Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

An overview was presented of our approach of inhibition of de novo and salvage pathways in pyrimidine and purine metabolism. 1. Combination of acivicin, an inhibitor of de novo biosynthesis, and dipyridamole, a transport inhibitor, provided synergistic cytotoxicity in hepatoma and colon carcinoma cells. 2. AZT, a competitive inhibitor of the salvage enzyme, thymidine kinase, and 5-FU or MTX provided synergistic cytotoxicity in hepatoma 3924A. In human colon carcinoma HT-29 cells AZT and methotrexate yielded synergistic cytotoxicity and thymidine and hypoxanthine together provided protection from the action of these drugs. 3. These observations are significant because in rat hepatoma 3924A and in human cell lines HT-29, HL-60 and K562 thymidine kinase activity was 16- to 67-fold higher than that of dTMP synthase. Therefore, inhibition of dTMP synthase activity alone may provide poor responses because the salvage pathways can circumvent this block. 4. In leukemic patients treated with tiazofurin, an inhibitor of IMP dehydrogenase, the rate-limiting enzyme of GTP biosynthesis, and with allopurinol, which inhibits GPRT activity through raising plasma hypoxanthine levels, synergistic therapeutic results were obtained. The responses in sensitive patients entailed a decrease in IMP dehydrogenase activity and GTP concentration in leukemic cells and down-regulation of the ras and myc oncogenes. The down-regulation of the ras oncogene by tiazofurin through the decrease of GTP concentration has now been shown in K562, HL-60 and hepatoma cells and in patients with chronic granulocytic leukemia in blast crisis. Tiazofurin may be useful in studies on selective depression of the expression of the ras oncogene. 5. In 27 consecutive patients 50% responded positively to tiazofurin treatment. From this group, 10 out of 12 patients (83%) with chronic granulocytic leukemia in blast crisis responded to tiazofurin treatment.
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PMID:Regulation of de novo and salvage pathways in chemotherapy. 187 99

For a range of rat tissue extracts, the concentrations of total folates and of short-chain pteroylpolyglutamates were assayed by Lactobacillus casei with and without conjugase treatment, respectively, and the concentration and chain length of H4PteGlnn and 5,10-CH2-H4PteGlnn together were assayed after binding to thymidylate synthase and tritiated fluorodeoxyuridylate. For rats fed a nonpurified diet and consuming 26 micrograms of folic acid daily, the respective concentrations of these total folates, short-chain folates and thymidylate synthase bindable folates were, in nmol/g, 10.2, 2.5 and 3.5 in liver, 3.9, 1.8 and 2.0 in kidney, 4.2, 1.2 and 1.0 in bone marrow, 2.3, 0.6 and 0.2 in adrenal, 2.1, 0.3 and 0.5 in spleen, 2.1, 0.9 and 0.8 in jejunal smooth muscle, 1.2, 0.9 and 0.2 in jejunal mucosa, 1.0, 0.3 and 0.6 in testis, 0.7, 0.1 and 0.2 in heart, 0.3, 0.1 and 0.1 in skeletal muscle, 0.5, 0.1 and 0.3 in brain and 0.7, 0.002 and 0 in erythrocytes. The predominant pteroylpolyglutamate chain length was 6 residues in all tissues except kidney, jejunal mucosa, skeletal muscle and brain, in which the value was 5 residues. A folate-deficient diet (30 ng/d) fed for 3 wk resulted in a depression in the total folate concentration of all tissues (except brain); the depression was generally greater for short-chain than for long-chain folates and was accompanied by a lengthening of the pteroylpolyglutamate chain. Opposite results followed folate excess of 4 to 5.4 mg/d. The fractional change in the folate concentration of the individual tissues, following perturbation of dietary folate, did not vary greatly among tissues.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Modulation of pteroylpolyglutamate concentration and length in response to altered folate nutrition in a comprehensive range of rat tissues. 223 Oct 31

Recent studies have clarified the critical role that polyglutamylation plays in methotrexate (MTX) action. Polyglutamate derivatives of MTX bind to dihydrofolate reductase (DHFR) with affinities comparable to the monoglutamate, but their retention in cells results in a sustained block in tetrahydrofolate (FH4) synthesis. One important element in the selectivity of MTX action is the preferential buildup and retention of these polyglutamyl forms in susceptible tumor cells as compared to host cells of the bone marrow or gastrointestinal mucosa. This selectivity in the accumulation of MTX polyglutamyl forms has now been further shown to play an important role in the selectivity of leucovorin rescue and may provide a unique new approach to nucleoside protection as well. This paper reviews the current understanding of the biochemical basis for leucovorin rescue and its selectivity. Important elements in leucovorin rescue are reactivation of DHFR with depression of cellular dihydrofolate (FH2) and provision of folate substrate to circumvent the block in FH4 synthesis. Selectivity of leucovorin rescue may be attributed to direct inhibition by MTX polyglutamyl forms, as well as FH2 polyglutamates that accumulate in their presence, at the levels of thymidylate synthase and transformylation during purine nucleotide biosynthesis. The presence of cellular MTX polyglutamates impairs reactivation of endogenous DHFR activity by leucovorin metabolites, and the resultant maintenance of high cellular levels of cellular FH2 and the polyglutamyl derivations of MTX impair the utilization of added FH4 in susceptible tumor cells. This paper also develops the concept of "early" nucleoside protection in antifolate therapy. In this approach, nucleosides are administered simultaneously with a pulse of MTX to provide early host protection from the cytotoxic effects of modest doses of MTX. Cessation of protection occurs at a time when extracellular and intracellular monoglutamate has fallen to low levels, and the polyglutamyl forms of the drug are present in susceptible tumors but not in host tissues of the gut and bone marrow. Data are presented to demonstrate that increased doses of MTX can be administered in normal and tumor-bearing animal systems as well as in humans by this technique.
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PMID:Biochemical factors in the selectivity of leucovorin rescue: selective inhibition of leucovorin reactivation of dihydrofolate reductase and leucovorin utilization in purine and pyrimidine biosynthesis by methotrexate and dihydrofolate polyglutamates. 244 54

The increases in the activities of hepatic thymidylate synthetase and thymidine kinase were significantly suppressed at 24 h after 70% partial hepatectomy in rats which had been administered a microtubule disrupter, colchicine or vincristine. The decrease of these enzymic activities was accompanied by a reduction of DNA content in 24 h regenerating liver. The immunoblotting assay showed that the depression of the thymidylate synthetase activity by the injection of colchicine or vincristine was due to the decrease of the enzyme protein. These results indicate that colchicine and vincristine inhibit the DNA synthesis during liver regeneration by inhibiting the induction of the key enzyme in DNA synthesis.
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PMID:Effect of colchicine and vincristine on DNA synthesis in regenerating rat liver. 280 79

Thyroparathyroidectomy (TPTX) carried out at 72 h before partial hepatectomy (PH) reduced the induction of hepatic thymidylate synthetase (TS) and thymidine kinase (TK), which are rate-determining enzymes in DNA synthesis, at 24 h after PH. When TPTX was carried out at 24 h before PH, TK activity at 24 h after PH was not reduced at all, yet TS activity was reduced significantly. Thus the effect of TPTX differed in time dependence between TS and TK. The depression of TK activity in rats which were subjected to TPTX at 72 h before PH, was recovered by Ca2+ supplementation. This result demonstrated that the rise of TK activity in regenerating liver is regulated by plasma Ca2+. Since a high dose of tri-iodothyronine (T3) was required to cause elevation of the activities of these enzymes and DNA content in 24 h-regenerating liver of TPTX rats, the relative contribution of T3 to liver regeneration may be small.
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PMID:Effect of thyroparathyroidectomy on the activities of thymidylate synthetase and thymidine kinase during liver regeneration after partial hepatectomy. 382 94

The amounts of intracellular nucleotides of dThd and dUrd were measured in cultured human lymphoblasts with and without treatment with methotrexate (plus hypoxanthine) to inhibit thymidylate synthetase. dTTP fell from approximately 40 pmol/10(6) cells (untreated) to approximately 1 pmol/10(6) cells with drug treatment. dUMP, increased approximately 10(3)-fold with methotrexate. dUTP was not detected in the cell without drug treatment (less than or equal to 0.3 fmol/10(6) cells), but was easily measured at approximately 0.2 pmol/10(6) cells in drug-inhibited cells. Thus the ratio dUTP/dTTP incrased from less than or equal to 10(-5) in untreated cells to approximately 0.2 in cells treated with methotrexate, indicating that dUMP may be incorporated in substantial amounts into the DNA of the drug-treated cells. The magnitude of these effects on nucleotide pools suggests the possibility that the normal nucleolytic mechanism for removal of dUMP from DNA may play a part in the toxic effects on the cell that result from depression of thymidylate synthetase activity.
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PMID:The effect of methotrexate on levels of dUTP in animal cells. 743 Jan 42

In a chronic toxicity study in the rat, bidisomide administered as a dietary admixture produced a dose-related lowering of reticulocytes and leucocytes. Plasma alanine aminotransferase activity was increased at 300 mg/kg and decreased at 900 mg/kg. The potential mechanisms of these effects were investigated by comparing the responses in groups of male Sprague-Dawley rats receiving a control diet, or 300 or 1200 mg/kg/day bidisomide. Subsets of these groups were co-treated subcutaneously with folinic acid or with a vitamin B1, B6, B12 complex. Subsets of control and 300 mg/kg groups were maintained on a 20-25% feed restriction regimen for 3 months, to mimic the depression in body weight gain observed in animals receiving 1200 mg/kg. Body weight gains were significantly reduced at 1200 mg/kg and in all feed-restricted animals. Plasma and liver alanine aminotransferase (ALT) and plasma aspartate aminotransferase (AST) levels were also reduced at this dose level. At 300 mg/kg, plasma transaminases, glutamate dehydrogenase (GLDH) and sorbitol dehydrogenase (SDH) activities were increased. These changes were prevented in animals receiving folinic acid supplementation. Plasma glucose, triglycerides, and unsaturated and total iron binding capacities were decreased, while plasma iron levels tended to increase, mainly at the high dose. Vitamin supplementation prevented a decrease in reticulocyte counts at 300 mg/kg. Bidisomide increased urinary formimino-glutamic acid (FIGLU) excretion but did not affect methylmalonic acid (MMA) or taurine excretion. The effect on FIGLU at 1200 mg/kg was prevented by folinic acid co-treatment. Absolute liver weight was lowered at both dose levels and in feed-restricted animals. However, the relative liver weights were unaffected. Thymidine kinase and thymidylate synthase activity of the bone marrow cells were not altered by the bidisomide treatment. Except for the increase in plasma transaminase, GLDH and SDH levels at 300 mg/kg, changes in clinical chemistry parameters are considered to result mainly from nutritional restrictions. Changes in hematologic parameters appear to be related to the combination of decreased feed consumption (leukocytes) and decreased availability or utilization of folates (reticulocytes). This alteration, however, did not affect DNA synthesis in bone marrow. The prevention by folinic acid, but not by feed restriction, of the elevation of liver enzymes at 300 mg/kg is an intriguing, yet unexplained finding. There was no evidence that bidisomide affected B6 and B12 availability.
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PMID:Effect of folate supplementation on clinical chemistry and hematologic changes related to bidisomide administration in the rat. 858 20

The purpose of this paper was to clarify critical aspects of the behavior of signal transduction activity in normal and cancer cells. 1. Signal transduction activity in the conversion of phosphatidylinositol through PI and PIP kinases and PLC to IP3 is regulated at multiple sites. In liver, hepatomas and human carcinomas PIP kinase is the rate limiting enzyme and PLC activity is present in great excess. 2. The steady-state signal transduction activity as measured by the three enzyme activities and IP3 concentration was markedly up-regulated in rat hepatomas of different growth rates. The steady-state specific activities of the three signal transduction enzymes were elevated in ovarian carcinomas as compared to normal ovary. Increased enzyme activities were also observed in human breast carcinoma cells as compared to normal human breast parenchymal cells. In breast, ovarian and rat hepatoma cells as they go through lag, log and plateau phases, IP3 concentration in the early lag phase increased 4.5- to 20-fold and PI and PIP kinase activities peaked in mid-log phase. These events returned to baseline levels in the plateau phase. PLC activity did not change. 3. The bone marrow PI and PIP kinase activities in 3-day starvation were decreased to 13% and IP3 concentration was reduced to 24%; at 1-day refeeding they returned to normal. PLC activity changed little. These alterations are in line with the rapid t1/2 degradation rates (12 min) of PI and PIP kinases observed in studies with cycloheximide. By contrast, PLC has a long half-life. 4. The molecular action of tiazofurin entails inhibition of IMP DH activity, decrease in GTP and IP3 concentrations, reduction of ras and myc oncogene expression, and signal transduction enzyme activities. These events are followed by induced differentiation and apoptosis. There are also decreases in enzyme activities which have rapid turnover, including TdR kinase, dTMP synthase, and GPRT. In vitro studies indicated that these events are abrogated by addition of guanine which restores GTP concentrations. Therefore, most or all these events were brought about by the reduced GTP concentration in the tiazofurin target cells. 5. Quercetin and genistein are able to inhibit PI and PIP kinase activities and reduce IP3 concentration in vivo and in tissue culture systems. These flavonoids are also inhibitors of cell proliferation and clonogenic ability in rat hepatoma 3924A and in human OVCAR-5 and MDA-MB-435 cells. Quercetin down-regulated the expression of c-myc and Ki-ras oncogenes and led to induced differentiation and apoptosis in K562 cells. Genistein reduced IP3 concentration in vivo and in the tissue culture system. Genistein is antiproliferative and has cytototoxicity in human carcinoma cells. All three drugs, tiazofurin, quercetin and genistein, act, in part at least, through depression of cellular IP3 concentration although the mechanisms may not be identical. 6. Quercetin and genistein, which attack different targets and different phases of the cell cycle, proved to be synergistic in OVCAR-5 cells. The impact of tiazofurin, genistein and quercetin is of interest because the drugs crucially inhibit the display of the neoplastic program of cells and lead to induced differentiation and apoptosis.
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PMID:Regulation of the signal transduction program by drugs. 938 80