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)

3-Deazauridine (DAUrd), a competitive inhibitor of CTP synthetase, inhibits both RNA and DNA synthesis. Murine leukemia cells resistant to cytosine arabinoside (ara-C) due to a deletion of deoxycytidine kinase are collaterally sensitive to DAUrd, which inhibits the de novo production of CTP and hence results in dCTP depletion. We evaluated DAUrd in combination with the palmitate derivative of ara-C (palmO-ara-C) in mice bearing L1210 leukemia cells with a subpopulation resistant to ara-C. Both simultaneous administration and a sequential schedule of palmO-ara-C at its maximally tolerated dose (MTD), followed by DAUrd treatment, failed to produce a therapeutic gain. We also studied whether non-toxic doses of DAUrd (15-250 mg/kg i.p. at h 0 and 6 on days 4 and 8) could modulate the antileukemic activity of palmO-ara-C (7.5-120 mg/kg i.p. at h 3 on days 4 and 8). The addition of DAUrd produced a modest (but statistically significant) prolongation of life span and a further 2-log10 reduction in tumor burden compared to the same dose of palmO-ara-C alone, and resulted in long-term survivors in five of 30 treated animals. Two-dimensional dose-response analysis of the survival data indicated a positive drug interaction (p less than or equal to 0.01) when the dosage of DAUrd was modeled to reflect an apparent threshold effect. Cyclopentenyl cytosine (CPE-C; 0.625-2.5 mg/kg i.p. at h 0 and 6 on days 4 and 8), a more potent inhibitor of CTP synthetase, was also given with palmO-ara-C. This combination resulted in an additional 2-6 log10 units of cell kill and occasional long-term survivors at palmO-ara-C dosages that alone resulted in no more than 2 log10 units of cell kill and no long-term survivors. However, DAUrd and CPE-C given with palmO-ara-C increased host toxicity, compromising the tolerable dose of palmO-ara-C. Single-agent palmO-ara-C given at its MTD produced a similar reduction in tumor burden and increase in life span compared to the highest palmO-ara-C dose that could be given in combination with either modulator.
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PMID:Modulation of cytosine arabinoside toxicity by 3-deazauridine in a murine leukemia model. 203 Jun 4

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 ability to accumulate and retain the active metabolite of Ara-C varies widely among patients. Our studies demonstrate a significant correlation between clinical response and the pharmacokinetics of Ara-CTP in leukemia cells during therapy. Knowledge of the cellular pharmacology of Ara-CTP has been used to optimize dose rates and to design combination treatment schedules. An understanding of the cellular pharmacodynamics of other drugs is likely to be a useful parameter for planning treatment protocols.
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PMID:Pharmacologically directed design of leukemia therapy. 218 51

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

T-cell acute lymphoblastic leukemia is an aggressive disease that responds poorly to "standard" therapy designed for the more common B-lineage ALLs in childhood. The principles of this "standard" therapy were derived from empiric clinical trials. Thus, it is not surprising that the therapy that had the greatest impact on survival in the group as a whole would be found to be most successful for the most common subset of patients. T-cell malignant lymphoblasts share many biologic features that set them apart from the more common B-lineage lymphoblasts. Some of these biologic features suggest therapeutic approaches that should be particularly successful in treating patients with T-cell leukemia. The use of aggressive, multiple-agent "pulse" chemotherapy has been shown through empiric trials to have relative efficacy in T-cell lymphoblastic leukemia, presumably because of the rapid generation time and high growth fraction. Future studies will (1) determine the optimal dose and schedule of cytosine arabinoside needed to exploit the increased Ara-CTP accumulation in T-cell blasts, (2) determine the efficacy of a new agent, deoxycoformycin, an inhibitor of adenosine deaminase, to exploit the biochemical phenotype of T-cell blasts, and (3) assess the ability of conjugated anti-T monoclonal antibodies to deliver a cytotoxic agent, thus exploiting unique antigenic determinants at the cell surface. As more is learned about the biology of T-cell malignancies, further treatment strategies may be suggested to exploit the new features that are discovered. Similarly, it is hoped that the unique features of the B-lineage leukemias will suggest treatment strategies that will improve survival in those patients as well. Certainly, improved survival has already been achieved in the case of the B-cell leukemias and Burkitt's lymphomas, and improvement may also be possible for the pre-B and early pre-B phenotypes of lymphoblastic leukemia.
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PMID:Treatment of T-lineage acute lymphoblastic leukemia. 226 86

We evaluated relationships between ara-CTP pharmacokinetics in myeloblasts, response, and karyotype in 147 patients with newly diagnosed AML treated on three protocols each initiated by a 3 g/m2 ara-C dose given over 2 h. Area under the curve of ara-CTP concentration times time (AUC) or peak ara-CTP concentration after this dose did not predict response or response duration, suggesting that inability to form ara-CTP is an unlikely mechanism of ara-C resistance. Following high-dose bolus ara-C therapy patients with INV [16] or del [16q] had long remissions despite low AUC and peak values while patients with -5, del [5q], -7, or del [7q] were frequently resistant despite average AUC and peak values. In 55 patients treated with high-dose continuous infusion ara-C as a single agent, steady-state ara-CTP concentrations were significantly lower in resistant patients (who again were disproportionately those with -5, del [5q], -7, or del [7q]) although there was no correlation with CR duration.
Leukemia 1990 Feb
PMID:Cellular ara-CTP pharmacokinetics, response, and karyotype in newly diagnosed acute myelogenous leukemia. 230 61

Concentrations of ara-CTP in leukemic cells isolated from CSF and of ara-C in lumbar CSF were measured following intraventricular ara-C administration in two girls with refractory meningeal leukemia. CSF samples were collected with a permanent intrathecal-lumbar catheter. In contrast to the comparatively short retention of ara-C in the CSF (t1/2 1.8 to 2.9 hours), there was a high accumulation and an extremely long retention of ara-CTP in the leukemic cells (t1/2 8.1 to 36 hours). The patients included in this study had an ara-C-resistant disease. No obvious relationship was seen between concentrations of ara-C in the CSF and of ara-CTP in the leukemic cells. Similar studies were performed after simultaneous intraventricular administration of hydrocortison and ara-C. Hydrocortison did not increase ara-CTP retention in the leukemic cells, nor did it effect CSF pleocytosis.
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PMID:Pharmacokinetics of cytosine arabinoside in cerebrospinal fluid and of its metabolite in leukemic cells. 230 22

Sequential treatment of murine leukemia L5178Y with cytosine arabinoside (ara-C) followed by dipyridamole (DP) resulted in synergistic cytotoxicity. Viability of cells exposed to 1 microM ara-C for 4 h was 88% of control values, but if DP was included in the cloning medium, cell viability was reduced to only 30%. When cells exposed to 1 microM ara-C were resuspended in ara-C-free medium containing 10 microM DP, intracellular ara-C and its metabolites were retained for a significantly longer period than when cells were resuspended in drug-free medium. At 4 h after resuspension in ara-C-free medium, total intracellular [3H] was 1.9 pmol/10(6) cells in control cells but amounted to 6.2 pmol/10(6) cells in DP-treated cells. Unchanged ara-C was 5.5-fold higher in the DP-treated cells. Presumably because of its effect on the concentration of intracellular ara-C, DP increased the half-life for ara-CTP from 97 to 250 min. Ara-CDP-choline declined with a half-life of 76 min on the transfer of cells to control medium, but levels of this metabolite remained constant or increased slightly in cells transferred to medium containing DP. After 4 h in ara-C-free medium with DP, [3H]-ara-C incorporated into the acid-insoluble fraction was 140% of the level attained when cells were transferred to control medium. The increased levels of ara-C metabolites presumably represent the basis for the enhancement of ara-C cytotoxicity by sequential DP treatment.
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PMID:Enhanced retention of cytosine arabinoside and its metabolites and synergistic cytotoxicity by sequential treatment with dipyridamole in L5178Y leukemia. 234 39

The glutamine antagonists, acivicin (NSC 163501), azaserine (NSC 742), and 6-diazo-5-oxo-L-norleucine (DON) (NSC 7365), are potent inhibitors of many glutamine-dependent amidotransferases in vitro. Experiments performed with mouse L1210 leukemia growing in culture show that each antagonist has different sites of inhibition in nucleotide biosynthesis. Acivicin is a potent inhibitor of CTP and GMP synthetases and partially inhibits N-formylglycineamidine ribotide (FGAM) synthetase of purine biosynthesis. DON inhibits FGAM synthetase, CTP synthetase, and glucosamine-6-phosphate isomerase. Azaserine inhibits FGAM synthetase and glucosamine-6-phosphate isomerase. Large accumulations of FGAR and its di- and triphosphate derivatives were observed for all three antagonists which could interfere with the biosynthesis of nucleic acids, providing another mechanism of cytotoxicity. Acivicin, azaserine, and DON are not potent inhibitors of carbamyl phosphate synthetase II (glutamine-hydrolyzing) and amidophosphoribosyltransferase in leukemia cells growing in culture although there are reports of such inhibitions in vitro. Blockade of de novo purine biosynthesis by these three antagonists results in a "complementary stimulation" of de novo pyrimidine biosynthesis.
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PMID:Cytotoxic mechanisms of glutamine antagonists in mouse L1210 leukemia. 235 67

1-beta-D-Arabinofuranosylcytosine 5'-diphosphate-rac-1-S-octadecyl-2-O- palmitoyl-1-thioglycerol (ara-CDP-DL-PTBA) is an effective stable 1-beta-D-arabinofuranosylcytosine (ara-C) conjugate of thioether phospholipid against a variety of transplantable tumors in mice. The conjugate was formulated in a micellar solution by sonication, in which the conjugate exists as micellar discs (size, 0.01 to 0.04 micron). Analyses on thin-layer and high-pressure liquid chromatography showed that the conjugate was chemically stable upon storage at 3-4 degrees C for more than a 6-mo period. However, stored at room temperature for 3 mo it began to degrade (3 to 11%) to 1-beta-D-arabinofuranosylcytosine 5'-monophosphate and phosphatidic acid. At 3-4 degrees C, the micellar structure remained generally unchanged for 6 mo (size, less than 0.1 micron). Samples stored for 4 mo at room temperature formed some larger vesicles (size, 0.1 to 0.4 micron). Antitumor activity against i.p. implanted L1210 leukemia in mice remained relatively constant with samples stored for 6 mo at 3-4 degrees C or 3 mo at room temperature. 1-beta-D-Arabinofuranosylcytosine 5'-triphosphate (ara-CTP) levels were elevated (greater than 500 pmol/10(7) cells) in L1210 leukemia cells within 1 h following i.p. administration of 400 mg/kg of ara-CDP-DL-PTBA to mice. More importantly, retention of cellular ara-CTP was prolonged (greater than 24 h) in these tumor cells as compared with ara-C treatments. Administration of ara-CDP-DL-PTBA to mice with colon 26 carcinoma (s.c.) resulted in both significant antitumor activity with an increased life span greater than 100% and decreased tumor size. The conjugate also demonstrated a dose-dependent therapeutic effect in mice with M5076 sarcoma (s.c.) as demonstrated by decreases in tumor size and liver metastases. Overall, ara-CDP-DL-PTBA, a stable lipid conjugate of ara-C in a micellar solution, appears to offer substantial therapeutic benefit to mice with leukemia and solid tumors warranting its further development and clinical investigation.
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PMID:Formulation, stability, and antitumor activity of 1-beta-D-arabinofuranosylcytosine conjugate of thioether phospholipid. 236 92


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