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)

Gemcitabine is a novel antimetabolite drug that acts by multiple mechanisms, including inhibition of ribonucleoside diphosphate reductase, of dCMP deaminase and of dCTP incorporation into DNA and RNA. Here, we report that gemcitabine induces cytotoxic and clonogenic death of 12 human malignant glioma cell lines at clinically relevant concentrations around 1 microM. Gemcitabine is thus approximately 100-fold more active than the congener drug, cytarabine. Gemcitabine cytotoxicity of glioma cells does not require wild-type p53 activity: (i) there was no difference in the susceptibility to gemcitabine between cell lines with wild-type p53 and cell lines with mutant or deleted p53; (ii) ectopic expression of a temperature-sensitive p53 protein either at wild-type (32.5 degrees C) or at mutant (38.5 degrees C) conformation had no significant influence on gemcitabine-induced cell death. Gemcitabine cytotoxicity was unaffected by the antioxidants, N-acetylcysteine and phenyl-N-tert-butyl-alpha-phenylnitrone. There was no correlation between the susceptibility to gemcitabine and the endogenous expression of the B cell lymphoma-2 (BCL-2)-family proteins BCL-2, BCL-XL, myeloid cell leukemia-1 (MCL-1), BCL-2-associated X protein (BAX), BCL-2 homologous antagonist/killer (BAK) and BCL-XS. Ectopic expression of BCL-2 moderately attenuated gemcitabine-induced cell death. Similarly, preexposure to the synthetic steroid, dexamethasone, which is commonly used to control cerebral edema in brain tumor patients, reduced gemcitabine cytotoxicity. We conclude that the clinical evaluation of gemcitabine for the adjuvant chemotherapy of malignant glioma is warranted.
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PMID:Gemcitabine cytotoxicity of human malignant glioma cells: modulation by antioxidants, BCL-2 and dexamethasone. 998 15

Previous studies from our laboratories have shown that (a) Triapine() is a potent inhibitor of ribonucleotide reductase activity and (b) hydroxyurea-resistant L1210 leukemia cells are fully sensitive to Triapine. In an analogous manner, Triapine was similarly active against the wild-type and a hydroxyurea-resistant subline of the human KB nasopharyngeal carcinoma. Triapine was active in vivo against the L1210 leukemia over a broad range of dosages and was curative for some mice. This agent also caused pronounced inhibition of the growth of the murine M109 lung carcinoma and human A2780 ovarian carcinoma xenografts in mice. Optimum anticancer activity required twice daily dosing due to the duration of inhibition of DNA synthesis which lasted about 10 hr in L1210 cells treated with Triapine in vivo. DNA synthesis in normal mouse tissues (i.e. duodenum and bone marrow) uniformly recovered faster than that in L1210 leukemia cells, demonstrating a pharmacological basis for the therapeutic index of this agent. Triapine was more potent than hydroxyurea in inhibiting DNA synthesis in L1210 cells in vivo, and the effects of Triapine were more pronounced. In addition, the duration of the inhibition of DNA synthesis in leukemia cells from mice treated with Triapine was considerably longer than in those from animals treated with hydroxyurea. Combination of Triapine with various classes of agents that damage DNA (e.g. etoposide, cisplatin, doxorubicin, and 1-acetyl-1,2-bis(methylsulfonyl)-2-(2-chloroethyl)hydrazine) resulted in synergistic inhibition of the L1210 leukemia, producing long-term survivors of tumor-bearing mice treated with several dosage levels of the combinations, whereas no enhancement of survival was found when Triapine was combined with gemcitabine or cytosine arabinoside. The findings demonstrate the superiority of Triapine over hydroxyurea as an anticancer agent and further suggest that prevention by Triapine of repair of DNA lesions created by agents that damage DNA may result in efficacious drug combinations for the treatment of cancer.
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PMID:Triapine (3-aminopyridine-2-carboxaldehyde- thiosemicarbazone): A potent inhibitor of ribonucleotide reductase activity with broad spectrum antitumor activity. 1069 63

Complexes containing Ta, Fe, Co, Mo, or W metal centers that are bound to C2B4 or C2B3 small carborane ligands proved to be potent cytotoxic agents in murine and human tissue cultured cells, being more effective in suspended leukemia and lymphomas but surprisingly also effective against the growth of selected solid tumors. These complexes inhibited nucleic acid metabolism, specifically DNA and purine de novo syntheses. Key enzyme activities in nucleic acid metabolism which were inhibited by the complexes were P388 DNA polymerase a, ribonucleotide reductase, dihyrofolate reductase, PRRP-amidotransferase and IMP dehydrogenase. The complexes afforded a moderate amount of DNA-fragmentation in P388 lymhocytic leukemia cells and were moderate inhibitors of human DNA topoisomerase II activity; however, the DNA molecule itself was not a target of the complexes in that there was no evidence that the complexes caused intercalation between base pairs, caused cross-linking of the strands of DNA or alkylated the bases of DNA.
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PMID:Antitumor activity of mono- and dimetallic transition metal carborane complexes of Ta, Fe, Co, Mo, or W. 1095 95

Lithium has been known for its ability to induce the production of hematopoietic cells following administration in vivo to minimize the toxic effects on hematopoiesis as a consequence of drug treatment. The drug hydroxyurea (HU), a ribonucleotide reductase inhibitor, has been used in the treatment of a variety of neoplastic and non-neoplastic diseases, such as cancer and sickle cell anaemia. Hydroxyurea has more recently been implicated for use in the treatment of acquired immunodeficiency syndrome (AIDS). However, its major limitations have been due to its toxicity. Hydroxyurea selectively inhibits DNA synthesis and due to its brief duration, the drug is only toxic to those cells which are selectively synthesizing DNA during the period of exposure. The most important of these toxicities, and which serves as a dose limiting factor in treatment, is the induction of bone marrow suppression. In this study we investigated the possible beneficial effects of administering lithium (LiCl) to murine leukemia virus (MuLV) infected and non-infected long term bone marrow cultures (LTBMC). These cultures were then treated with either 0.2 mM hydroxyurea, 1.0 mM LiCl, or a combination of both. Samples were collected from LTBMC supernatants at 1, 2, 3, 4, 5 and 6 weeks post-treatment. Culture supernatants were then monitored to observe their repopulation of hematopoietic progenitors. The results demonstrated the effects of lithium in restoring hydroxyurea suppressed numbers of myeloid (CFU-GM) progenitors to within a normal range and also in re-establishing erythroid (BFU-E) progenitors.
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PMID:The effects of lithium in reversing hydroxyurea induced suppression of hematopoietic progenitor cells in vitro using retroviral infected long-term marrow cultures. 1100 Aug 67

Trimidox (3,4,5-trihydroxybenzohydroxamidoxime), a recently synthesized inhibitor of ribonucleotide reductase (RR), was shown to exert anti-proliferative activities in HL-60 and K562 human leukemia cell lines and to prolong the life span of mice inoculated with L1210 mouse leukemia cells. Here we test whether trimidox also exhibits anti-neoplastic properties in ovarian carcinoma cells. Since the mode of action of trimidox on cell fate has not been investigated so far, we addressed this unresolved item and find that this polyhydroxybenzoic acid derivative induces apoptosis of N.1 human ovarian carcinoma cells when tested in growth factor deprived medium. Utilizing an improved analysis, based on Hoechst 33258/propidium iodide double staining, apoptosis is quantified and discriminated from necrosis. Trimidox induces c-myc expression, which is indispensible for apoptosis of N.1 cells, and expression of plasminogen activator/urokinase type (upa), which supports the apoptotic process under more physiological conditions. Surprisingly, trimidox does not block dNTP synthesis in N.1 cells at the concentrations tested and, therefore, trimidox induces apoptosis independent of RR-inhibition. Like TNFalpha or benzamide riboside, which are also inducers of apoptosis of N.1 cells, trimidox also down-regulates the G1 cell cycle phosphatase cdc25A, whereas cyclin D1 becomes up-regulated. This report shows that trimidox destroys human ovarian carcinoma cells by inducing them to undergo apoptosis as well as corroborating previous investigations which demonstrated that apoptosis of these cells depends on c-myc over-expression when survival factors are withdrawn.
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PMID:The ribonucleotide reductase inhibitor trimidox induces c-myc and apoptosis of human ovarian carcinoma cells. 1119 20

The rate of ara-cytosine triphosphate (ara-CTP) accumulation and its retention has been correlated with 1-beta-D-arabinofuranosylcytosine (ara-C)-mediated toxicity and clinical outcome in childhood and adult leukemia. We tested to what extent preincubation with the ribonucleotide reductase inhibitors fludarabine (F-ara-A) and hydroxyurea (HU) enhanced ara-CTP levels in two human myeloid (HL-60, CMK) and two lymphoblastic leukemia cell lines (MOLT-4, BLIN-1) and also in blasts from 28 children with acute leukemia (AML: 14, ALL: 14). Incubation experiments carried out with cell lines showed F-ara-A and HU to be equipotent in increasing ara-CTP levels. The highest increase was observed in HL-60 cells whereas preincubation had no modulatory effect in MOLT-4 cells. Accordingly, modulation of intracellular ara-CTP levels differed between the subtypes of childhood acute leukemia: whereas in T-ALL (five) preincubation with F-ara-A and HU had no effect on intracellular ara-C metabolism, increased ara-CTP levels were seen in some cases of pre-B-ALL (seven). In myelogenous blasts (12) clinically relevant enhancement of ara-C toxification was regularly obtained with both, F-ara-A (1.9-fold) and HU (1.5-fold). In conclusion, our data suggest that combinations of ara-C and ribonucleotide reductase inhibitors are apt to increase ara-CTP levels depending on the individual cell type and its sensitivity towards ara-C modulators.
Leukemia 2001 Jan
PMID:Modulation of ara-CTP levels by fludarabine and hydroxyurea in leukemic cells. 1124 2

Transition-state theory has led to the design of Immucillin-H (Imm-H), a picomolar inhibitor of purine nucleoside phosphorylase (PNP). In humans, PNP is the only route for degradation of deoxyguanosine, and genetic deficiency of this enzyme leads to profound T cell-mediated immunosuppression. This study reports the biological effects and mechanism of action of Imm-H on malignant T cell lines and on normal activated human peripheral T cells. Imm-H inhibits the growth of malignant T cell leukemia lines with the induction of apoptosis. Imm-H also inhibits activated normal human T cells after antigenic stimulation in vitro. However, Imm-H did not inhibit malignant B cells, colon cancer cell lines, or normal human nonstimulated T cells, demonstrating the selective activity of Imm-H. The effects on leukemia cells were mediated by the cellular phosphorylation of deoxyguanosine and the accumulation of dGTP, an inhibitor of ribonucleotide diphosphate reductase. Cells were protected from the toxic effects of Imm-H when deoxyguanosine was absent or when deoxycytidine was present. Guanosine incorporation into nucleic acids was selectively blocked by Imm-H with no effect on guanine, adenine, adenosine, or deoxycytidine incorporation. Imm-H may have clinical potential for treatment of human T cell leukemia and lymphoma and for other diseases characterized by abnormal activation of T lymphocytes. The design of Imm-H from an enzymatic transition-state analysis exemplifies a powerful approach for developing high-affinity enzyme inhibitors with pharmacologic activity.
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PMID:Immucillin H, a powerful transition-state analog inhibitor of purine nucleoside phosphorylase, selectively inhibits human T lymphocytes. 1128 38

Mouse leukemia L1210 cells selected for resistance to deoxyadenosine contain ribonucleotide reductase that is not feedback inhibited by dATP. These deoxyadenosine-resistant cells (Y8) also do not express p53 protein but do have WAF1 and Gadd45 mRNA and protein. The Y8 cells show increased sensitivity to DNA damaging agents and kinase inhibitors. In these studies we show that in the presence of sodium salicylate (NaSal), the parental wild-type (WT) cells block in G2/M phase of the cell cycle while the Y8 cells show a marked increased in the G0/G1 population of cells. The Y8 cells are more sensitive to apoptosis induced by NaSal than the WT cells. NaSal treatment causes the induction of caspase-3-like activity in Y8 cells but no induction of caspase-3 activity in the WT cells. The caspase inhibitor, Ac-DEVD-CHO, decreased the percentage of Y8 cells in the early apoptotic fraction, but this decrease was reflected by an increase in the percent of cells in the late apoptotic/necrotic fraction. SB20358, a p38-MAP kinase inhibitor did not protect the Y8 cells from NaSal-induced apoptosis indicating that the p38-MAP kinase pathway was not involved in the NaSal-induced apoptotic pathway in the p53-independent Y8 cells.
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PMID:Increased sensitivity to sodium salicylate-induced apoptosis in drug-resistant leukemia L1210 cells. 1129 31

Published evidence from the U.S. and Europe supports the effect of the anticancer drug hydroxyurea against HIV-1, and its potential synergistic effect with ddl. Approved as an oral chemotherapeutic agent for leukemia and other cancers, hydroxyurea acts as a radical free quencher, inhibiting the cellular enzyme ribonucleotide reductase as well as cellular DNA synthesis during the S phase of the cell division, and it may be through this mechanism that hydroxyurea inhibits tumor cell growth. French scientists at the Centre Leon Bernard in Lyon tested hydroxyurea and a related compound, D-aspartic acid beta-hydroxamate alone and in combination with AZT, ddl, or ddC. Total suppression of viral production and total production against the toxic effects induced by viral replication were demonstrated using the combination of either of the two hydroxamates and ddl after 14 days. In test tube experiments conducted at the National Cancer Institute, both hydroxyurea and ddl inhibited or delayed HIV replication in a dose-dependent manner; in combination, they blocked HIV replication by more than 99.9 percent.
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PMID:Hydroxyurea, a potential new anti-HIV agent. 1136 81

The 3,5-pyrazolidinediones proved to be potent cytotoxic agents against the growth of a number of murine and human tumor cell lines, e.g. human THP-I monocytic leukemia, Hut-78 lymphoma, MCF-7 breast effusion, A549 lung carcinoma, U87MG glioma, Hela uterine and A431 epidermoid skin cancer. In human Tmolt4 cell leukemia, the agents substantially suppressed DNA and RNA syntheses after 60 min at 100 microM. The de novo purine biosynthetic pathway appeared to be the major target of the agents with the inhibition of both PRPP-amido transferase and IMP dehydrogenase (IMPDH) activities. Suppression of IMPDH activity was due to the inhibition of both the Type I and II isoforms through an uncompetitive mechanism; however, the Type II isoform was preferentially inhibited at lower concentrations of compounds tested (>50-150 microM). Therefore IMPDH Type II activity, which predominates in cancer cells, was selectively inhibited over the Type I isoform (208-312 microM). The activities of other enzymes examined were inhibited which added to the overall suppression of DNA synthesis, i.e., ribonucleotide reductase, dihydrofolate reductase and nucleoside kinases. The agents caused Tmolt4 DNA strand scission but the DNA molecule itself did not appear to be a target of the compounds since there was no induced cross-linking of the DNA, intercalation between base pairs or alkylation of the DNA bases.
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PMID:Cytotoxicity and mode of action of 1-(1-cyclohexenyl) and 1-unsubstituted 3,5-pyrazolidinediones in human Molt4 T cell leukemia. 1149 69


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