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)

Tumor cells were isolated from malignant effusions of three patients with disseminated solid tumors of different origin. Intracellular accumulation of nondiffusible cytosine arabinoside (ara-C) nucleotides was used to measure phosphorylation. Mouse leukemia L 1210 and L 1210/CA, and ara-C-resistant subline, were used as reference cells. Phosphorylation activity was similar in the cells from all three solid tumors and showed a linear increase with drug concentrations of 0.1--100 micograms/ml. In contrast to activity in L 1210 cells, the in vitro activity was not saturable at drug levels up to 100 micrograms/ml. Ara-C inhibited the incorporation of thymidine into DNA 84%--90% in the solid tumor cells at a concentration of 10 micrograms/ml. Higher drug concentrations did not result in further inhibition. In one patient, DNA synthesis of tumor cells isolated before and after intraperitoneal instillation of 1,000 mg ara-C was measured. The in vivo inhibition was found to correspond to the in vitro data. Solid tumor cells isolated from malignant effusion have no greatly reduced capacity for cellular formation of ara-C/nucleotides, but higher drug levels than achieved with conventional therapy are necessary for sufficient ara-C nucleotide synthesis.
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PMID:Action of cytosine arabinoside on human tumor cells isolated from malignant effusions: in vitro phosphorylation and inhibition of DNA synthesis. 48 20

Two lines of the 6C3HED (Gardner lymphosarcoma), 6C3HED-LeP and 6C3HED-ADL, were studied. The former is exquisitely sensitive to 9-beta-D-arabinofuranosyladenine (ara-A) and the latter is resistant. Cytological examinations and strain specificity tests indicated that they are both 6C3HED. DNA synthesis in the sensitive line was found to be more sensitive to ara-A in whole-cell incubations than it was in the resistant line. In cell-free extracts, the DNA synthesis of the sensitive line showed greater inhibition by 9-beta-D-arabinofuranosyladenine 5'-triphosphate. Lower ability to form 9-beta-D-arabinofuranosyladenine 5'-triphosphate or to allow access to the intracellular space was eliminated as an explanation for the resistance. Cells from an ara-A-resistant human leukemia were tested, and the DNA synthesis of the cells, in either whole cells or cell-free extract, was unaffected by ara-A or 9-beta-D-arabinofuranosyladenine 5'-triphosphate, respectively. This suggests that resistance has emerged by reason of change in the DNA polymerase(s) and that the finding may be important in the clinical use of ara-A.
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PMID:Resistance to 9-beta-D-arabinofuranosyladenine in murine tumor cells. 58 Sep 2

We derived a cellular model for the use of the cytidine analogue 1-beta-D-arabinofuranosylcytosine (ara-C) against L1210 leukemia in vivo from dose- and time-survival studies. We employed a quantitative assay for leukemia colony-forming cells to construct dose- and time-survival curves for single, divided, and infused doses of ara-C. Time-survival curves for a large dose range of ara-C indicated not only cell killing but also progression delay effects in vivo. Divided dose studies showed the extent of cell killing (optimum effect) to be dependent upon both the dose and the interval of time between administration of the drugs. When the drug was given as an infusion, the extent of cell killing was as great as that produced by the best fractionation schedule, an effect which was verified in terms of therapeutic efficacy in leukemic mice.
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PMID:Cellular quantitation of in vivo effects of 1-beta-D-arabinofuranosylcytosine on leukemia L1210. 84 97

When cyclophosphamide and 1-beta-D-arabinofuranosylcytosine were administered to mice previously given injections of L1210 leukemia cells, the combination was more effective than either drug given alone. The effectiveness of the 2 drugs in combination was strongly influenced by the stage of the circadian system at which the drugs were administered. With the use of a chronobiological (sinusoidal) approach, in comparison with one or two conventional treatment schedules, it was possible to demonstrate an overall lower toxicity as monitored by death or weight loss. In general, mean survival times and cures (when obtained) were circadian stage dependent; for example, in 1 study the cure rate was 94% in mice treated at 1 circadian stage, but only 44% in those treated at another stage. It cannot be overemphasized, however, that just as the "right" timing can enhance (with statistical significance) both the tolerance to chemotherapeutic agents and the rate of cure in leukemic mice, so can the "wrongly" timed (wrongly placed) ara-C sinusoid or "wrongly" timed cyclophosphamide enhance toxicity and host death rate.
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PMID:Survival and cure of leukemic mice after circadian optimization of treatment with cyclophosphamide and 1-beta-D-arabinofuranosylcytosine. 90 13

An integrated mathematic computer-based model of the pharmacokinetics, intracellular enzyme kinetics, and cell kinetics of the treatment of L1210 leukemia by cytosine arabinoside (ara-C) is described. The compartment model of Bischoff and Dedrick is extended to the intracellular level by inclusion of equations describing the phosphorylation, dephosphorylation, and deamination of ara-C with enzymatic feedback control. The activities of kinase, deaminase, and phosphatase are explicitly included in the models and are estimated from relevant data. Cell proliferation is described by a continuous-flow mathematic model in which cellular maturation and cell-to-cell variability in maturation rates are key variables. Cell proliferation is related to intracellular biochemistry through mathematic expressions which relate cell lethality and progression delay to the time course of intracellular ara-CTP. In vitro and in vivo experiments performed in a number of laboratories are compared by simulation. The most sensitive parameters in dose-response and cell-survival simulations are deoxycytidine kinase activity, ara-CTP half-life, renal clearance of ara-C, and cell-kinetic parameters for proliferation and cell killing. Progression delay is vital to the realistic simulation of divided-dose schedules. By comparative simulation we have identified areas of uncertainty which can be classified by a few additional measurements. The applications of simulations combining pharmacokinetic, biochemical, and cell-kinetic data in vitro and in vivo are discussed, exploring consistency among different measurements, and relating experimental protocols to clinical treatment.
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PMID:Computer simulation of leukemia therapy: combined pharmacokinetics, intracellular enzyme kinetics, and cell kinetics of the treatment of L1210 leukemia by cytosine arabinoside. 102 30

This study investigated the arabinosyl cytosine (ara-C) sensitivity of colony formation in culture by human granulopoeitic progenitor cells (CFU-C). Wide variations were observed in the effects of ara-C on CFU-C from the marrow of patients with leukemia in remission after treatment using a chemotherapeutic regimen that included ara-C, or for CFU-C from the marrow of non-leukemic patients. These variations in sensitivity to ara-C could not be attributed to a lack of reproducibility of the culture conditions used, nor to variations in the proliferative state of the CFU-C at the time of exposure to ara-C. No significant correlation was observed between the sensitivity of CFU-C to ara-C and the level of cytidine deaminase in the marrow sample. These results provide some support for the view that cell kill may not be the only basis for the chemotherapeutic effectiveness of ara-C.
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PMID:Effect of arabinosyl cytosine on granulopoietic colony formation by marrow cells from leukemic and non-leukemic patients. 106 75

Phosphorylation versus deamination of ara-C by tumor homogenates was measured in 10 patients prior to treatment with ara-C infusion. The ratio ranged from 0.24 to 1.2 in 5 malignant melanomas, 2.6 to 3.2 in 3 histiocytic lymphomas and 0.9 in a hemangiopericytoma. Treatment of the 9 patients with 2 courses of 5-day continuous ara-C infusion failed to produce objective evidence of tumor regression. The tenth patient had lymphosarcoma leukemia. The baseline ratio of ara-C phosphorylation over deamination activity of the tumor cells was 1.23. Treatment with 2 courses of continuous ara-C infusions produced a brief state of complete remission. The ratio of araC phosphorylation over deamination activity in the tumor cells after relapse was only 0.1 and retreatment with ara-C infusions failed to produce antitumor response. This study indicates that factors other than a high ratio of phosphorylation over deamination activity by the tumor seem to play an important role in the susceptibility of tumors to ara-C treatment.
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PMID:Correlation of response to 1-beta-D-arabinofuranosyl cytosine and metabolism of drug by tumor. 106 85

The selectivity of action of 1-beta-D-arabinofuranosylcytosine (ara-C) against leukemic cells was studied in vivo. Dynamic state tissue levels of ara-C and of its mono-, di-, and triphosphate (ara-CTP) were measured in L1210 leukemic cells and in C57BL x DBA/2 F1 host tissues at different times after various doses of the agent. The levels were correlated with inhibition of thymidine incorporation into DNA and with cytocidal effects as measured by loss of isotopically prelabeled DNA. ara-CTP levels, but not those of the mono- and diphosphates of ara-C, were higher in leukemic cells and in host cell renewal systems than in other host tissues. DNA synthesis was equally inhibited by similar levels of ara-CTP in ascitic L1210 cells, in leukemic infiltrates in liver, and in small intestine. However, L1210 cells accumulated higher levels of ara-CTP for longer periods than did small intestine, and correspondingly the inhibition of DNA synthesis was greater and more prolonged in leukemic cells. ara-C caused greater losses of prelabeled DNA in ascites cells and in infiltrated liver than in host small intestine. It appears that the differential net tissue level of ara-CTP and its duration are the determinants of chemotherapeutic efficacy of ara-C against L1210 leukemia. ara-C was the predominant nucleoside present in hydrolysates of ara-CTP fractions. By contrast, 1-beta-D-arabinofuranosyluracil predominated in hydrolysates of monophosphate nucleotide fractions from ascites cells, liver, small intestine, and blood. Monophosphate nucleotide was also present in ascites fluid and plasma.
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PMID:Metabolism and selective effects of 1-beta-D-arabinofuranosylcytosine in L1210 and Host tissues in vivo. 110 91

We examined the feasibility of maintaining specific plasma concentrations of ara-C and VP-16 in children with AML. Sixty-one children were treated with 6 sequential cycles of intensive chemotherapy consisting of: (1) cytarabine (ara-C)/VP-16, (2) ara-C/daunorubicin (Dauno), (3) VP-16/amsacrine (m-AMSA), (4) VP-16/5-azacytidine (5-Az), (5) ara-C/Dauno, and (6) ara-C/VP-16. Fifty-nine children had de novo AML, and 2 had a previous myelodysplastic syndrome. The number of patients with each specific FAB subtype was: M0-1; M1-7; M2-24; M3-7; M4-5; M5-11; and M7-6. Simultaneous continuous infusions of ara-C and VP-16 (cycle 1) given at individualized doses to achieve drug plasma concentrations of 1 microM and 30 microM, respectively, produced complete remission (CR) in 26 of 61 patients (43%); an additional 17 patients entered CR after Dauno/ara-C (cycle 2), and one patient required 4 cycles of chemotherapy to achieve CR (total CR rate = 72%). The preliminary 2-year event-free survival (EFS) for patients with FAB-M1 and -M2 AML was only 15% versus 40% for those with FAB-M4 and -M5 AML. Overall, 21 of the 61 patients remain in CR (2-yr EFS = 29%). We conclude that intense treatment with ara-C and VP-16 at doses individualized to achieve target plasma concentrations is feasible although severely myelosuppressive. It results in an acceptable CR rate, but does not improve EFS.(ABSTRACT TRUNCATED AT 250 WORDS)
Leukemia 1992
PMID:Current strategies for treatment of acute myeloid leukemia at St Jude Children's Research Hospital. 137 92

Between 1976 and 1988 we treated 228 children age 18 years or less with AML on three consecutive protocols: Vapa, 80-035 and Hi-C Daze. All three protocols used intensive consolidation chemotherapy. VAPA and 80-035 used an anthracycline with standard dose cytosine arabinoside (ara-c) for remission induction followed by twelve to fourteen months of intensive sequential chemotherapy. Results were similar for these two treatment protocols. 90/125 (72%) of the patients achieved a complete remission with 45% projected disease free survival for the complete responders, and an event free survival of 31%. 8/26 (VAPA) and 3/21 (80-035) relapses were primary CNS. No factor significantly influenced the rate of complete remission, but M4 and M5 FAB subtypes and WBC greater than 100,000/ul predicted for shorter remission duration. 103 children received Hi-C DAZE. The protocol differed by utilizing high-dose ara-c during induction and consolidation and pairing VP-16 with azacytidine. Hi-C DAZE was modified after the first 33 patients (group 1) because of CNS toxicity; VP-16/azacytidine were substituted for high dose ara-c/daunorubicin as the second induction course for the next 70 patients (group 2). Twenty eight of 33 (85%) of group 1 and 54/70 (77%) of group 2 entered remission.
Leukemia 1992
PMID:Intensive sequential chemotherapy for children with acute myelogenous leukemia: VAPA, 80-035, and HI-C-Daze. 137 93


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