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)

Two groups of children with refractory acute lymphoblastic leukemia were treated with a regimen of methotrexate (MTX) and asparaginase (Asn'ase) based on studies of the effect of MTX in vitro on human lymphoblasts exposed to Asn'ase. Induction therapy in 12 children produced 4 complete remissions, 3 partial remissions, and 5 failures. Responsiveness to Asn'ase seemed necessary for successful induction with the drug combinations. Maintenance therapy in 18 children produced a median hematologic remission of 31 weeks (range 3-85 weeks). During remission, 2 children developed central nervous system leukemia and 2 died of infection. The mean maximally tolerated dose of MTX was 361 mg/m2. The results of this trial suggest therapeutic synergy in maintenance therapy and the capability of Asn'ase to attenuate MTX toxicity.
Cancer 1979 Mar
PMID:Methotrexate and asparaginase combination chemotherapy in refractory acute lymphoblastic leukemia of childhood. 28 40

The characterization of two human T-lymphocyte lines revealed that they required exogenous L-asparagine for cell growth, whereas all four B-cell lines studied were L-asparagine independent. T-cells were 800-2,000 times more sensitive to Escherichia coli L-asparaginase than were B-cells. The cytotoxic effects of a high concentration of L-asparaginase on B-cells were not related to the hydrolysis of L-asparagine but were due to heat-labile and heat-resistant substances in the enzyme. The findings were consistent with reports that L-asparaginase is effective in suppressing cellular immunity and inducing remission in patients with acute lymphocytic leukemia, mainly a non-B-cell disease. Thus these cell lines provide in vitro models for the study of a nutritional approach to chemotherapy or immunotherapy.
J Natl Cancer Inst 1977 Oct
PMID:L-asparagine requirements of human T-lymphocytes and B-lymphocytes in culture. 30 63

After previous work from this laboratory revealed that asparaginase was 800-2,000 times more inhibitory against human T-lymphocytes in culture than against B-lymphocytes, a similar further study of 13 chemotherapeutic and immunosuppressive agents was done. Cytosine arabinoside and 5-fluorouracil also had differential inhibitory activities on human T- and B-cells in culture. On the basis of the dose producing 50% inhibition of viable cell growth on day 5, cytosine arabinoside had 45-80 times more inhibitory activity against T-cells than against B-cells. In contrast to asparaginase and cytosine arabinoside, 5-fluorouracil had 10-20 times more inhibitory activity against B-cells. The rest of the chemotherapeutic and immunosupressive agents tested had minor or no differential activity. These findings indicated that T-cell response to asparaginase and cytosine arabinoside and B-cell response to 5-fluorouracil may be exploitable for the differential immunosuppressive effects presumed to be active in vivo. In addition, such differential responses may predict differential tumor cell behavior against these chemotherapeutic agents by T- and B-cell neoplasms in vivo.
J Natl Cancer Inst 1978 Apr
PMID:Differential chemotherapeutic susceptibility of human T-lymphocytes and B-lymphocytes in culture. 30 85

The sensitivity of the neoplastic cell to amino acid deprivation shows considerable variation. The responsiveness of human leukemic cell cultures to L-asparaginase indicates that those of T cell origin are much more sensitive to the action of this L-asparagine-depleting enzyme than those of B cell origin. A cautionary note is raised concerning amino acid analogs. Minor changes such as substituting selenium for sulfur to make seleno-L-methionine rather than L-methionine may lead to considerable differences in their respective metabolic polls in vivo. A systemic survey of amino acid requirements of human neoplasms is desirable before designing new analogs.
Cancer Treat Rep 1979 Jun
PMID:Lessons from the study of induced alterations in amino acids in patients with cancer. 31 38

This controlled study of children with ALL was designed to test the efficacy and toxicity of one-, two-, three- and four-drug therapy during remission and whether more aggressive therapy in the first eight weeks prolongs remission in patients with features associated with a particularly poor prognosis. After inducing remission with prednisone, vincristine and asparaginase, patients received cranial irradiation and IT methotrexate and were randomized to receive: 1--methotrexate alone; 2--methotrexate plus mercaptopurine; 3--same as in group 2 plus cyclophosphamide; and 4--same as in group 3 plus arabinosyl cytosine. Patients with CNS leukemia at diagnosis received IT methotrexate weekly during the induction period and a higher dose of CNS irradiation. Patients with anterior mediastinal enlargement at diagnosis received radiotherapy to the mass during the induction period. Patients who failed to attain bone marrow remission after four weeks of therapy were given daunorubicin and prednisone for 2--4 additional weeks. Of the 282 patients entering this study between January 1972 and November 1975, 268 (95%) attained complete remission and 228 (85%) were randomized to receive continuation chemotherapy with 1, 2, 3 or 4 drugs. In Group 1 (methotrexate alone), 14 of 20 patients relapsed and 9 developed leukoencephalopathy without antecedent CNS leukemia apparently due to higher doses of intravenous methotrexate; in Groups 2, 3 and 4 the results were equivalent, but without leukoencephalopathy in initial CR. The addition of cyclophosphamide and arabinosyl cytosine increased toxicity and complications without demonstrably increasing the leukemocidal effect. In the 40 patients given additional early therapy, the modalties employed in this study did not prolong remission.
Cancer 1978 Nov
PMID:Childhood acute lymphocytic leukemia: study VIII. 36 52

The effects of E. coli L-asparaginase on cultured human pancreatic carcinoma (MIA PaCa-2) have been studied. The enzyme (1 U/ml) inhibited growth and protein synthesis in both MIA PaCa-2 and PANC-1, another pancreatic carcinoma cell line, but had little or no effect on human breast carcinoma or melanoma cells. The inhibition of protein synthesis by E. coli L-asparaginase was largely reversed by L-glutamine but not by L-asparagine. The growth of both MIA PaCa-2 and PANC-1 showed absolute dependence on L-glutamine. These results indicate that the effect of E. coli L-asparaginase on cultured pancreatic carcinoma cells is exerted at least in part through its L-glutaminase activity. Although the addition of L-glutamine to the culture appeared to prevent cell death caused by L-asparaginase, it did not restore the ability of the cells to proliferate. Asparaginase derived from vibrio succinogenes, which is virtually free of L-glutaminase activity, was equally inhibitory to MIA PaCa-2 cell growth but did not affect protein synthesis. It is concluded that the inhibition of growth of cultured pancreatic carcinoma cells by E. coli asparaginase is a combined function of both its L-asparaginase and L-glutaminase activity.
Int J Cancer 1978 Dec
PMID:Mechanism of sensitivity of cultured pancreatic carcinoma to asparaginase. 36 26

The combination of sequential L-asparaginase and methotrexate (MTX) was evaluated in 33 patients with advanced refractory breast cancer. There were nine partial responses and one complete response, giving an overall response rate of 30% and a median duration of response of 8 months. Five of 17 patients (28%) who had received prior MTX at doses of less than 50 mg/m2 responded. Toxicity was acceptable. Moderate-to-severe stomatitis occurred in most patients and was the dose-limiting factor. Myelosuppression was minimal until the dose of MTX was escalated to greater than or equal to 180 mg/m2. The maximum tolerated dose of MTX was 280 mg/m2 and the median toxic dose was 220 mg/m2. These data indicate a selective "rescue" from MTX damage to normal target tissue by L-asparaginase. The antitumor effect observed even in patients who had been previously exposed to conventional doses of MTX suggests a possible improved therapeutic index of MTX given sequentially with L-asparaginase in this combination.
Cancer Treat Rep 1979 Jan
PMID:Phase II study with sequential L-asparaginase and methotrexate in advanced refractory breast cancer. 36 95

Thirty previously untreated adults with diffuse histiocytic and diffuse undifferentiated lymphoma were treated with a combination of adriamycin, vincristine, prednisolone, and L-asparaginase. Complete remission was achieved in 11 out of 12 cases with stage III and 7 out of 18 cases with stage IV disease (P less than 0.005). Bone marrow infiltration, clinical central nervous system involvement, and massive intra-abdominal disease all influenced the prognosis adversely. Complete remission was followed by cranial irradiation and intrathecal methotrexate, and maintained with weekly cyclophosphamide and methotrexate and daily 6-mercaptopurine. The duration of remission was significantly longer for patients with stage III disease (the median of which has not been reached), than for patients with stage IV disease (P = 0.007). Survival was significantly longer for patients in whom complete remission was achieved than for those in whom it was not (P = 0.001), and also for patients with stage III than for those with stage IV disease (P = 0.02).
Cancer Chemother Pharmacol 1978
PMID:Combination chemotherapy for advanced non-Hodgkin's lymphoma of unfavourable histology. 37 11

Nutrients as therapy for patients with cancer are important as adjunctive therapy, i.e., adequate nutrition may be important for the success of whatever form of therapy is administered. Diets deficient in certain amino acids have some selectivity when tested against experimental tumors propagated in vivo. Such diets have had limited clinical trial and have been characterized by poor patient acceptance. Enzymes that produce deficiencies of certain amino acids, e.g., asparaginase, glutaminase, methioninase appear to offer a more reasonable approach to development of selective amino acid deficiencies in man. Trace metals in excessive amounts may be toxic or carcinogenic to the host. Two heavy metal salts, Cis-diamine dichloroplatinum and gallium nitrate, have recently been shown to have anti-neoplastic effects in man. There is no conclusive evidence that vitamins, administered in large doses, have significant antineoplastic effects although large doses of vitamin A, vitamin C, and vitamin B12 have been used for this purpose. In contrast, certain vitamin analogs such as folate antimetabolites can cause tumor regression and are useful clinical treatment. An enzyme, carboxypeptidase G1, by splitting naturally occurring folates, may also have promise as a method of producing enzymic folate deficiency.
Cancer 1979 May
PMID:Nutrients, vitamins and minerals as therapy. 37 10

L-Asparaginase, in the dose of greater than or equal to 6000 IU/sq m three times weekly, was demonstrated to be an effective agent in reinduction of remissions in childhood leukemia. Four hundred thirteen children with acute lymphocytic leukemia were treated with L-asparaginase. Doses i.m. ranged from 300 to 12,000 IU/sq m. None of the patients had received prior asparaginase therapy. 6-Mercaptopurine was given p.o. concurrently. All of the patients had experienced several previous relapses, and their disease was not responsive to 6-mercaptopurine. L-Asparaginase was found to be effective in reinducing remissions at the following rates: 9.5% for 300 IU/sq m; 35.1% for 3,000 IU/sq m; 53.5% for 6,000 IU/sq m; and 62.5% for 12,000 IU/sq m. The drug was given three times weekly for four weeks. Hypersensitivity reactions occurred in 6.5% of patients.
Cancer Res 1979 Oct
PMID:Effective dose of L-asparaginase for induction of remission in previously treated children with acute lymphocytic leukemia: a report from Childrens Cancer Study Group. 38 78


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