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)

Eight patients with hairy-cell leukaemia (HCL) complicated by pancytopenia were treated with low dose regimens of the adenosine deaminase (ADA) inhibitor 2'-deoxycoformycin (DCF). All patients had significant haematological and clinical improvement. One patient who had been splenectomized and five patients with mild to moderate splenomegaly achieved normal blood counts within 2 months, which have been maintained for up to 18 months. Complete remissions occurred in two patients and four patients had 50-95% marrow clearance of hairy cells. The initial DCF treatments produced a 1-3 g/dl fall in the haemoglobin levels and one patient had a temporary reduction in granulocyte and platelet counts. Five patients had nausea/vomiting, and/or lethargy following DCF, but there was no correlation between the plasma levels of deoxyadenosine and adenosine and the incidence or severity of these side effects. An increased incidence of infection and drug hypersensitivity may reflect the effects of DCF on the immune system. Low dose DCF is a highly effective agent in HCL.
 ...
PMID:The treatment of hairy-cell leukaemia with 2'-deoxycoformycin. 348 71

Five patients from the Kyushu area in Japan with adult T-cell leukaemia (ATL) refractory to conventional chemotherapeutic agents were treated with 5 mg/m2 of the adenosine deaminase inhibitor, 2'-deoxycoformycin (DCF), intravenously (i.v.) for 3 consecutive days, followed by 5 mg/m2 i.v. weekly. Two patients showed a good response, and three were resistant to DCF. One patient with ATL receiving DCF had a continuous remission without further therapy. Another patient in the terminal stage received three daily injections of 7.5 mg of DCF. The most prominent change was the drop in the leucocyte count. The cell count fell from 116.4 X 10(9)/l to 2.0 X 10(9)/l on day 7. The only adverse effects of DCF therapy were gastrointestinal toxicity, nausea and vomiting. These results suggest that DCF may be a valuable drug for treating refractory ATL.
 ...
PMID:Clinical consequences of 2'-deoxycoformycin treatment in patients with refractory adult T-cell leukaemia. 348 40

Simplified Moloney murine leukemia virus-based recombinant retrovirus vectors have been constructed which transduce human adenosine deaminase (ADA) cDNA. ADA transcription is under the control of the constitutive promoter for the human X chromosome phosphoglycerate kinase (pgk) gene. In these simplified vectors, dominant selectable markers are not included and selection is dependent on overproduction of functional ADA enzyme. Primary murine hematopoietic cells were infected with helper-free recombinant ADA virus generated from Psi-2 packaging cells. Protein analysis revealed that human ADA enzyme was expressed in progenitor-derived hematopoietic colonies in vitro and CFU-S-derived spleen colonies in vivo. Enzyme expression was dependent on transcription from the pgk promoter. ADA expression in primary murine hematopoietic cells directed by the internal promoter was not adversely affected by the presence of the Moloney virus long terminal repeat enhancer sequence. Use of these vectors allows systematic evaluation of the effects of specific sequences in recombinant retrovirus vectors on expression in primary murine hematopoietic cells in vivo.
 ...
PMID:Retrovirus-mediated gene transfer of human adenosine deaminase: expression of functional enzyme in murine hematopoietic stem cells in vivo. 368 89

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.
 ...
PMID:Differences in the metabolism and metabolic effects of the carbocyclic adenosine analogs, neplanocin A and aristeromycin. 370 57

Alkylation of adenine (5a) or 2-amino-6-chloropurine (5b) with excess trans-1,4-dichloro-2-butene (4), effected by K2CO3 in dimethyl sulfoxide or tetra-n-butylammonium fluoride in tetrahydrofuran, led in 90-95% regioselectivity to 9-alkylpurines 6a and 6b. The title compounds 2a and 2b were obtained by refluxing intermediates 6a and 6b in 0.1 M NaOH or HCl. Adenine derivative 2a is a substrate for adenosine deaminase whereas both 2a and 2b exhibit 50% inhibition of the growth of murine leukemia L 1210 cell culture at 1 mM concentration.
 ...
PMID:Synthesis and biological properties of 9-(trans-4-hydroxy-2-buten-1-yl)adenine and guanine: open-chain analogues of neplanocin A. 380 25

Previous work has shown that 6-thioguanine (TGua) is an effective inducer of differentiation of Friend and HL-60 leukemia cells which lack hypoxanthine-guanine phosphoribosyltransferase but is at best only weakly active in inducing maturation in parental wild-type cells. Studies in wild-type and mutant HL-60 cells have provided evidence that the free-base TGua is the form of this drug that induces differentiation, while the formation of TGua nucleotides leads to cytotoxicity and inhibits differentiation. To attempt to increase the potential of TGua to serve as an inducer of parental HL-60 leukemia cells, physiological purine and pyrimidine nucleosides were tested for their ability to protect HL-60 cells against TGua-induced cytotoxicity. Adenosine, deoxyadenosine, inosine, and deoxyinosine completely prevented the toxic action of the purinethiol, while guanosine and deoxyguanosine were only partially effective. The capacity of adenosine and deoxyadenosine to prevent the cytotoxicity of TGua was abolished by the inhibitor of adenosine deaminase, deoxycoformycin, implying that inosine and deoxyinosine were the active forms of the protecting agents. The protective activities of inosine and deoxyinosine appeared to depend on phosphorolysis catalyzed by purine nucleoside phosphorylase, since exogenously added hypoxanthine was as effective as inosine in reducing the cytotoxicity of the purine antimetabolite. Accumulation of TGua nucleotides in the acid-soluble fraction of HL-60 cells treated with TGua was significantly decreased by the presence of inosine. Inosine also served under these circumstances as a D-ribose 1-phosphate donor to TGua, as evidenced by its increased conversion to 6-thioguanosine. The prevention of the cytotoxicity of TGua by the simultaneous administration of hypoxanthine or its nucleosides resulted in an expression of the differentiation-inducing properties of TGua in HL-60 cells, as measured by the accumulation of nitroblue tetrazolium-positive cells. These findings support the concept that the processes of cytotoxicity and differentiation are separable events produced by different metabolic forms of the purine antimetabolite.
 ...
PMID:Enhancement of the differentiation-inducing properties of 6-thioguanine by hypoxanthine and its nucleosides in HL-60 promyelocytic leukemia cells. 385 87

Cultured human T-lymphoblastoid cell lines are more sensitive than B-cell lines to 2'-deoxyadenosine in the presence of 2'-deoxycoformycin, a potent inhibitor of adenosine deaminase. This difference is related to the greater efficiency with which T-lymphoblasts accumulate cytotoxic levels of dATP derived from the adenosine deaminase substrate 2'-deoxyadenosine (dAdo). Previous work has shown that differences in dATP accumulation by cultured T- and B-lymphoblastoid cell lines cannot be explained by large differences in the levels of dAdo-phosphorylating or dAdo nucleotide (dAXP)-degrading activities in cytoplasmic extracts of these cells, although it has been proposed that intact B-cell lines may catabolize intracellular dAXP more rapidly than do T-cell lines. To further examine the determinants of dAdo sensitivity in T- and B-lymphoblasts, we have studied dAdo and dAXP metabolism in the human T- and B-cell lines CEM and WI-L2 and in hybrids generated by fusion of these cell lines. The hybrid nature of the fusion products was established by nutritional studies and by analyses of cellular surface antigens, DNA content, and enzymatic activities. We found that WI-L2 X CEM hybrids and another T X B hybrid derived from fusion of the SB human B-cell line with CEM were 30- to 40-fold less sensitive to dAdo and about 10-fold less sensitive to the dAdo analogue 9-beta-D-arabinofuranosyladenine than was CEM, or about as resistant as were their B-cell parental lines. Our studies confirm that CEM avidly accumulates dAXP from dAdo but does not catabolize intracellular dAXP. In contrast, WI-L2, SB, and WI-L2 X CEM and SB X CEM hybrids rapidly degraded intracellular dAXP, which limited their ability to undergo dAXP pool expansion. Expression of dAXP catabolic activity in T X B hybrids behaved as a dominant mechanism, conferring resistance to dAdo- and dAdo-related nucleosides to T X B hybrids. It has been postulated that cell fusion may play a role in the progression of tumors and contribute to diversity among the cells that compose clonal tumors. We have speculated that fusion of a malignant T-lymphoblast with an activated B-cell might be a mechanism for the evolution of drug resistance in acute T-cell leukemia.
 ...
PMID:Determinants of deoxyadenosine toxicity in hybrids between human T- and B- lymphoblasts as a model for the development of drug resistance in T-cell acute lymphoblastic leukemia. 387 67

Both established cell lines and human leukemic cells in circulating blood which were incubated in vitro with 2'-deoxyadenosine (AdR) plus adenosine deaminase inhibitor, 2'-deoxycoformycin (dCF), showed different metabolic responses depending upon the histologic and immunologic types of leukemia. The leukemic T-cell lines in tissue culture were 200-fold more sensitive than B-cell lines to the toxic effect of deoxyadenosine. The increased sensitivity of T-cell lines to AdR plus dCF was associated with the accumulation of deoxyadenosine triphosphate (dATP) in the cells. In established cell lines, an inverse correlation was observed between ED 50 of AdR plus dCF and the relative increase of dATP levels in the cells after the incubation of the cells with AdR plus dCF. In circulating leukemic cells that had been incubated with AdR and dCF, dATP arose in all groups but the correlation was not found between the sensitivity of AdR and the relative dATP accumulation. The failure to find the correlation in patients's leukemic cells may be attributed to the heterogeneity of the response of the blasts to AdR and dCF.
 ...
PMID:Differential sensitivity of leukemic cells to growth inhibition by deoxyadenosine and deoxycoformycin. 387 63

Chronic lymphocytic leukemia and prolymphocytic leukemia of the B-cell immunophenotype are closely related disorders, but differ in their cytomorphologic and clinical features. In an attempt to differentiate further between these two forms of leukemia, we measured adenosine deaminase and purine nucleoside phosphorylase activities by using a linked-enzyme spectrophotometric assay on peripheral-blood leukemic cells from seven patients with chronic lymphocytic leukemia, three patients with prolymphocytic leukemia, and one patient with prolymphocytoid transformation of chronic lymphocytic leukemia. By using discriminant analysis, we were able to distinguish the two groups only on the basis of purine nucleoside phosphorylase activity (F1,9; p less than 0.001). The purine nucleoside phosphorylase activity in leukemic cells with prolymphocytic cytomorphology was significantly elevated (mean = 58.6 nM/min/mg protein) compared to the activity in leukemic cells with lymphocytic cytomorphology (mean = 25.6 nM/min/mg protein). There was only one patient with chronic lymphocytic leukemia who was assigned to the prolymphocytic leukemia group on the basis of her purine nucleoside phosphorylase activity. Our study suggests that purine nucleoside phosphorylase activity in leukemic cells may be useful in the distinction of prolymphocytic leukemia from chronic lymphocytic leukemia, and that it may be an enzymatic marker for the early detection of prolymphocytoid transformation of chronic lymphocytic leukemia.
 ...
PMID:Enzymatic differences between chronic lymphocytic leukemia and prolymphocytic leukemia. 393 67

We have established the DU.528 cell line from the pretreatment leukemia cells of a patient who underwent a T lymphoblastic-to-promyelocytic phenotype conversion during treatment with the adenosine deaminase inhibitor, deoxycoformycin. The cell line and clones obtained from it by limiting dilution have the same karyotype previously found in the patient's pretreatment T lymphoblasts and post-deoxycoformycin treatment promyelocytes. DU.528 cells in continuous culture for greater than 2 yr display a predominant undifferentiated T lymphoblastoid phenotype. These cells spontaneously generate progeny of at least three lineages, T lymphoid, granulocytic/monocytic, and erythroid. The surface marker most consistently expressed by DU.528 cells in the undifferentiated state is the 3A1 antigen, which has been found on prothymocytes in the embryonic thymus. Some undifferentiated DU.528 cells also expressed the IL-2 receptor, but no other T cell differentiation antigens. Exposure of DU.528 cells to a variety of agents induced myeloid maturation; adenosine and deoxyadenosine, in the presence of deoxycoformycin, induced expression of myeloid differentiation antigens. Our results suggest that DU.528 is a lymphohematopoietic stem cell line and support the hypothesis that differentiation of pluripotent stem cells may be altered by genetic deficiency of adenosine deaminase. DU.528 cells may provide a useful model for examining factors that regulate stem cell proliferation and differentiation.
 ...
PMID:Establishment of the DU.528 human lymphohemopoietic stem cell line. 405 59


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