in vivo; N-acetylation of the 5-amino derivative did not alter the in vitro inhibitory properties, but did eliminate the antitumor properties in vivo. When the most active HCTs were studied in more detail, it was found that the incorporation of [3H]thymidine into DNA was inhibited completely without the inhibition of [3H]uridine incorporation into RNA. Further, the conversion of [14C]cytidine to deoxycytidine nucleotides and incorporation into DNA was inhibited by the HCTs without an effect on the incorporation of cytidine into RNA. These data support the conclusion that ribonucleotide reductase is the major site of action of these HCTs. The 3-aminopyridine-2-carboxaldehyde thiosemicarbazones emerge as strong candidates for development for clinical trials in cancer patients.
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PMID:Structure-function relationships for a new series of pyridine-2-carboxaldehyde thiosemicarbazones on ribonucleotide reductase activity and tumor cell growth in culture and in vivo. 757 54


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