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)

Acute myeloid leukemia (AML) was induced in C57Bl mice through the i.v. innoculation of C-1498 cell line. One week later, i.e. at mid-term disease, the leukemic mice received an i.p. injection of 200 ng rmGM-CSF and 24 h later, two consecutive i.p. cytosine arabinoside (ara-C) injections at 6 h intervals (2 x 200 mg/kg). The leukemic mice received 3-4 weekly courses of combined therapy and survived 4-5 weeks following leukemia induction. Control mice received ara-C only and survived 2-3 weeks. Moreover, leukemic mice administered both GM-CSF and ara-C had a lower marrow leukemic load than mice treated with ara-C only. From these findings, we conclude that therapy of murine AML with combined rmGM-CSF and ara-C is more effective than ara-C only. Leukemic mice treated with GM-CSF and ara-C had a longer life expectancy and a smaller leukemic load than mice administered ara-C only.
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PMID:Improved prognosis in mice with advanced myeloid leukemia following administration of GM-CSF and cytosine arabinoside. 204 85

A regimen of aclarubicin (ACR) of 75 mg/m2 daily for 3 days plus a continuous intravenous infusion of cytosine arabinoside (ara-C) of 100 mg/m2 per day for 7 days was compared with daunorubicin (DNR) 45 mg/m2/day for 3 days plus ara-C for 7 days as first-line chemotherapy of de novo acute myeloid leukemia (AML) in a randomized, nationwide Danish study. A total of 180 patients aged between 17 and 65 years were entered onto the protocol. Patients who achieved complete remission (CR) were given five courses of intensive consolidation therapy consisting of two courses of high dose ara-C, two courses of amsacrine plus etoposide, and one course of DNR plus ara-C. Of 174 evaluable patients, 99 achieved CR. The rate of CR was significantly higher on ACR plus ara-C than on DNR plus ara-C [66% versus 50% (p = 0.043)] and decreased significantly with increasing age. The hematological toxicity was identical for the two regimens. A total of 83 patients entered consolidation therapy. At 4 years, 37% of patients with CR following ACR were still in remission compared with 33% following DNR (p = 0.48), and the total survival at 4 years was 29% versus 20% (p = 0.26). The duration of remission and total survival both decreased with increasing age. ACR plus ara-C seem at least as good or better than DNR plus ara-C as first-line chemotherapy of AML.
Leukemia 1991 Jun
PMID:Aclarubicin plus cytosine arabinoside versus daunorubicin plus cytosine arabinoside in previously untreated patients with acute myeloid leukemia: a Danish national phase III trial. The Danish Society of Hematology Study Group on AML, Denmark. 205 74

Leukemia inhibitory factor (LIF) was tested using three established acute myelocytic leukemia (AML) cell lines. In growth assays in two of the three lines, we found that the addition of LIF increased the doubling time of the clonogenic population but not the total population as assessed by nucleated cell counts. Similarly, tritiated thymidine uptake into total AML populations was not affected by LIF, but the percentage of clonogenic cells killed by exposure to high specific activity 3HTdR was reduced in LIF-treated cultures compared to controls. We interpret these results to indicate that LIF prolongs the cell cycle of stem cells in some AML lines, possibly by increasing the time spent in the G2-M-G1 parts of the cycle. Consistent with this interpretation, we observed a decrease in ara-C sensitivity in LiF treated cultures. Variable results were obtained when freshly obtained AML blasts were exposed to LIF.
Leukemia 1990 Aug
PMID:The effects of leukemia inhibitory factor (LIF) on the blast stem cells of acute myeloblastic leukemia. 211 85

The metabolism and toxicity of 1-beta-D-arabinofuranosylcytosine triphosphate (ara-CTP) directly injected into cells by electroporation was studied in human leukemia cell lines. The intracellular accumulation of ara-CTP (ara-CTP-Ep) was dependent on the cell type, extracellular ara-CTP concentration and pulse voltage on electroporation. In a promyelocytic leukemia cell line, HL-60, ara-CTP-Ep revealed a cytotoxic effect in a dose-dependent manner, although electroporation alone did not have any significant toxicity. Furthermore, simultaneous injection of dCTP, or continuous exposure to deoxycytidine, but not to other deoxyribonucleosides, immediately after electroporation rescued the cells from the toxicity of ara-CTP-Ep. The degradation of ara-CTP-Ep consisted of an early rapid phase followed by a slower phase with a half life of 1.5 h. The addition of dipyridamole (10 microM), an inhibitor of nucleoside transport, retarded this degradation process. These data indicate that transfer of ara-CTP by electroporation is a useful method for the study of ara-CTP metabolism.
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PMID:Metabolism and toxicity of electroporated 1-beta-D-arabinofuranosylcytosine triphosphate in a human leukemia cell line. 212 1

The in vitro action of recombinant human leukemia inhibitory factor (LIF) and 1-beta-D arabinofuranosylcytosine (ara-C) was studied on the human leukemia cell line U 937. Parameters investigated included monitoring of transcript levels of the proto-oncogenes C-MYC, C-FOS, and C-FMS, and analysis of nitroblue tetrazolium (NBT) reduction and of surface expression of the C3 bi receptor. Furthermore clonal proliferation of U 937 cells was assessed in soft agar cultures. The results indicate that both agents have only little effects on U 937 cells when acting alone. When combined in culture, however, they synergize to induce monocytic differentiation of U 937 cells as disclosed by significant increase of cells capable of reducing NBT and displaying surface C3 bi receptor that was accompanied by reduction of clonogenicity in colony assays. Induction of differentiation and inhibition of proliferation of U 937 cells was preceded by downregulation of transcript levels of C-MYC, increase of C-FOS mRNA, and induction of accumulation of C-FMS mRNA. By sequential use of LIF and ara-C we also demonstrate that the basis of synergism of both agents does not involve mechanisms at the level of receptor ligation but that synergism may be initiated by complementary intracellular metabolic cascades.
Leukemia 1990 Sep
PMID:Synergistic effect of recombinant human leukemia inhibitory factor (LIF) and 1-beta-D-arabinofuranosylcytosine (Ara-C) on proto-oncogene expression and induction of differentiation in human U 937 cells. 214 31

The Cancer and Leukemia Group B (CALGB) utilized a randomized phase II trial design to evaluate two cisplatin-based combinations, cisplatin-cytarabine (ara-C) and cisplatin-vinblastine, in 151 patients with advanced non-small cell lung cancer. Patients entered on study had not received prior chemotherapy. Platinum doses were equivalent in the two treatment programs. The total response rate (complete response, partial response, regression of evaluable disease) for the cisplatin-vinblastine group was 22% (16/73). Failure-free survival at six months for this group was 41%, survival at six months was 63%. The cisplatin-ara-C group had a total response rate of 9% (7/78) with a failure-free survival at six months of 14% and a six-month survival of 47%. Severe or life-threatening toxicity was seen in 73% of cisplatin-vinblastine cases and 59% of cisplatin-ara-C patients. Neither regimen is active enough to warrant designation as "standard therapy" for patients with M1 disease.
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PMID:Platinum-based combination chemotherapy in advanced non-small cell lung cancer: a randomized phase II trial of the Cancer and Leukemia Group B. 215 14

We administered recombinant granulocyte-macrophage colony-stimulating factor (GM-CSF) (120 micrograms/m2/d by continuous intravenous [IV] infusion) to 12 patients with newly diagnosed acute myeloid leukemia (AML) at relatively high risk of early death during remission induction. GM-CSF began 3 days after completion of induction chemotherapy (ara-C 1.5 g/m2 d x 4 days by continuous IV infusion after a 3 g/m2 bolus). Rates of fatal infection (42%), pneumonia and/or sepsis (83%), and CR (50%) did not differ significantly (P less than .05) from those observed after administration of the identical chemotherapy without GM-CSF to 53 historical controls with newly diagnosed AML at similarly high risk of early death. There were no significant differences between the GM-CSF-treated and the historical groups in the time required to reach neutrophil counts of 500 or 1,000/microL after administration of chemotherapy. Four patients died of infection before they could have benefited from the earliest recovery of neutrophil count observed in patients who entered CR. Growth of leukemia after GM-CSF administration was observed in only 1 of the 8 patients who survived long enough for response to induction therapy to be fully evaluated. This observation suggests that it might be safe to undertake larger, randomized studies, perhaps using earlier administration of GM-CSF, to definitively determine the role of GM-CSF added to chemotherapy in patients with newly diagnosed AML.
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PMID:Treatment of poor-prognosis, newly diagnosed acute myeloid leukemia with ara-C and recombinant human granulocyte-macrophage colony-stimulating factor. 218 1

Human acute myelocytic leukemia (AML) marrow cells respond to stimulation with increased proliferation and enhanced intracellular metabolism of the cytotoxic antimetabolite 1-B-D arabinofuranosylcytosine (ara-C). Our previous studies have focused on the drug-induced humoral stimulatory activity (HSA) present in serum following initial cytoreduction which augments in vitro growth and biochemical pharmacology. The activity of HSA likely relates to the presence of multiple stimulators. The effect of 18-hr culture in purified recombinant human granulocyte-macrophage colony stimulating factor (rhGM-CSF) (1 ng/ml) on in vitro AML marrow cell [3H]dThd incorporation into DNA, intracellular ara-C activation to the triphosphate form (ara-CTP), and subsequent ara-CTP retention were determined in leukemic cells of 11 patients and compared with cells similarly cultured in HSA-containing sera. The stimulatory effects of rhGM-CSF and HSA on both growth and pharmacologic parameters were comparable for each AML population, with maximal response to both regulators detected for FAB M2. These data demonstrate that GM-CSF acts similarly to HSA as an active stimulator of leukemic cell proliferation and net intracellular ara-C metabolism in vitro, and support clinical trials designed to examine the role of rhGM-CSF in enhancing ara-C cytotoxicity by increasing the growth fraction of drug-responsive target cells in vivo.
Leukemia 1990 Aug
PMID:Effects of rhGM-CSF on intracellular ara-C pharmacology in vitro in acute myelocytic leukemia: comparability with drug-induced humoral stimulatory activity. 220 33

YNK01 (a daily oral dose of 450 mg) was administered for 22 days to a 58-year-old-female with Ph1-positive acute unclassified leukemia. Leukemia cells were negative for peroxidase and esterase, but were positive for CD19, CD13, CD34, CD9, HAL-DR, CD25, and TdT. Complete remission was obtained and continued for at least a month. The main side effects noted were diarrhea and melena. The administration of YNK01 resulted in plasma ara C levels that ranged between 15.4 to 23.0 ng/ml, which appear to be nearly equivalent to dose achieved during continuous IV infusion of a low dose (20 mg/m2/day) of ara C.
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PMID:[A case of complete remission from acute unclassified leukemia achieved by using a prodrug of ara C, stearyl-ara-CMP (YNK01)]. 223 91

Though data from cell lines are abundant, the reason for the development of resistance to 1-beta-D arabinofuranosylcytosine (ara-C) in vivo remains unresolved. A broad interpatient variation of metabolic parameters has further complicated interpretation of the results. The present study compares ara-C metabolism in leukemic blasts of two patients with newly diagnosed disease, before and after repeated treatment with ara-C containing chemotherapy regimens in vivo. Membrane transport of ara-C was unchanged after treatment. In addition, cell-free extracts of blasts obtained after treatment failure showed an unchanged cytidine deaminase activity. Though deoxycytidine kinase activity in cell extracts was unaltered or increased after treatment failure, the activity in situ, measured as the rate of 1-beta-D-arabinofuranosylcytosine triphosphate (ara-CTP) formation, was decreased. This could be shown to be due to an expansion of the deoxycytidine triphosphate (dCTP) pool. The severalfold increase in dCTP pool was accompanied by a decrease in thymidine triphosphate (dTTP) pool and correlated with a decrease in deoxycytidylate deaminase (dCMP-deaminase) activity in cell free extracts. Low dCMP-deaminase activity had been shown to confer an ara-C resistant phenotype to cell lines in vitro. Data presented in this paper show that a selection for leukemic blasts with low dCMP-deaminase activity can also be favored by ara-C containing treatment regimens in vivo. Our data suggest that this mechanism might contribute to treatment failure.
Leukemia 1990 Nov
PMID:Concordant changes of pyrimidine metabolism in blasts of two cases of acute myeloid leukemia after repeated treatment with ara-C in vivo. 223 89


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