Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:6.3.5.5 (CPS)
 1,262 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Over the past 40 years, the American Cancer Society has led in large-scale, prospective studies of behavioral and environmental risk factors in association with cancer development. Through results of its 1952 study, cigarette smokers were found to have a 10-fold higher risk of lung cancer than nonsmokers. Cancer Prevention Study I (1959-1972) extended these results and also showed the relationship between age smoking began, depth of inhalation, smoking cessation, air pollution, body weight, etc., on all causes of death as well as specific cancer sites. Cancer Prevention Study II began in 1982 and after six years of follow-up has confirmed many earlier findings, and additionally has found: aspirin may be protective against colon cancer; persons reporting themselves to be heavy exercisers had higher standardized mortality ratios (SMR) for lung, colorectal, and pancreas cancer than moderate exercisers; more women who were long-term users of artificial sweeteners reported gaining weight during the past year than nonusers; diesel fume exposure elevated the risk of lung cancer among men ages 40-79; pesticide exposure was associated with an increased risk of multiple myeloma; and based on CPS II mortality rates, an estimated 250 million of the 1.25 billion persons living in developed countries will die because they smoke.
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PMID:Cancer Prevention Study II. The American Cancer Society Prospective Study. 147 48

An automated non-chiral high-performance liquid chromatographic method is described for the determination of the new anti-proliferative agent B859-35 in serum. This method employs sample clean-up of 1 ml of biofluid by liquid-solid extraction with the AASP (Advanced Automatic Sample Preparation) system. First separation is achieved on a LiChrospher-60-RP-Select-B column. A fraction of this elute is then collected by solid-phase trapping. Thereafter, the final chromatogram is developed on a narrow-bore Hypers1-CPS column and quantified with ultraviolet detection at 230 nm. The limit of quantitation of the assay is 250 ng/ml. Linearity was proven in the range 0.25-100 ng/ml. Typical figures for precision at these concentrations are 7.4 and 3.3%, and for accuracy 8.0 and 1.3%, respectively. An application of this method to the study of pharmacokinetics of B859-35 in serum samples of cancer patients is given.
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PMID:Two-dimensional high-performance liquid chromatography at low ng/ml levels of the anti-proliferative agent B859-35 in serum with automated sample clean-up, solid-phase trapping and ultraviolet detection. 178 69

A study was made of the in vivo effects of equitoxic doses of AT-125 and 5-FU combination, being administered either simultaneously (% ILS 152) or with a 6-h pretreatment with AT-125 (% ILS 184). To examine the biochemical basis for the scheduled synergism, measurements were made of the concentration of PRPP, the specific activities of CPS II, cytidine, thymidine, uridine, deoxyuridine kinases, and fluorinated nucleotide formation in P388 tumors and the small intestine. Two hours after in vivo simultaneous treatment of mice bearing tumors the concentration of PRPP increased 9- and 6-fold above baseline in the tumor and the small intestine, respectively. In the AT-125 pretreatment arm the concentration of PRPP increased 18- and 7-fold above baseline in the tumor and the small intestine, respectively. CPS II activity was reduced to 28%-18% of control in the tumors in the simultaneous and pretreatment groups, respectively, whereas it remained unchanged in the small intestine. Specific activities of cytidine kinase (5.5 +/- 1), thymidine kinase (4.0 +/- 1.6), uridine kinase (35.6 +/- 6.5), and deoxyuridine kinase (2.4 +/- 1.1) nmol/mg protein/h remained unchanged with treatment. In concert with the increased intratumor concentration of PRPP, fluorinated nucleotide formation was proportionally increased in the treatment arms. These results indicate the importance of drug scheduling of the above two agents in treating P388 leukemia.
Cancer Chemother Pharmacol 1985
PMID:Biochemical mechanisms for the scheduled synergism of (alpha S, 5S)-2 amino-3-chloro-4,5-dihydro-5-isoxazoleacetic acid and 5-fluorouracil in P388 leukemia. 240 73

Acivicin [L-(alpha S,5S)-alpha-amino-3-chloro-4,5-dihydro-5-isoxazoleacetic acid; NSC 163501] is a fermentation-derived amino acid antibiotic antagonistic to L-glutamine which exhibits potent oncolytic properties. We have developed a variant of P388 leukemia resistant to acivicin (P388/ACIA) and compared its properties with those of the parent line (P388/S). An examination of the enzymes utilizing L-glutamine revealed that the basal specific activities of L-asparagine synthetase and L-glutaminase were 1-to 3-fold higher in the parent line. The activities of carbamoyl phosphate synthetase II, L-asparagine synthetase, formylglycinamide ribonucleotide amidotransferase, and guanosine monophosphate synthetase were about equally inhibited in the two cell lines, while there was a partial inhibition of 5-phosphoribosyl-1-pyrophosphate amidotransferase, fructose-6-phosphate amidotransferase, and L-glutaminase activities, found only in the sensitive line. Cytidine triphosphate synthetase activity was not inhibited in either line. There was no difference in the dose response or restitution of L-glutamine utilizing enzyme activities between the two lines. Acivicin treatment produced a 2- to 3-fold augmentation of the L-glutamine pools only in the sensitive line. Drug injection induced increased 5-phosphoribosyl-1-pyrophosphate levels in both lines. Acivicin perturbed guanosine nucleotide pools only in the sensitive line, indicating that the primary mechanism of action of acivicin in P388 leukemia may be directed at guanosine monophosphate synthetase. Transport studies demonstrated a restricted uptake of acivicin by the resistant cells. These studies suggest that the transport of acivicin and L-glutamine plays an important role in determining the sensitivity or resistance to acivicin in these tumors.
Cancer Res 1985 Jan
PMID:Mechanism of resistance of a variant of P388 leukemia to L-(alpha S,5S)-alpha-amino-3-chloro-4,5-dihydro-5-isoxazoleacetic acid (acivicin). 257 92

In order to study the histogenesis of gallbladder cancer, metaplastic changes and dysplasia in the mucosal epithelium were investigated in 30 cases of gallbladder cancer and 300 cases of chronic cholecystitis. Intestinal metaplasia was observed more frequently in the cases of cancer, both in cancerous and non-cancerous tissues, than those of chronic cholecystitis. In addition, CPS III type of mucin, which is preferably demonstrated in the pyloric glands, was observed in the tumor cells of 50% of cancers. Thus, gastric metaplasia as well as intestinal metaplasia seems to be important as a predisposing lesion to gallbladder cancer. By means of reconstruction method carried out on the specimens of cancer, multifocal gradual transition among metaplasia, dysplasia and cancer was observed and dysplasia is an important step in cancer development. As for mucin secretion, the rate of sialomucin-containing cells was notably high in the lesions of dysplasia and cancer, increasing in intensity in this order, accompanied with positive CEA. The results of the present study support the hypothesis that cancer arises from such pre-existing mucosal lesions as metaplasia and dysplasia.
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PMID:[Histogenesis of gallbladder cancer with special reference to metaplastic changes and distribution of various mucins and CEA]. 279 60

Carbamoyl-phosphate synthase II (glutamine-hydrolyzing) (EC 6.3.5.5) (synthase II) is the first and rate-limiting enzyme in the de novo UTP biosynthetic pathway. Leucine pulse-labeling in the rat demonstrated that in the rapidly proliferating hepatoma 3924A the ratio of radioactivity of synthase II to that of total cytosolic protein was 168.2 +/- 11.0 (SE) X 10(-3). This synthetic rate for the tumor enzyme was 9.7-fold higher than that for the liver synthase II, 17.4 +/- 4.0 X 10(-3). Since the degradation rate for hepatoma 3924A enzyme (t1/2 = 65.5 h) was similar to the rate for liver synthase II (t1/2 = 69.3 h), the increase in tumor synthase II activity and amount was due primarily to an elevation in enzyme synthesis in the presence of an unaltered catabolic rate. The results indicate that the reprogramming of gene expression in the hepatoma entails an increased production rate of the rate-limiting enzyme of UTP synthesis. This increase in the activity, concentration, and synthesis of tumor synthase II should provide a heightened capacity for the de novo pyrimidine biosynthetic pathway, thus conferring a selective advantage to the cancer cells.
Cancer Res 1986 Jul
PMID:Increased synthesis of carbamoyl-phosphate synthase II (EC 6.3.5.5) in hepatoma 3924A. 351 20

Acivicin pharmacokinetics were studied in Phase I patients receiving i.v. treatment on single-dose or daily x5 (daily times five doses) regimens repeated every 3 weeks. In 14 patients, the time course of plasma concentrations was characterized by a biexponential equation with a terminal (elimination-phase) half-life of 9.92 +/- 3.91 h (mean +/- SD), distribution phase half-life of 0.32 +/- 0.28 h, total body clearance of 1.69 +/- 0.48 liters/h/m2, and volume of distribution of 21.79 +/- 2.94 liters/m2. Acivicin kinetics appeared to be dose-independent over the range of 8.5-150 mg/m2/day. Urinary excretion of intact acivicin in nine patients ranged from 2-42% in the first 24 h following administration; interpatient variability in urinary excretion was large, but daily urinary recovery within patients on the daily x5 schedule was quite consistent. Measurements of acivicin effects on the activity of carbamyl phosphate synthetase II (CPS II) were conducted using leukocytes and/or malignant ascites of three colon cancer patients. Acivicin given to one patient at 8.5 mg/m2/day on the daily x5 schedule caused a 70% reduction in leukocyte CPS II activity within 5 h after therapy was initiated. Leukocyte CPS II activity remained suppressed at this level over the 5-day dosing regimen. In this patient, CPS II activity in malignant ascitic cells had decreased by 75% on day 4 of the daily x5 regimen. On the single dose schedule, treatment of two patients with 100 mg/m2 caused leukocyte CPS II activity to decrease by greater than 90% within 4 h of treatment with gradual recovery over the next 2 days.
Cancer Res 1985 Sep
PMID:Pharmacokinetic and biochemical studies on acivicin in phase I clinical trials. 389 81

Carbamoyl-phosphate synthetase II (glutamine hydrolyzing, EC 6.3.5.5) (synthetase II), the rate-limiting enzyme of de novo uridine monophosphate biosynthesis, was purified 230-fold to apparent homogeneity from rapidly growing rat hepatoma 3924A. The antiserum (produced in rabbits against purified hepatoma 3924A enzyme) yielded a single precipitin line with crude and partially purified synthetase II of normal liver and three hepatomas. In hepatomas of slow (20), intermediate (7787), and rapid (3924A) growth rates, synthetase II activity was elevated 1.5-, 2.3-, and 7.9-fold, and the amount of antiserum required to inactivate the activity was 1.6-, 2.3-, and 8.2-fold higher than that in normal liver. Thus the increase in synthetase II activity in the tumors was due to an elevation in the amount of the synthetase II enzyme protein.
Cancer Res 1985 Sep
PMID:Increased carbamoyl-phosphate synthetase II concentration in rat hepatomas: immunological evidence. 402 25

Blockade of a metabolic pathway by interaction of a drug with a particular 'target enzyme' results in depletion of essential end-products of the pathway and accumulation of intermediates prior to the blockade. Metabolic resistance to a particular drug can arise if the substrate of the inhibited enzyme accumulates to levels sufficiently high to compete effectively with the inhibitor, leading to restoration of full activity of the metabolic pathway after a transitory delay. Such resistance has recently been demonstrated in vitro for the interaction of the tight-binding inhibitor N-phosphonacetyl-L-aspartate (PAcAsp) with the aspartate transcarbamoylase activity of the trifunctional protein which initiates pyrimidine biosynthesis in mammals [Christopherson, R. I. and Jones, M. E. (1980) J. Biol. Chem. 255, 11381-11395]. Carbamoyl phosphate, the product of the carbamoyl phosphate synthetase activity of this trifunctional protein, accumulates to a sufficiently high concentration that the inhibitory effect of PAcAsp is effectively abolished. We have developed a theoretical model for metabolic resistance which quantitatively accounts for these experimental data. This model has been used to simulate the interaction between the following potential or proven anti-cancer drugs and their target enzyme, under conditions similar to those which would occur in vivo: PAcAsp with aspartate transcarbamoylase; various OMP analogues [the 5'-monophosphates of 6-azauridine, pyrazofurin and 1-(beta-D-ribofuranosyl)-barbituric acid] with OMP decarboxylase; 5-fluorodeoxyUMP with thymidylate synthase; methotrexate with dihydrofolate reductase; and deoxycoformycin with adenosine deaminase.
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PMID:Metabolic resistance: the protection of enzymes against drugs which are tight-binding inhibitors by the accumulation of substrate. 687 66

A single injection of the anti-glutamine drug, acivicin (NSC 163501), in tumor-bearing rats in 30 min decreased the activities of amidophosphoribosyltransferase, carbamoyl-phosphate synthetase II and CTP synthetase to 56, 50, and 7% of those of the controls. By 1 hr the activities were down to 32, 13 and 3% and they remained low for 12 hr, after which they slowly returned towards normal range in 72 hr. The decline of the activity of CTP synthetase (a loss of 80% in 10 min) was the most rapid, and the activity only returned to 60% of the controls by 3 days after the acivicin injection. In the hepatoma the concentrations of ATP and UTP changed little, but those of GTP and CTP rapidly decreased, reaching at the lowest point 32 and 2%, respectively, of control values 2 hr after acivicin; concentrations started to rise at 12 hr, reaching normal levels by 48 hr. The drop in enzyme activities preceded the decline in the pools of GTP and CTP. The behavior of enzyme activities and nucleotide concentrations in the host liver had a pattern similar to that in the hepatoma; however, the changes were less extensive than those in the tumor. The differential response between tumor and liver is attributed, in part at least, to the tissue L-glutamine concentration which in the hepatoma (0.5 mM) was 9 times lower than in the liver (4.5mM). The selectivity of acivicin action in inhibiting glutamine-utilizing enzymes is also demonstrated by the lack of effect on aspartate carbamoyltransferase, an enzymic activity which resides in the same complex as that of carbamoyl-phosphate synthetase II. The rapid decline in the activities of glutamine-utilizing enzymes is attributed to an inactivation of the enzymes by acivicin which functions as an active sitedirected affinity analog of L-glutamine. The rapid modulation of the enzymic phenotype and ribonucleotide concentrations by acivicin provides a useful tool for elucidating the role of enzymic and nucleotide imbalance in the commitment of cancer cells to replication and in the targeting of anticancer chemotherapy.
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PMID:Rapid in vivo inactivation by acivicin of CTP synthetase, carbamoyl-phosphate synthetase II, and amidophosphoribosyltransferase in hepatoma. 707 46


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