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)

Growth of human hematopoietic cell lines showed a 100-fold range of sensitivity to inhibition by 2-chloro-2'-deoxyadenosine (CldAdo), with highly sensitive lines in all three groups: T-lymphoblastic, B-lymphoblastic, and non-T, non-B. Formation of nucleotides from [8-3H]CldAdo was investigated in ten lines. In cells exposed to 0.15 microM CldAdo, CldAdo 5'-phosphate (CldAMP) reached 0.7-14 microM and CldAdo 5'-triphosphate (CldATP) reached 0.05-6 microM in 1 h. In most cases these nucleotide concentrations at 1 h were close to the steady-state concentrations, and the latter concentrations were approximately proportional to extracellular CldAdo concentration. On removal of extracellular CldAdo, intracellular CldAMP and CldATP declined rapidly with half times of 0.56-0.9 and 0.64-1.46 h, respectively. There was no correlation between these rates of catabolism and steady-state levels. The different sensitivities of the lines to CldAdo is explained only in part by the different steady-state concentrations of CldATP, and must be more directly related to differential effects on target enzymes. Mice inoculated with L1210 leukemia were treated with 2-bromo-2'-deoxyadenosine (BrdAdo) paired with one of 18 other therapeutic agents. Eight of the drugs paired with BrdAdo gave therapeutic responses from the combination greater than the sum of the responses of members of the pair. They included alkylating agents, antimetabolites blocking deoxyribonucleotide synthesis, and DNA polymerase inhibitors. Toxic dosages of CldAdo caused damage chiefly to the hemic-lymphatic systems and the kidneys.
 ...
PMID:Biochemical pharmacology of 2-chlorodeoxyadenosine in malignant human hematopoietic cell lines and therapeutic effects of 2-bromodeoxyadenosine in drug combinations in mice. 256 29

Two patients showed an unusual serologic response to hepatitis B virus infection during intensive chemotherapy for acute lymphoblastic leukemia. Before treatment, one patient was anti-HBs- and anti-HBc-positive. During intensive chemotherapy these antibodies disappeared and HBsAg and HBeAg became detectable. Twenty months later, still on maintenance chemotherapy, active viral replication with high DNA polymerase levels was present. The second patient developed anti-HBc during the first course of intensive chemotherapy for acute lymphoblastic leukemia. She had anti-HBc and anti-HBe when a bone marrow relapse of the leukemia was diagnosed 3 years later and became HBsAg-positive together with high DNA polymerase levels in the serum while receiving intensive chemotherapy. Clinically no signs of active hepatitis were noted in these patients.
 ...
PMID:Recurrence of hepatitis B in children with serologic evidence of past hepatitis B virus infection undergoing antileukemic chemotherapy. 271 23

Exponentially growing human lymphoblasts (culture LS-2) were separated by cell sorting (FACS II, Becton Dickinson) according to their deoxyribonucleic acid (DNA) content, designating them at particular phases of the cell cycle. Prior to cell sorting the DNA has been fluorochrome-labeled with the Hoechst stain H 33342. Maximum cell enrichments of 94% for G0 + G1 cells, 96% for S cells and 74% for G2 + M cells could be achieved. The enzyme activities of thymidine kinase (TK), thymidylate synthase (TS), DNA polymerase (DNA-P), dihydrofolate reductase (FH2-R), methionine synthase (MS), and hexokinase (HK) were determined in the obtained cell fractions. Although incorporation of 3H-thymidine (3H-dTR) and the 3H-dTR labeling index were significantly inhibited by the dye, no evidence of cell staining's having a significant effect on the enzyme activities was found. The enzyme activities for approximately 100% pure G0 + G1, S, and G2 + M cells were computed. With exception of TK, all the enzymes under study were shown to exhibit activities--although of differing degree--in the G0 + G1, S, and G2 + M cells. No TK activity was shown in G0 and G1 cells; its activity, however, was approximately the same in S and G2 + M cells. This applies likewise for TS which, in contrast to TK, exhibits minor activity in G0 + G1 cells. DNA-P was highly active in G0 + G1 cells, but maximum activity was in S cells. FH2-R exhibited maximum activity in S cells, although the difference in activity between S and G2 + M cells was not significant. None of the observed differences in MS activity was significant, indicating equally high activity in cells of all cell cycle phases. HK activity is approximately twice as high in G2 + M cells as in G0 + G1 cells.
Leukemia 1989 May
PMID:Relation between cell cycle stage and the activity of DNA-synthesizing enzymes in cultured human lymphoblasts: investigations on cells separated according to DNA content by way of a cell sorter. 271 50

An insertion mutation in the pol gene of Moloney murine leukemia virus (M-MuLV) was found to render the virus temperature-sensitive for replication. A provirus containing a 12-bp insertion at the boundary between the reverse transcriptase (RT) and integrase (IN) domains induced the formation of mutant virions containing a partially processed RT-IN fusion protein. Some proteolytic processing to form mature RT and IN was observed at 32 degrees, but only aberrantly processed proteins were detected at 39 degrees. The uncleaved precursor was found to exhibit DNA polymerase activity, even though it could not support replication of the virus in vivo at 39 degrees.
 ...
PMID:An insertion mutation in the pol gene of Moloney murine leukemia virus results in temperature-sensitive pol maturation and viral replication. 278 80

3'-Amino-2',3'-dideoxycytidine (3'-NH2-dCyd) produced an S-phase-specific block in exponentially growing L1210 leukemia cells. The monophosphate and triphosphate forms of the drug were detected within a few hours of 3'-NH2-dCyd treatment of intact cells. No significant change in the deoxynucleoside triphosphate levels was observed during the early stages of treatment. However, by 24 h a 2-fold increase in the amount of the deoxynucleoside triphosphates was seen. The triphosphate form of the drug competitively inhibited dCTP incorporation into calf thymus DNA using highly purified DNA polymerase alpha. The Ki was determined to be 9.6 microM with respect to dCTP. Incorporation of the analogue into DNA was not detected. On the other hand, sucrose gradient analysis suggested that incorporation of the analogue into actively synthesized DNA may account for the biological activity of this compound. Treatment with 3'-NH2-dCyd induced single-strand breaks in actively synthesized DNA, but no double-strand breaks were observed in the presence of the analogue. The data indicate that 3'-amino-2',3'-dideoxycytidine specifically interferes with DNA replication at the level of DNA polymerase by inhibiting chain elongation.
 ...
PMID:Specific inhibition of DNA biosynthesis induced by 3'-amino-2',3'-dideoxycytidine. 324 12

A series of synthetic oligonucleotide primers, annealed at various positions along the lacZ-alpha region of bacteriophage M13mp9 template, were elongated by purified DNA polymerases in the presence of only 3 of the 4 deoxynucleoside triphosphates to achieve misincorporation at a total of 49 different positions along the template. The newly synthesized strands (containing misincorporated bases) were isolated and sequenced to determine the identity of misincorporated deoxynucleoside monophosphates. The results indicate that the kind of mispairing that occurs during DNA synthesis is greatly influenced by the nucleotide sequence of the template. Transition-type base substitutions predominated overall, but at many template positions, transversion-type base substitutions occurred, most commonly via A.A mispairing. The results of parallel determinations made with Escherichia coli DNA polymerase I ("large fragment" form) and DNA polymerase of Maloney murine leukemia virus indicated that, overall, the identity of polymerase had only a small effect on the kind of misincorporation that occurred at different positions along the template. However, at certain template positions, the nature of mispairing during DNA synthesis was reproducibly affected by differing polymerase active-site environment.
 ...
PMID:Influence of DNA sequence on the nature of mispairing during DNA synthesis. 328 88

We have utilized an electrophoretic assay of misincorporation to investigate the possibility that ionization of 5-bromouracil (BU) may play a role in its mispairing during DNA synthesis in vitro. We examined the effects of increasing pH on the relative rates of formation of BU.G and T.G mispairs during chain elongation catalyzed by various DNA polymerases. For the Klenow fragment of Escherichia coli DNA polymerase I, increasing pH facilitated BU.G mispair formation (relative to T.G mispairing) when BU was present in the template strand. This effect showed a strong dependence on sequence context. Increasing pH had little effect on the relative rate of misincorporation of BrdUMP versus dTMP (at template G) by the Klenow polymerase. Misincorporation opposite template BU residues catalyzed by Maloney murine leukemia virus DNA polymerase and DNA polymerase beta (Novikoff hepatoma) also increased with pH, but for these two enzymes, there was no apparent dependence on sequence context. With T4 DNA polymerase and E. coli DNA polymerase III holoenzyme, a similar occurrence of BU.G and T.G mispairing during polymerization was observed, whether BU was present in the template or in the incoming nucleotide, and there was little effect of pH. The results reported here are consistent with a mispairing mechanism for template BU wherein the anionic form of the base mispairs with G.
 ...
PMID:Effect of pH on the base-mispairing properties of 5-bromouracil during DNA synthesis. 328 89

Until recently, lineage fidelity was thought to be preserved in leukaemic cells, which by available tests showed surface markers and enzymatic patterns characteristic of an appropriate normal cell lineage and stage of differentiation. Our data indicate that this theory is too restrictive. If leukaemogenesis occurs in pluripotent progenitors in a relatively high percentage of cases, we would propose a model in which lymphoid and myeloid differentiation antigens are expressed simultaneously until the progenitor cell commits to a single lineage. Lineage commitment could involve external factors, e.g. growth factors (Sherr et al, 1985), that cause genes specific for the opposite lineage to be 'switched off'. The control of gene expression in mammalian cells and the specific chromosomal sites of genes coding for the various lineage-associated markers remain uncertain. However, recent studies indicate that most, if not all, leukaemic cells contain chromosomal abnormalities, many involving rearrangements of DNA (Williams et al, 1986). Since the control of eukaryotic gene expression is known to involve numerous sequence elements, some acting at a distance from the site of transcription (Dynan and Tjian, 1985), genetic perturbations within the cell (e.g. a reciprocal translocation) could be expected to deregulate certain genes, leading to their under- or overexpression analogous to activation of the c-myc oncogene by the 8;14 translocation in Burkitt's lymphoma. Thus, an almost infinite variety of cell lineage-related phenotypes could be expected from this mechanism alone, even if the transforming event did not involve a pluripotent stem cell. Also, we have hypothesized that enzymes such as TdT, a DNA polymerase that catalyses polymerization of deoxyribonucleotides without a DNA template, could serve as a modifier of DNA sequences, permitting otherwise inactive genes to be expressed (Stass and Mirro, 1985). It is interesting that most cases of childhood acute mixed-lineage leukaemia are TdT positive, even though this is not true for the chronic leukaemias of adults. It is now clear that unusual combinations of myeloid and lymphoid cell lineages are much more common in acute leukaemia than have been generally recognized or suspected. The traditional division of the acute leukaemias into ALL and AML may not be the most accurate way to represent this class of haematological malignancies. That mixed-lineage leukaemia may require alternative therapy is a clinically important observation and underscores the need for comprehensive testing of blast cells at diagnosis.(ABSTRACT TRUNCATED AT 400 WORDS)
 ...
PMID:Lineage heterogeneity in acute leukaemia: acute mixed-lineage leukaemia and lineage switch. 353 42

We evaluated a newly developed solid-phase immunoassay (EIA) of terminal deoxynucleotidyl transferase (TdT, EC 2.7.7.3) and compared it with the enzymatic assay of TdT involving DNA polymerase. We assessed the precision, performance characteristics, and clinical efficacy of the EIA procedure, using 249 specimens of peripheral blood and bone marrow and 118 specimens of whole blood. On linear regression analysis of results for these 249 samples as measured by the two procedures, the correlation coefficient was 0.87. Distribution of TdT in mononuclear cells isolated from whole blood and bone marrow of subjects in several disease categories indicated good concordance between the two assay procedures. The EIA procedure is precise, can be performed on whole blood without first isolating mononuclear cells, is nonisotopic, and shows potential as a quantitative indicator for the differential diagnosis and monitoring of human leukemia.
 ...
PMID:Solid-phase enzyme immunoassay of terminal deoxynucleotidyl transferase evaluated. 354

Undifferentiated human lymphoblasts (culture LS-2) were separated according to cell size during their exponential growth phase by way of centrifugal elutriation. The cell fractions thus obtained were characterized in terms of different cell cycle stages by flow cytometric measurement of their deoxyribonucleic acid (DNA histogram), the [3H]thymidine labeling index, and by determining the rate of [3H]thymidine incorporation. In these cell fractions the activities of thymidine kinase, thymidylate synthase, DNA polymerase, dihydrofolate reductase, methionine synthase, and hexokinase were determined. The results showed that all the enzymes investigated exhibited activities in all cell fractions. With the exception of DNA polymerase, all of the enzymes exhibited the lowest level of activity in the fraction containing the highest proportion of G0 + G1 phase cells (fraction 2); the activity of thymidine kinase was particularly low. This would suggest that thymidine kinase is not active in G0 + G1 phase cells and that the activity measured in fraction 2 is perhaps attributable to contamination of this fraction by S and G2 + M phase cells.
Leukemia 1987 Mar
PMID:Relation between cell cycle stage and the activity of DNA-synthesizing enzymes in cultured human lymphoblasts: investigations on cell fractions enriched according to cell cycle stages by way of centrifugal elutriation. 366 41


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>