Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Inoculation of bone marrow and spleen cells of C3H/Sumice strain mice demonstrated that on the ninth day of growth of Gardner lymphosarcoma these tissues were invaded with tumor cells. The weights of mice with advanced tumors increased. Yet the deterioration of health status of mice is characterized by decreased food and water consumption, as well as by lower concentrations of proteins in mouse sera and plasma. The albumin fraction shows a remarkable drop. These changes could not be detected in tumor free mice following LDH-virus infection. The treatment with L-asparaginase influenced the manifestations of tumor growth, but not the effectivity of LDH-virus contaminating the tumor as demonstrated by the increased activity of lactate-dehydrogenase in the mouse sera.
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PMID:Changes in hemopoiesis of mice of the C3H strain following transplantation of Gardner lymphosarcoma and infection with LDH-virus. III. Blood proteins. 689 6

Polymeric conjugates of L-asparaginase and an excess of homologous albumin were compared with free L-asparaginase for antitumor activity using a mouse model 6C3HED lymphosarcoma and a human pancreatic tumor cell line, PANC-1. The asparaginase-albumin polymer is more resistant to proteolytic degradation compared to equivalent amounts of free enzyme and is more effective as an antitumor agent in prolonging survival of C3H/HeJ mice receiving 6C3HED lymphosarcoma. In terms of antitumor activity, the enzyme is approximately 20 times more effective, compared to free enzyme, when given in polymeric form with albumin. Similarly, the polymeric form of L-asparaginase is more effective in inhibiting cell growth of human pancreatic tumor cells grown in tissue culture. The increased effectiveness of the polymeric form of L-asparaginase is probably related to its resistance to biodegradation. The use of cell surface-specific monoclonal antibodies to target the polymer to tumor cells is also demonstrated.
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PMID:Advantages in the use of L-asparaginase-albumin polymer as an antitumor agent. 689 61

Twelve dogs with lymphosarcoma and hypercalcemia were treated over a period of 36 months. Signs and laboratory findings were referable to hypercalcemia and azotemia. All dogs were staged, classified histologically, and given cytoreductive chemotherapy, using 5 drugs (vincristine sulfate, cytosine arabinoside, cyclophosphamide, L-asparaginase and prednisone). For azotemia, symptomatic therapy (0.9% NaCl solution and furosemide) was given. Seven dogs responded completely, with marked reduction of lymphadenopathy and return of serum calcium concentration to normal. Median duration of remission in this group was 48 days (range, 14 to 93), and median survival time was 112 days (range, 85 to 153). Five nonresponding dogs had less than 50% reduction in measurable tumor mass, although serum calcium concentration returned to normal. The median survival time for this group was 34 days (range, 23 to 68). Two of the nonresponders died from sepsis and another from disseminated intravascular coagulation. Response to therapy did not appear to be influenced by age, breed, sex, initial calcium concentration, degree of azotemia, or histologic classification.
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PMID:Chemotherapeutic responses in dogs with lymphosarcoma and hypercalcemia. 689 39

In a variety of cell culture and in vivo experiments with normal and tumor-bearing animals, the antecedent or simultaneous use of protein synthesis inhibitors with antimetabolites or alkylating agents will significantly attenuate the cytotoxic effects of the latter. The protein synthesis inhibitor asparaginase shares this potential. In murine leukemia L5178Y which is sensitive to both asparaginase and methotrexate (MTX), the prior use of asparaginase or the simultaneous administration of both drugs results in subadditive effects. In tumor-bearing mice, multiple courses of sequential MTX followed by asparaginase cured 55% of the leukemic mice whereas the converse sequence cured none. Partial explanation for this pharmacologic antagonism includes asparaginase-induced decrease in cellular uptake of MTX and delay in cell cycle traverse. It is of importance to recognize such pharmacologic antagonism for the proper design of clinical trials. Studies with human leukemic lymphoblasts suggest that the optimal time interval between asparaginase and a subsequent dose of MTX was 9-10 days. A 24-hour interval between methotrexate and a subsequent dose of asparaginase permits at least an additive therapeutic effect. The repeated use of this 2-day tandem schedule (MTX AsNase) permits the host to tolerate increasingly larger doses of MTX. These larger doses of MTX may have therapeutic benefit for the following reasons: 1) the steep dose-response relationship for MTX, 2) larger doses may overcome "transport-resistant" populations, and 3) larger doses may penetrate pharmacologic sanctuaries such as the blood-brain barrier. Trials of this combination in adults and children with advanced lymphoblastic leukemia, many of whom were previously treated with asparaginase and were refractory to conventional doses of MTX, resulted in complete remissions of 64% and 50%, respectively.
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PMID:Asparaginase-methotrexate in combination chemotherapy: schedule-dependent differential effects on normal versus neoplastic cells. 704 75

Mouse P388 and L1210 leukemia cells grown in vitro were found to be 4 to 10 times more sensitive to 6-diazo-5-oxo-L-norleucine and 3 to 5 times more sensitive to Acivicin than were 3T3 and C57BL x DBA/2 F1 embryonic fibroblasts. The combined actions of succinylated Acinetobacter glutaminase-asparaginase and 6-diazo-5-oxo-L-norleucine or Acivicin produced synergistic inhibition of nucleic acid synthesis in P388 tumor cells. An uptake system for Acivicin is described. Its properties in P388 and 3T3 cells are similar in their strong temperature dependence, utilization of the "L" transport system, presumably competitive inhibition by glutamine, similar Km's (about 200 microM), and potent inhibition by p-chloromercuribenzene sulfonate, NA+. However, Acivicin uptake was inhibited in 3T3 (but not in P388) cells by KCN or 2,4-dinitrophenol. At equilibrium in P388 cells, the intracellular level of Acivicin was approximately 57-fold greater than was the extracellular concentration. The accumulated Acivicin was not metabolized by P388 cells, nor does exchange of 3H label into water occur. Rapid efflux of Acivicin occurred with both cell lines at 37 degrees, but efflux from 3T3 cells was greatly diminished at 0 degrees. The rate of efflux was accelerated by including glutamine or unlabeled Acivicin in the extracellular medium.
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PMID:Enhancement of antitumor activity of glutamine antagonists 6-diazo-5-oxo-L-norleucine and acivicin in cell culture by glutaminase-asparaginase. 721 22

The effects of Acinetobacter glutaminase-asparaginase (AGA) on protein and energy requirements were evaluated in mice bearing Ehrlich ascites tumors. In an initial experiment with normal mice, a zero protein diet resulted in a significant decrease in carcass nitrogen, liver nitrogen, and carcass energy relative to the animals on a normal, low, or high protein diet. In a second experiment, mice bearing Ehrlich ascites tumors were randomized into diet groups (zero or normal protein) and treatment groups (daily injections of AGA or 0.9% NaCl solution). In both treatment groups, the zero protein diet resulted in significant decreases in weight, liver nitrogen, carcass nitrogen, and carcass energy. Neither tumor nor AGA treatment affected body composition or the efficiency of nitrogen utilization. By Day 8, either the zero protein diet or AGA treatment significantly reduced ascites volume and tumor nitrogen content relative to controls. In a modification of Experiment 2, AGA treatment was stopped on Day 8, and all animals were given a normal protein diet. AGA, but not the zero protein diet, significantly enhanced ultimate survival. These experiments indicate that the requirements and utilization of energy and nitrogen are normal in mice with Ehrlich ascites tumor whether or not they are treated with AGA.
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PMID:Nitrogen utilization in mice bearing Ehrlich ascites tumor treated with Acinetobacter glutaminase-asparaginase. 723 13

Succinylated Acinetobacter glutaminase-asparaginase (SAGA) has broader antitumor activity than Escherichia coli L-asparaginase in experimental systems; moreover, drug resistance does not develop in tumor cell lines initially sensitive to this enzyme. We have investigated the pharmacology and toxicology of SAGA after both single-dose and serial daily dose injections in 20 adult patients. Glutaminase activity in plasma after i.v. injection of single doses did not follow simple first-order kinetics (half-life during the initial 24 hr was 21 +/- 9 hr. A linear relation was observed between increasing doses of SAGA and resultant levels of plasma enzyme activity and blood glutamate. Assay of whole blood which had been deproteinized immediately following phlebotomy showed that single doses of SAGA lowered glutamine only transiently to nondetectable levels; serial daily doses were required to achieve and maintain continuous glutamine depletion. Reversible depression of the central nervous system, ranging from encephalopathy to coma, occurred in a dose-related manner and was dose limiting. Other prominent reactions included respiratory alkalosis, hyperglycemia, nausea, and vomiting. Transient antitumor effects were noted in two patients with solid tumors and in two patients with leukemia. SAGA causes considerable neurotoxicity in adults which requires close patient monitoring. Phase II studies in leukemic patients are in progress.
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PMID:Phase I evaluation of succinylated Acinetobacter glutaminase-asparaginase in adults. 743 89

L-Asparaginase was given to ten patients with advanced nonresectable pancreatic carcinoma because of the demonstration of in vitro sensitivity of the tumor to the drug. No therapeutic value was demonstrated for L-asparaginase. Toxicity was significant, mainly as evidenced by increasing mental confusion and early signs of a coagulopathy. On the basis of this limited study, L-asparaginase seems to have no value in advanced pancreatic carcinoma. The usefulness of L-asparaginase as primary therapy in patients with less advanced disease remains to be determined.
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PMID:Phase II study of L-asparaginase in the treatment of pancreatic carcinoma. 747 Nov 24

An L-asparaginase produced by Pseudomonas stutzeri MB-405 was isolated and characterized. After initial ammonium sulfate fractionation, the enzyme was purified by consecutive column chromatography on Sephadex G-100, Ca-hydroxylapatite, and DEAE-Sephadex A-50. The 665.5-fold purified enzyme thus obtained has the specific activity of 732.3 units mg protein-1 with an overall recovery of 27.2%. The apparent M(r) of the enzyme under nondenaturing and denaturing conditions was 34 kDa and 33 kDa respectively, and the isoelectric point was 6.38 +/- 0.02. It displayed optimum activity at pH 9.0 and 37 degrees C. The enzyme was very specific for L-asparagine and did not hydrolyze L-glutaminate. The Km of the L-asparaginase was found to be 1.45 x 10(-4) M towards L-asparagine and was competitively inhibited by 5-diazo-4-oxo-L- norvaline (DONV) with a Ki of 0.03 mM. Metal ions such as Mn2+, Zn2+, Hg2+, Fe3+, Ni2+, and Cd2+ potentially inhibited the enzyme activity. The activity was enhanced in the presence of thiol-protecting reagents such as DTT, 2-ME, and glutathione (reduced), but inhibited by PCMB and iodoacetamide. The tumor inhibition study with Dalton's lymphoma tumor cells in vivo indicated that this enzyme possesses antitumor properties.
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PMID:Purification, characterization and antitumor activity of L-asparaginase isolated from Pseudomonas stutzeri MB-405. 776 57

Ten percent (214/2,059) of all dogs with cancer at North Carolina State University Veterinary Teaching Hospital had thrombocytopenia. The thrombocytopenia was associated with infectious/inflammatory etiologies in 4%, miscellaneous disorders (therapy, bone marrow failure, disseminated intravascular coagulation) in 35%, and neoplasia without identifiable secondary factors in 61% of cancer-bearing dogs. Classifying these dogs by tumor groups revealed the following proportionate ratios: lymphoid, 29%; carcinoma, 28%; sarcoma, 20%; hemic neoplasia, 7%; multiple, 5%; unclassified, 3%; benign, 3%; brain, 3%; and endocrine, 3%. Dogs with hemangiosarcoma, lymphoma, and melanoma were at increased risk of developing thrombocytopenia. Cytotoxic therapy was the major factor increasing the risk of thrombocytopenia in dogs with melanoma. Golden Retrievers were the only breed recognized with a predisposition to develop thrombocytopenia. If thrombocytopenia is identified in a dog with cancer, we recommend thorough evaluation of the coagulation system before surgery or therapy, and careful consideration of the risks and potential benefits of myelosuppressive or L-asparaginase therapy.
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PMID:Thrombocytopenia associated with neoplasia in dogs. 788 25


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