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)

In preparation for a clinical trial using GM-CSF on days 4-10 of sequential high-dose cytarabine (ara-C) and asparaginase (ASNase) on days 1-3 and 8-10, potential interactions between the protein synthesis inhibitor ASNase and GM-CSF were evaluated. Granulocyte-macrophage colony-stimulating factor (GM-CSF) can stimulate acute myeloid leukemia (AML) cells to proliferate in vitro and in vivo. Log phase HL-60 cells were exposed to ara-C (10 microM x 3 h) and/or ASNase (10 U/ml during the last 2 h of ara-C). Ara-C and/or ASNase was removed and cells were incubated with or without GM-CSF (10 ng/ml). After 24, 48 and 72 h of GM-CSF there was no significant difference in the S phase fraction of cells exposed to ASNase prior to GM-CSF. Soft agar cloning efficiency was determined after retreatment with ara-C +/- ASNase 24 h into the GM-CSF incubation. GM-CSF enhanced cytotoxicity for all combinations, although this effect was of borderline significance (P = 0.0621); addition of ASNase to the treatment regimen significantly (P = 0.0229) enhanced cytotoxicity without any evidence of a negative interaction with GM-CSF. In addition, ara-C metabolism was assessed during simultaneous exposure to ara-C (10 microM x 3 h) +/- ASNase (10 U/ml the last 2 h) +/- GM-CSF (10 ng/ml beginning 24 h prior to ara-C). Ara-C incorporated into DNA (P = 0.0302) and ara-CTP formation (P = 0.0084 and P = 0.0003 at 2 and 3 h timepoints, respectively) were both increased significantly by GM-CSF, with modest non-significant increases with ASNase exposures. Neither ASNase nor GM-CSF inhibited the effects of the other in this in vitro model. Therefore, when appropriately scheduled, both GM-CSF and ASNase may potentiate ara-C cytotoxicity.
Leukemia 1995 Mar
PMID:GM-CSF and asparaginase potentiate ara-C cytotoxicity in HL-60 cells. 788 38

The anti-proliferative activity of S-D-lactoylglutathione is of interest since it has a low toxicity to differentiated and non-malignant proliferating tissues, and its mechanism of action appears to be dissimilar to other anti-proliferative agents. Addition of uridine completely and addition of cytidine partially prevented S-D-lactoylglutathione-induced growth inhibition of human leukaemia 60 (HL60) cells in vitro. Other nucleosides had no significant effect. The concentrations of UTP, CTP, UDP and also ATP, ADP, GTP and GDP decreased in S-D-lactoylglutathione-treated HL60 cells, whereas the concentration of UDP-N-acetylhexosamine (UDP-N-acetyl-glucosamine + N-acetyl-galactosamine) increased, prior to cell death. This suggests that the anti-proliferative effects of S-D-lactoylglutathione are mediated by inhibition of uridylate synthesis.
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PMID:Prevention of S-D-lactoylglutathione-induced inhibition of human leukaemia 60 cell growth by uridine. 793 47

The alkyl-lysophospholipids are a new family of anticancer drugs which target the cell membrane as their site of action. Enzymes involved in signal transduction (protein kinase C and phosphatidylinositol phospholipase C), phospholipid biosynthesis (lysophosphatidyl acyltransferase and CTP:cholinephosphate cytidylyltransferase) and maintenance of membrane integrity (Na,K ATPase sodium pump) are inhibited. A unique feature of the alkyl-lysophospholipids is their selective cytotoxicity to neoplastic cells. This suggests that the compound would be an excellent agent for purging residual leukemic cells from marrows of patients in remission prior to autologous bone marrow transplantation. Preclinical studies in a murine leukemia model and in an in vitro human system demonstrated successful elimination of leukemic cells from a mixture of normal and leukemic marrows. Twenty-nine poor risk patients with acute leukemia underwent autologous bone marrow transplantation and were reinfused with marrow treated in vitro with edelfosine. Nine of these patients remain in remission free of leukemia from 368 to 1369 days. These encouraging results warrant further investigation.
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PMID:Bone marrow purging in acute leukemia with alkyl-lysophospholipids: a new family of anticancer drugs. 802 24

The long-term results in 130 patients with newly diagnosed acute myelogenous leukemia treated with continuous infusion high-dose ara-C (1.5 gm/m2/day x 4 days, CIHDAC) were compared with those in 264 patients treated in previous studies with standard dose ara-C (70-90 mg/m2/d x 7 days) plus either adriamycin (Ad-OAP), or amsacrine (AMSA-OAP). All patients have been followed at least 5 years. Patients in first CR at 5 years (FCR5) treated on protocols prior to CIHDAC had only 5% chance of relapse (median subsequent follow-up of 9 years). Therefore, we considered patients in FCR5 potentially cured. The two groups were similar with respect to known prognostic factors and CR rates. Although remission duration and survival were shorter with CIHDAC than Ad-OAP/AMSA-OAP, the percent of patients potentially cured was similar (10 vs. 15%). Marked differences between regimens were seen in inv(16) and t(15;17) patients. CIHDAC was better for patients with inv(16) with more patients in FCR5 (80 vs. 38%), longer remission duration and survival, and lower incidence of CNS relapse (0 vs. 43%). The Ad-OAP/AMSA-OAP protocols were superior in patients with t(15;17). We also measured steady-state ara-CTP concentrations (ara-CTPss) in 54 CIHDAC-treated patients presenting with high-blast count. While there was no correlation between ara-CTPss and response duration, all five patients in FCR5 in whom ara-CTPss was measured had high concentrations. These data support the concept that patients with AML should be treated differently according to cytogenetics. Inv(16) patients should be treated with high-dose ara-C while t(15;17) should rely more on anthracycline exposure.
Leukemia 1994 Aug
PMID:Long-term results following treatment of newly-diagnosed acute myelogenous leukemia with continuous-infusion high-dose cytosine arabinoside. 805 60

The pattern of incorporation of [14C]uridine showed that in MOLT-3 cells an increased proportion of CTP was synthesized via CTP synthetase, compared to proliferating normal human T lymphocytes at a physiological concentration of cytidine (< 0.5 microM). Furthermore, in the proliferating normal human T lymphocytes similar patterns of incorporation of [14C]uridine were observed in the presence of the physiological concentration of cytidine and after addition of 2 microM of cytidine. In contrast, in the MOLT-3 cells after addition of 2 microM of cytidine the proportion of CTP synthesized by conversion of UTP into CTP was substantially decreased, whereas the salvage of cytidine was proportionally increased. We conclude that the reutilization of uridine is a preferred route in the synthesis of CTP for MOLT-3 cells at physiological concentrations of uridine and cytidine, whereas in proliferating normal human T lymphocytes CTP is largely synthesized through reutilization of cytidine. This difference in salvage of pyrimidine ribonucleosides may be exploited for selective chemotherapy.
Leukemia 1994 Aug
PMID:The roles of uridine-cytidine kinase and CTP synthetase in the synthesis of CTP in malignant human T-lymphocytic cells. 805 76

Because in vitro studies have indicated that granulocyte-macrophage colony-stimulating factor (GM-CSF) stimulates arabinosylcytosine (ara-C) metabolism in leukemia blasts, we analyzed the pharmacokinetics of ara-C triphosphate (ara-CTP) in the blasts of patients with chronic myelogenous leukemia who were undergoing therapy with GM-CSF and ara-C. Patients received a 2-h infusion of 1.0 g/m2 ara-C followed by daily infusions of GM-CSF (125 micrograms/m2/day i.v. over 6 h) for 2-4 days. After the last GM-CSF infusion, a second, identical dose of ara-C was administered. The cellular pharmacokinetics of ara-CTP in circulating blasts were determined during and after each ara-C dose, and the area under the accumulation and elimination curve (AUC) measured over 12 h was compared before and after GM-CSF. Ara-CTP accumulation peaked within 1 h after the end of each ara-C infusion. Comparison of the AUC of ara-CTP before and after GM-CSF administration suggested that in the blasts of three of four patients, GM-CSF treatment decreased the ara-CTP AUC; the AUC values were altered only slightly in a fourth patient. Studies of these patients' blasts incubated in vitro with ara-C before and after clinical infusion of GM-CSF revealed similar ara-CTP accumulation patterns. Together, these studies suggest that 2-4 days of GM-CSF administration does not increase the accumulation of ara-CTP in the circulating blasts from patients in the blastic phase of chronic myelogenous leukemia.
Leukemia 1994 Sep
PMID:Effect of granulocyte-macrophage colony-stimulating factor on the metabolism of arabinosylcytosine triphosphate in blasts during therapy of patients with chronic myelogenous leukemia. 809 26

Anti-metabolites are among the most important agents used in cancer chemotherapy. Ara-C, the thiopurines and MTX are active drugs for both induction and maintenance chemotherapy of childhood and adult leukaemia, while the new adenosine analogues are active against hairy cell leukaemia, with promising activity against other malignancies such as malignant lymphomas. Methotrexate and 5FU are being used in the treatment of several solid malignancies. Recent advances in the clinical pharmacology of widely used antimetabolites have shown a relationship among dose, plasma concentrations and clearance with the toxicity and anti-tumour activity. Thus, it has been shown that adaptative control of 5FU administration is possible, limiting the toxicity of this drug. Recent advances in the pharmacogenetics of, for example, 6MP and 5FU will possibly enable researchers to identify patients who may have an increased risk of toxicity. For ara-C, some evidence has been obtained to identify populations at risk of no response. In addition, for most anti-metabolites, convincing evidence of their intracellular (intratumour) metabolism has been obtained, thus making it possible to identify patients who are likely to respond to treatment. These studies (eg accumulation of active metabolites such as ara-CTP, thioguanine nucleotides, FdUMP, MTX-polyglutamates; and inhibition of target enzymes such as thymidylate synthase) have made it possible to develop the basis of biochemical modulation--that is, specific manipulation of intracellular metabolism of the drug. It is anticipated that new technical developments in molecular biology, biochemistry, cell biology and immunology will make it possible to improve the identification of resistant patients in order to modulate specifically drug metabolism in the tumour cells. Biochemical modulation has been successful in achieving significant improvements in treatment and currently is a keystone in cancer chemotherapy. Together with the development of promising new anti-metabolites, biochemical modulation (with other drugs, biologicals) will be a major strategy for the future.
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PMID:Clinical pharmacokinetics of anti-metabolites. 813 39

The purpose of this paper was to ascertain whether results obtained in cell cultures of AML clonogenic blast cells would provide a useful model for a clinical regimen that combines fludarabine (F-ara-AMP) and cytosine arabinoside (ara-C). In the cultures the nucleoside F-ara-A was used. Blast cells from the continuous lines OCI/AML-2 and OCI/AML-3 were grown, either in methylcellulose to quantify clonogenic cells, or in suspension to measure self-renewal as reflected in changes in numbers of clonogenic cells. F-ara-A, like ara-C, was found to be more toxic to blast stem cells in suspension than in the clonogenic assay, indicating that F-ara-A might, in addition to general cytotoxicity, have some specific inhibitory effects on self-renewing stem cells. F-ara-A was less cytotoxic than ara-C; but, when F-ara-A was given before ara-C, synergism was seen at some F-ara-A doses, as manifested by increased ara-C cytotoxicity. In contrast, when ara-C was given before F-ara-A, protection was observed. Control experiments make it unlikely that this effect is related to changes in the cell cycle following ara-C exposure. We conclude that the cellular studies reported here confirm previous pharmacological data indicating that F-ara-A before ara-C increases the effectiveness of ara-C by increasing the accumulation of ara-CTP. However the present experiments show that the synergism between F-ara-A and ara-C is dependent on both dose and schedule.
Leukemia 1993 Jul
PMID:A cell culture model for the treatment of acute myeloblastic leukemia with fludarabine and cytosine arabinoside. 832 Oct 50

There is a strong association between ability of leukemia blasts to accumulate ara-CTP, the active metabolite of ara-C, and response to ara-C in patients with relapsed or refractory AML. Ara-C dose rates in excess of 0.5 g/m2/h do not produce further ara-CTP formation. In contrast, when given 4 h prior to ara-C at this dose rate, fludarabine, at doses that are free of neurotoxicity in CLL, enhances ara-CTP accumulation. This led us to administer fludarabine and ara-C to 59 patients with AML in relapse or unresponsive to initial therapy. Fludarabine was given at 30 mg/m2 once daily for 5 doses and ara-C at 0.5 g/m2/h for 2-6 h daily for 6 doses. Doses of fludarabine preceded those of ara-C by 4 h. Results with fludarabine and ara-C (FA) were compared with those of patients treated at M.D. Anderson with high-dose ara-C (HDAC) or intermediate-dose ara-C (IDAC). The complete remission rate with FA was 21/59 (36%) and the actuarial median CR duration 39 weeks. FA produced significantly higher remission rates than HDAC or IDAC in patients with initial remissions > 1 yr (14/20 vs 9/23 vs 6/18, p < 0.05). Response rates were similar for all three treatments in patients with initial remissions < 1 yr or with primary refractory disease. The regimen was well tolerated; one patient developed peripheral neuropathy. This low level of toxicity encourages combination with other antileukemia agents.
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PMID:Fludarabine and arabinosylcytosine therapy of refractory and relapsed acute myelogenous leukemia. 839 69

Cytosine arabinoside (ara-C) and etoposide are often used in combination in the treatment of acute myelocytic leukemia (AML). The intracellular phosphorylation of ara-C to its 5'-triphosphate (ara-CTP) is a prerequisite for its cytotoxic effects. It has been shown in vitro that etoposide can impair the formation of ara-CTP in leukemia cells. The present study was undertaken in order to elucidate whether this interaction may be of clinical importance. Leukemia cells were isolated from 3 patients with acute myelocytic leukemia and incubated in medium (RPMI-1640) with or without 10% fetal calf serum or in human plasma. When the cells were incubated in RPMI-1640 with ara-C (10 mumol/l) and etoposide during 2 h, the formation of ara-CTP was decreased to 71 +/- 18 (mean +/- S.D.) and 30 +/- 15% of control at 1 and 10 micrograms/ml etoposide, respectively. When the cells were incubated in human plasma, the formation of ara-CTP was not influenced by the presence of etoposide (101 +/- 6 and 103 +/- 20% at 1 and 10 micrograms/ml etoposide). When incubated in RPMI supplemented with 10% fetal calf serum, the corresponding figures were 81 +/- 8 and 70 +/- 20%. Six patients with AML were therefore treated with ara-C 0.5 or 1.0 g/m2 as a 2-h infusion every 12 h and, during 1 h before the second ara-C infusion, 100 or 200 mg/m2 etoposide was administered. The median change in the AUC of cellular ara-CTP between the first and second ara-C dose was 0% (-37 to +21%). The corresponding median change in rate of accumulation of ara-CTP in leukemia cells was 12% (-26 to +110%). The concentration of etoposide in plasma during the ara-C infusion was 18.7 +/- 5.1 micrograms/ml while the non-protein bound etoposide was 0.73 +/- 0.34 micrograms/ml. Thus, despite exposure to higher etoposide concentrations in vivo than in vitro, no impairment of ara-CTP formation was seen in the patients. This corresponds to the results obtained when leukemic cells were incubated in plasma. It is concluded that the inhibition of ara-CTP formation by etoposide seen in vitro is offset by the high protein binding of etoposide in plasma (96%) and that etoposide does not impair the formation of ara-CTP in leukemia cells in vivo during treatment with standard-dose etoposide.
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PMID:On the interaction between cytosine arabinoside and etoposide in vivo and in vitro. 843 10


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