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

A one-step micromethod was developed to separate from human serum four different enzymes capable of hydrolysing dTTP to the respective diphosphate. According to the purification procedure, the enzymes are referred to as Fraction I, II, IIIa, and IIIb, respectively. In view of a putative tumor specificity the activities of the enzymes are investigated for five different groups, epithelial carcinoma, leukemia, and three control groups. The results indicate that an absolute tumor specificity could not be attributed to one of the enzyme fractions. The activity of Fraction I is, however, highly elevated in the sera of seriously ill patients, whereas the activity of the epithelial carcinoma and the leukemia is even slightly reduced compared to the blood donor group. These data provide evidence that the determination of Fraction IIIb along with Fraction I can reduce the false positive rate to a great extent.
 ...
PMID:Separation of deoxythymidine-5'-triphosphatase from unspecific hydrolases. A recommended micromethod in the diagnostic evaluation of human carcinoma. 609 28

The cupric and ferric complexes of isonicotinic acid hydrazide (INH) inhibit the DNA synthesis catalysed by avian myeloblastosis virus (AMV) reverse transcriptase. The inhibition was to the extent of 95% by 50 microM of cupric-INH complex and 55% by 100 microM of ferric-INH complex. These complexes have been found to bind preferentially to the enzyme than to the template-primer. Kinetic analysis showed that the cupric-INH complex is a non-competitive inhibitor with respect to dTTP. The time course of inhibition has revealed that the complexes are inhibitory even after the initiation of polynucleotide synthesis. In vivo toxicity studies in 1-day-old chicks have shown that the complexes are not toxic up to a concentration of 500 microgram per chick. Infection of the 1-day-old chicks with AMV pretreated with 150 microgram of either of the complexes prevented symptoms of leukemia due to virus inactivation.
 ...
PMID:Inhibition of avian myeloblastosis virus reverse transcriptase and virus inactivation by metal complexes of isonicotinic acid hydrazide. 618 90

Trimetrexate is a novel lipophilic folate antagonist that causes growth inhibition, inhibition of nucleic acid biosynthesis, and cytotoxicity at nanomolar concentrations in tissue cultures. The potency of trimetrexate cytotoxicity against most cell lines is greater than that of methotrexate. Trimetrexate has antitumor activity in vivo in several murine leukemia and solid tumor systems, including tumors in which methotrexate is inactive. Antitumor activity was seen following oral, intravenous, or intraperitoneal administration. Trimetrexate causes a pronounced and early depression in incorporation of deoxyuridine into DNA. In tumor cell lines resistant to methotrexate because of a drug transport defect, trimetrexate retains activity. In many such cases the methotrexate-resistant tumors show collateral sensitivity to trimetrexate. In methotrexate-resistant cells with impaired drug transport, trimetrexate sensitivity was even more pronounced when cells were grown in folate-free medium supplemented with physiological levels of tetrahydrofolate cofactor. In the human tumor stem cell colony assay, trimetrexate, at concentrations achievable in vivo, gave activity against many human tumors, including samples that were unresponsive to methotrexate. Trimetrexate crosses the blood-brain barrier, and at very high doses may cause neurotoxicity. At conventional doses the primary toxic effects in mice are gastrointestinal. This toxicity is reversible at therapeutic doses. Unlike earlier lipophilic antifolates, trimetrexate has rapid plasma clearance (t1/2 in mice of 45 minutes). Trimetrexate is a tight-binding competitive inhibitor of dihydrofolate reductase. The Ki,slope for inhibition of the human enzyme was 4 X 10(-11) M. A dose-dependent decrease in cellular purine ribonucleotide pools is given by trimetrexate. Pyrimidine ribonucleotide pools tend to increase in treated cells. Trimetrexate caused a marked depression of cellular pools of dTTP and dGTP, and a lesser depression in dATP. Cytotoxicity of trimetrexate in vitro was prevented by leucovorin. Leucovorin also protected mice from trimetrexate toxicity. Thymidine protected cells from lethal effects of low concentrations of trimetrexate, but not from high concentrations. The combination of thymidine and hypoxanthine completely protected cells from low and high concentrations of trimetrexate. A new, stable and highly water-soluble formulation of trimetrexate has been developed. Because of the interesting biochemical and pharmacological properties of trimetrexate, and its experimental antitumor activity, clinical trials are planned.
 ...
PMID:Biochemical pharmacology of the lipophilic antifolate, trimetrexate. 623 75

Deoxycytidylate deaminase has been highly purified (1232-fold) from human leukemia CCRF-CEM cells. The native molecular weight of the enzyme is 108 000 and subunit molecular weight 50 500, suggesting that the native enzyme exists as a dimer. The enzyme exhibits a sigmoidal initial velocity vs substrate concentration curve and is regulated by allosteric effectors, dCTP and TTP. The curve relating substrate concentration to initial velocity was changed from a sigmoidal shape to a hyperbolic one by the activator dCTP, while the inhibitor TTP increased the sigmoidicity of the curve. The molecular weight of deoxycytidylate deaminase was unchanged in the presence of allosteric effectors, indicating that aggregation-disaggregation is not the basis of regulation. Deoxycytidylate deaminase exhibited the greatest affinity for the substrate dCMP, with lesser affinity for ara-CMP, and least affinity for CMP. Ara-CMP was an effective substrate in the presence of dCTP concentrations exceeding 4 microM. These data indicate that human neoplastic cell deoxycytidylate deaminase is a highly regulated allosteric enzyme, which is likely to have a significant influence on cellular dUMP, dCTP and TTP pools. These findings further suggest, that the enzyme through its influence on dUMP levels is likely to modulate the biochemical effects of pyrimidine antimetabolites active against the thymidylate synthetase reaction and in the presence of elevated dCTP pools will promote deamination of ara-CMP to the inactive ara-UMP.
 ...
PMID:Kinetic behaviour and allosteric regulation of human deoxycytidylate deaminase derived from leukemic cells. 658 81

The toxicity of the deoxyribonucleosides, 2'-deoxyadenosine, 2'-deoxyguanosine, and thymidine, for human T lymphoblasts is mediated by the accumulation of the corresponding deoxyribonucleoside triphosphate (dATP, dGTP, or dTTP, respectively). We have examined whether leukemic cells of non-T-cell origin are capable of accumulating deoxyribonucleotides in culture and whether this capability correlates with the activities of purine metabolizing enzymes in these cells. We have found that non-T, non-B acute lymphoblastic leukemia cells with low ecto-5'-nucleotidase and high adenosine deaminase activities increase their dATP pools by greater than tenfold when exposed to deoxyadenosine and an inhibitor of adenosine deaminase in culture. Cells from 2 of 9 patients with chronic lymphocytic leukemia and 4 of 11 patients with acute nonlymphoblastic leukemia achieved similar elevations in dATP, but there was no relationship between dATP accumulation and adenosine deaminase, purine nucleoside phosphorylase, or ecto-5'-nucleotidase activities. Treatment of four individuals with acute lymphoblastic leukemia with the adenosine deaminase inhibitor, 2'-deoxycoformycin, resulted in elevations in plasma deoxyadenosine concentrations and in increments in lymphoblast dATP levels that were similar to those measured in lymphoblasts cultured with deoxyadenosine and deoxycoformycin prior to treatment. In vitro incubations of leukemic cells with deoxyribonucleosides may provide a rational basis for the use of these compounds as chemotherapeutic agents.
 ...
PMID:Deoxyribonucleoside triphosphate accumulation by leukemic cells. 660 41

Procoagulant activity of gastric cancer tissues and leukocytes obtained from various types of leukemia have been studied with special reference to TTP. The following results were obtained. Homogenates of APL leukocytes and gastric cancer tissues contained strong procoagulant activities, most of which have been identified as TTP since the activities were neutralized by a specific antibody against purified human placenta TTP, inactivated by the removal of phospholipid with heptane-butanol mixture, and inactivated by the addition of phospholipase C. The delipidated homogenates regained procoagulant activities by relipidation procedures. These results also confirmed that TTP from APL leukocytes and gastric cancer tissues have the same lipoprotein properties as those of TTP in normal tissues. Though slight proteolytic activity and fibrinolytic activity were demonstrated in the homogenate of gastric cancer tissues, it was noted that the TTP activity was different from these two activities by partial purification of TTP from gastric cancer tissues. The TTP activity of 9 homogenates of gastric cancer tissues was 301 +/- 289 (mean +/- SD) units per mg protein, being higher in homogenates of mucinous adenocarcinoma and signet-ring cell carcinoma than in those of tubular and poorly differentiated adenocarcinoma. The mean TTP activity of leukocyte homogenates from 14 patients with APL and one out of 4 patients with CML in blastic crisis was 81 +/- 76 units/10(7) cells. The TTP activity of the homogenates of leukocytes from 7 out of 18 patients with AML and another patient with CML in blastic crisis ranged from one to six units/10(7) cells with a mean of 3.3 +/- 1.2. The TTP activity of leukocyte homogenates from the other 11 cases of AML, two cases of CML in blastic crisis, 6 cases of CML, and one case each of ALL and CLL were less than one unit/10(7) cells. In leukemic patients, all cases with a value of more than 202 for the product of units of TTP activity per 10(7) cells and differential count (%) of leukemic cells in the bone marrow smear (MU value) were accompanied by DIC. The MU value of leukemic patients correlated well to the plasma fibrinogen and serum FDP levels. All patients with a MU value of more than 277 died of DIC when a sufficient amount of heparin was not administered. On the other hand, no DIC developed in any of the patients with a MU value of less than 90.(ABSTRACT TRUNCATED AT 400 WORDS)
 ...
PMID:The role of tissue thromboplastin in the development of DIC accompanying neoplastic diseases. 666 48

We studied the ability of 2'-deoxyguanosine (dGuo) to influence 1-beta-D-arabinofuranosylcytosine (ara-C) inhibition of soft agar cloning of the cultured human leukemia cell line K562. Ara-C alone inhibited cloning in concentrations of greater than 10 nM, with a steep drop in colony formation observed between 10 and 100 nM. dGuo and ara-C synergistically inhibited cloning; the combination of ineffective concentrations of dGuo (10-50 microM) and ara-C (less than or equal to nM) inhibited cloning by 40-70%. In K562 cells, dGuo is metabolized by both nucleoside kinase and purine nucleoside phosphorylase (PNP), resulting in augmentation of both the GTP pool (to more than 200% of control after a 3 hr incubation with 500 microM dGuo) and the dGTP pool (to more than 2700% of control after 3 hr with 500 microM dGuo). dGuo (50-500 microM) caused a decrease in the dCTP and dTTP pools and an increase in the dATP pool. Synergistic concentrations of dGuo plus 10 nM ara-C augmented the ara-CTP pool up to 800% of control after 3 hr to levels equivalent to those observed after incubation with 500 nM ara-C alone. Incorporation of 10 nM ara-CTP into DNA also increased in the presence of dGuo (up to a maximum of 300% of control), but only to a level that approximated the value observed with nM ara-C alone. The disparity between enlargement of the ara-CTP pool and augmentation of ara-C incorporation into DNA is consistent with the observation of Steinberg et al. [Cancer Res. 39, 4330 (1979)] that high concentrations of dGTP may inhibit DNA polymerase activity. Thus, synergy between dGuo and ara-C is multifactorial, possibly involving inhibition of DNA polymerase by elevated dGTP and ara-CTP pools and augmented incorporation of ara-C into DNA.
 ...
PMID:Synergistic inhibition of human leukemia cell growth by deoxyguanosine and 1-beta-D-arabinofuranosylcytosine. 671 15

Biochemical studies suggested that leukemia T-cells have low levels of TTP-catabolizing enzyme activity and are uniquely sensitive to thymidine (dThd). A child with T-cell acute lymphocytic leukemia (ALL), whose peripheral blood lymphoblasts manifested very low TTP catabolic capacity, was treated with 75 g dThd/m2/day by constant iv infusion for two courses of 5 and 8 days. The dThd caused an initial accumulation of peripheral blood blasts in S-phase at the expense of cells in G1, followed by a rapid reversal of this pattern consistent with a block in late G1 and/or early S. Concurrently, a prompt reduction of blasts was found in the peripheral blood. However, dThd treatment neither decreased the number of lymphoblasts in the cerebrospinal fluid (CSF) nor cleared the marrow. No major toxicity was observed, but the effect of dThd on normal marrow elements could not be evaluated in this patient. Blood concentrations of dThd were 1.4-3.0 mM, and concentrations of thymine were in the same range; beta half-life for dThd was 48 minutes. Steady-state CSF dThd was 9% of the simultaneous serum level. Clearance measurements demonstrated that catabolism of dThd was saturated and that renal clearance was a major determinant of total body clearance during high-dose dThd infusion. A good correlation was found between biochemical and cytokinetic parameters and response to dThd for the peripheral blood lymphoblasts. However, dThd did not produce a useful remission in this case of T-cell ALL.
 ...
PMID:Thymidine as a chemotherapeutic agent: pharmacologic, cytokinetic, and biochemical studies in a patient with T-cell acute lymphocytic leukemia. 696 27

Alteration of purine metabolism using adenine was studied in mouse L1210 leukemia cells for its effect on dThd-mediated inhibition of growth and deoxyribonucleotide pool perturbations. Inhibition of cell growth caused by 10 to 50 microM dThd was enhanced more than additively by 100 microM adenine which was only slightly inhibitory when administered alone. Adenine at 100 microM affected ribonucleotide levels by expanding the ATP pool and causing slight decreases in the GTP, UTP and CTP pools, while dThd alone or in combination with adenine had no effect on ribonucleotide pools. dThd at 10 microM caused a more than 2-fold increase in the dTTP pool and a marked but transient decrease in the dCTP pool with lesser effects on purine deoxyribonucleotide levels. Adenine at 100 microM produced only slight, transient increase in the dATP pool. Exposure of cells to dThd plus adenine compared with individual agents produced more than additive increases in dTTP and dATP pools. The decrease in the dCTP level was more with combined agents than with dThd alone. The results showed that an alteration in adenine nucleotide pools modifies the activity of dThd through greater enhancement of dTTP levels leading to a greater suppression of the dCTP pool.
 ...
PMID:Purine modulation of thymidine activity in L1210 leukemia cells in vitro. 714 28

Thymidine kinase (TK)-deficient cells were established from six human leukemia cell lines to evaluate the role of TK in maintaining intracellular TTP pools. The residual TK activities in mutant cells were less than 3% of those of wild-type strains, except for a B-lymphoid cell line, Ball-1 (8.7%). In a promyelocytic leukemia cell line (HL-60), a splenic B cell line (WI-L2) and Ball-1, a mutational loss of TK resulted in a decrease of TTP pools by 80%, 33% and 54%, respectively. On the other hand, in the T cell lines, Molt-3, Molt-4 and CEM, TTP did not show any significant differences between parent and TK-deficient cells. TK-deficient HL-60 cells had, however, comparable levels of dATP, dGTP and dCTP with wild-type cells. An analysis of growth characteristics showed that the decrease of TTP was not due to the change of the cell cycle distribution. These results indicate that TK plays a different role in maintaining TTP pools among human leukemia cell lines.
 ...
PMID:Different effect of thymidine kinase loss on TTP pools; comparison among human leukemia cell lines. 750 73


<< Previous 1 2 3 4 5 6 Next >>