Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.5.1.1 (asparaginase)
2,695 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

L-Asparagine synthetase appears in serum approximately 7 days after the s.c. implantation of 1 X 10(5) cells of Leukemia 5178Y/AR (resistant to L-asparaginase) and increases in activity as the neoplasm grows and metastasizes. The principal source of the enzyme is the primary tumor. After intravranial inoculation of tumor, the rate of leakage of the enzyme is more pronounced than when the subcutaneous, intramuscular, or intraperitoneal routes are used. 1-(2-Chloroethyl)-3-cyclohexyl-1-nitrosourea (NSC 79037), a nitro-sourea effective in the palliation of L5178Y/AR, temporarily halts the influx of enzyme into the blood stream, as does surgical excision of the s.c. tumor nodules. Treatment of mice with L-asparaginase within 24 hr of inoculation of the tumor markedly augments both tumor growth and the rate of penetration of L-asparagine synthetase into the circulation. Several other L-asparagine synthetase into the circulation. Several other L-asparaginase-resistant tumors also were found to spill L-asparagine synthetase into the serum, but the correlation between this phenomenon and the specific activity of the enzyme in homogenates of the tumor was imperfect.
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PMID:L-Asparagine synthetase in serum as a marker for neoplasia. 1 81

The cultured cell lines Yoshida ascites sarcoma, L-1210 mouse leukemia, OAT cell line derived from human lung cancer of the oat cell type, and P3HR-1 cell line derived from Burkitt's lymphoma have been used for the cell-killing kinetics study of anticancer agents and evaluation of the sensitivity of cells using the soft agar cloning assay method. It has been found that there are 2 types of actions: 1) Type I (cytocidal and concentration-dependent action). The dose survival curves of Type I agents fit the equation log S=log nminuskD (S, surviving fraction; D, concentration of agents; n and k are constant). The sensitivity of cells can be expressed by mean lethal dose 90% (MLD90=1/k). Four cell lines were compared on this basis, and some problems concerning the chemotherapy of human cancer are discussed. Alkylating agents and anticancer antibiotics belonged to this group.2) Type II (cytostatic and time-dependent action). The dose survival curves fit the Gompertz equation S=exp[(minusbeta/alpha)(1minus e-aD)] (beta, population reduction parameter; alpha, constant). The exposure survival curve is negative exponential, indicating that exposure time rather than concentration is the key fo effective cell killing of Type II agents. Difficulties in expression of sensitivity to Type II agents are discussed. Antimetabolites, Vinca alkaloids, and L-asparaginase belonged to this group. The cell-killing kinetics of anticancer agents and comparison of the sensitivity of cells may provide some indications not only of optimal dosage schedules but also of a new approach in screening systems for truly effective agents for human cancer.
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PMID:Cytocidal action of anticancer antigens: evaluation of the sensitivity of cultured animal and human cancer cells. 16 35

RNA synthesis in mouse leukemia L5178Y cells was inhibited depending upon the time of treatment by blasticidin S or by ricin, which inhibits specifically protein synthesis. When blasticidin S or ricin blocked protein synthesis by more than 90% of the control, marked accumulation of monosome was accompanied by the decrease of pulse-labeled RNA (20% of that in the control) in the polysomes and monosome fraction. The size distribution of pulse-labeled RNA among polysomal fractions including monosome obtained from the cells treated with either blasticidin S, ricin of L-asparaginase showed that the size of presumptive mRNA was shifted from 18 S to 9--10 S. TReatment of a blasticidin S-resistant (Bla-R) subline derived from L5178Y cells (Kuwano, M., Matsui, K., Takenaka, K., Akiyama, S. and Endo, H. (1977) Int. J. Cancer 20, 296--302) with L-asparaginase or ricin induced smaller size (9--10 S) RNA, but treatment of Bla-R cells with blasticidin S did not. Such shorter RNA fragments could not be observed even when cellular protein synthesis was inhibited by treatment for short time with blasticidin S (40--80% of the control activity). Smaller RNA fragments accumulated after drastic inhibition of protein synthesis were composed of 74% of polyadenylate sequence lacking poly(A)(-)RNA with peak of approx. 10 S and 26% of polyadenylate sequence containing poly(A)(+)RNA with a peak of 18 S, whereas cytoplasmic polysomal RNA of the control contained 46% poly(A)(+) with a peak of 18 S and 54% poly(A)(-)RNA with a 10--18 S peak. Cytoplasmic poly(A)(+)RNA degraded biphasically with half-lives of approx. 2 h and 8--10 h in exponentially growing mouse cells. However, in degradation of poly(A)(+)RNA molecules being formed in the cells pretreated with blasticidin S for 3 h, the rapid phase of decay with a half-life of approx. 2 h was interrupted by successively appearing poly(A)(+)RNA with a longer half-life of 8--10 h in cytoplasm. However, when the cells were pretreated with blasticidin S for 6 h, there appeared no poly(A)(+)RNA population with the rapid-decay in cytoplasm.
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PMID:The synthesis and degradation of presumptive messenger RNA in cultured mouse leukemia cells during the inhibition of protein synthesis. 71 32

After nitrosoguanidine mutagenesis we isolated from mouse leukemia L5178Y cells a mutant cell (Bla-R) resistant to blasticidin S, an inhibitor of protein synthesis. Neither growth nor leucine incorporation into hot-acid insoluble fraction of Bla-R cell was inhibited by 5 to 20 microgram/ml blasticidin S, which almost completely blocked protein synthesis as well as growth of the parental L5178Y cells. However, other inhibitors such as fusidic acid, cycloheximide, ricin D or L-asparaginase blocked protein synthesis in Bla-R cells to the same extent as in L5178Y cells. Protein synthesis in vitro using S-30 extracts from the parental cell line L5178Y was almost completely blocked in the presence of the antibiotic, while no inhibition by blasticidin S occurred when S-30 extracts -rom Bla-R mutant cells were used. Protein synthesis assays were made by using the S100 fraction from rat liver together with ribosomes from either L5178Y cells or Bla-R cells. Blasticidin S inhibited protein synthesis when ribosomes were derived from L5178Y cells, but not from Bla-R mutant.
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PMID:A mouse leukemia cell mutant resistant to blasticidin S. 89 36

We analyzed the effect of asparagine starvation and L-asparaginase on RNA metabolism of mouse leukemia cell lines L5178Y, whose growth is dependent on the presence of asparagine, and L5178Y-R, whose growth is independent of the presence of asparagine. The deprivation of asparagine from the medium inhibited cellular protein synthesis by 30 to 40% of the control value in L5178Y cells, but not in L5178Y-R cells, whereas L-asparaginase inhibited synthesis by more than 80% in both L5178Y and L5178Y-R cells. The decrease in protein synthesis caused by asparagine starvation in L5178Y cells was accompanied by a decrease in ribosomal RNA synthesis. The synthesis of rRNA was also markedly blocked when L5178Y and L5178Y-R cells were exposed to L-asparaginase. The rate of synthesis of pulse-labeled RNA decreased significantly in the cells treated with L-asparaginase, and smaller pieces of polyadenylate containing pulse-labeled RNA (presumptive messenger RNA) appeared among monosomes and polysomes. However, the rate of messenger RNA synthesis was constant during asparagine starvation, and a marked accumulation of monosome was observed.
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PMID:Effect of l-asparaginase and asparagine deprivation on RNA metabolism in mouse leukemia L 5178Y cells in suspension culture. 98 38

Essentially all the drugs which are active against human leukemias and lymphomas are active against one type or another of the rodent leukemias and lymphomas. Leukemia L1210 has been generally the most successful screening tool for clinically active compounds. Leukemia P388, however, seems to be better in detecting active antibiotics and natural products and P1534 is particularly sensitive to the Vinca alkaloids, while L5178Y, EARAD, and 6C3HED are useful in detecting the activities of various asparaginase containing fractions. Cell cultures of these leukemias can demonstrate mechanism of drug action and quantitate resistance. Spontaneous AKR leukemia is a model of the advanced human disease. In these leukemias vincristine and prednisone produce a 4 log cell kill. Cytoxan and arabinosyl cytosine (Ara-C) are also effective. On the other hand drugs such as mercaptopurine (6MP) and methotrexate which are highly active in the maintenance phase of acute lymphocytic leukemia (ALL) and in L1210 have little or no activity against the AKR spontaneous system. Mouse leukemias can also detect schedule dependence, synergistic combinations, cross resistance, oral activity, and the ability of drugs to pass the blood brain barrier. A case in point is the Ara-C analog 2,2'-anhydro-arabinofuranosyl-5-fluorocytosine (AAFC) which is not schedule dependent, is active orally, is potentiated by thioguanine, and is effective against intracerebrally inoculated mouse leukemia. AAFC and its analogs might thus be a considerable improvement over Ara-C which is at the present time the most important component of the combination treatment of acute myelogenous leukemia (AML).
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PMID:Murine and human leukemias. 110 47

The automated fluorometric microculture cytotoxicity assay (FMCA) was used for chemotherapeutic drug sensitivity testing of fresh and cryopreserved tumor cells from patients with acute lymphoblastic leukemia (ALL) at diagnosis and relapse. The technique success rate was 87% for fresh and 81% for cryopreserved samples. Up to 16 different cytotoxic drugs were routinely tested, but neither asparaginase nor methotrexate produced dose-response related cell kill. FMCA data showed good correlation to the well established Disc assay and the drug sensitivity reported by the FMCA was in good agreement with known clinical activity. Samples from children and initial ALL tended to be more drug sensitive than those from adults and ALL at relapse, respectively. For 36 samples clinical outcome was correlated to the quartile position in comparison to all other samples for the most in vitro active drug actually given to the patient. For patients with samples in the first, second, third, and fourth quartiles, the probabilities of complete remission were 89, 57, 38, and 0%, respectively. Using the median value as cut-off line, the sensitivity and specificity of the assay were 87 and 62%, respectively. It is concluded that the FMCA with a minimum of effort and with high success rate report clinically relevant drug sensitivity profiles for ALL.
Leukemia 1992 Nov
PMID:Feasibility of the fluorometric microculture cytotoxicity assay (FMCA) for cytotoxic drug sensitivity testing of tumor cells from patients with acute lymphoblastic leukemia. 143 93

From February 1986 to January 1991 the Pediatric Oncology Group (POG) treated 2404 children or adolescents with acute lymphoblastic leukemia (ALL) on immunophenotype (T-, B-, Pre-B, or Early pre-B-cell), age, and leukocyte count based treatment protocols (ALinC 14, T-cell 3, B-cell and infant leukemia studies). The immunophenotypic subgroups comprised 78.9% B-precursor cell, 15.1% T-cell, 2.0% B-cell, and 4% infant ALL. Patients with B-progenitor cell ALL were stratified by age and leukocyte count and randomized to receive induction therapy comprised of vincristine, prednisone, and asparaginase with triple intrathecal chemotherapy (methotrexate, hydrocortisone, cytarabine), followed by intensification with moderate-dose MTX (Regimen A), moderate-dose MTX plus asparaginase (Regimen B), moderate-dose MTX plus cytarabine given early (Regimen C), or moderate-dose MTX plus cytarabine given over the first 16 months of therapy (Regimen D). Continuation therapy comprised mercaptopurine and methotrexate with vincristine plus prednisone pulses. Central nervous system preventive treatment was continued for two years. Patients with T-cell or B-cell ALL or infants less than 1 yr old were treated on individual very intensive multiagent therapy protocols. The 4-year event-free survival for all patients was 66.4% +/- 2.4%; B-precursor ALL approximately 72%, T-ALL approximately 50%, B-ALL approximately 60%, and infants less than 1 yr old approximately 16.5%. We conclude that about two-thirds of newly diagnosed children with ALL can be cured with this approach which spares the majority of children exposure to alkylating agents, anthracyclines, epipodophylotoxins, and irradiation, diminishing the risks of serious acute and late effects.
Leukemia 1992
PMID:Current results of studies of immunophenotype-, age- and leukocyte-based therapy for children with acute lymphoblastic leukemia. The Pediatric Oncology Group. 157 22

Cytosine arabinoside (ara-C) is one of the most active compounds in the treatment of acute leukemias. In the majority of current protocols ara-C is combined with other cytotoxic agents in an attempt to increase antileukemic activity. The present study investigated the impact of etoposide, teniposide, amsacrine, mitoxantrone, anthracyclines, and asparaginase on the cellular accumulation of ara-C and its intracellular metabolism in order to provide a better rationale for combination therapy. Intracellular accumulation and phosphorylation of ara-C were determined in peripheral blast cells from twenty patients with acute leukemias after exposure to 1 and 10 mumol/l ara-C alone and after preincubation with 1 and 10 micrograms/ml etoposide, 10 and 100 micrograms/ml teniposide, 10 mumol/l amsacrine, 500 ng/ml mitoxantrone (or daunorubicin or doxorubicin) or 10 mumol/l asparaginase. Ara-C accumulation at 10 mumol/l was decreased by 1 microgram/ml etoposide (67 +/- 18% of control), 10 micrograms/ml etoposide (30 +/- 22%), 10 micrograms/ml teniposide (12 +/- 23%), 100 micrograms/ml teniposide (10 +/- 18%), and amsacrine (51 +/- 21%). Intracellular ara-CTP formation was determined at an extracellular concentration of 10 mumol/l and preincubation with these drugs. The intracellular formation of ara-CTP was decreased by 1 microgram/ml etoposide (77 +/- 15% of control), 10 micrograms/ml etoposide (32 +/- 22%), 10 micrograms/ml teniposide (10 +/- 9%), 100 micrograms/ml teniposide (0 +/- 0%), but not by amsacrine. These data indicate that prior exposure to etoposide and teniposide influence ara-C metabolism and possibly cytotoxicity, and thus should not immediately precede ara-C administration in clinical trials.
Leukemia 1992 Jun
PMID:Intracellular cytosine arabinoside accumulation and cytosine arabinoside triphosphate formation in leukemic blast cells is inhibited by etoposide and teniposide. 160 95

Cancer and Leukemia Group B undertook a randomized trial of intensification treatment in adults aged 15 to 79 years with acute lymphocytic leukemia (ALL) in complete remission (CR). Daunorubicin (DNR), prednisone, vincristine (VCR), intrathecal (IT) methotrexate (MTX), and asparaginase produced 177 CRs in 277 patients. One hundred fifty-one patients were randomly assigned to receive treatment as follows: 74 received intensive cytarabine and DNR, and 77 received cycles of mercaptopurine (6-MP) and MTX, followed by 6MP, MTX, VCR, and prednisone for 3 years in all. One hundred twelve patients received CNS prophylaxis. Intensification produced major myelosuppression but did not improve remission duration (median, 21 months). Of the 151 patients with CRs who entered the intensification phase, 29% remain in continuous CR (43 to 117 months); in 19 patients, CRs have lasted for longer than 7 years. No relapses occurred after 60 months. Median survival from the time of randomization was 30 months. Those under 30 years of age responded more frequently, with longer CR and survival. While 53% of those aged 15 to 19 years remain in continuous CR, 92% of patients over 59 years have relapsed. The presence of a myeloid antigen on the leukemic cells was adversely prognostic for CR achievement and for survival. Pretreatment WBC and platelet levels independently affected CR duration and survival. Early M1 marrow development presaged longer remissions. CNS relapse occurred in 47 of 256 patients with normal CSF before treatment, in 29 before CNS prophylaxis. CNS disease occurred after CNS prophylaxis in 18 patients: 13 of 61 who had received standard premaintenance and five of 51 who received intensification. No advantage in CR duration or survival resulted from intensive treatment with DNR and cytarabine following induction of CR.
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PMID:The effects of postinduction intensification treatment with cytarabine and daunorubicin in adult acute lymphocytic leukemia: a prospective randomized clinical trial by Cancer and Leukemia Group B. 194 Oct 59


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