UMLS:C0027651 - FACTA Search

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Query: UMLS:C0027651 (tumor)
685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Fluorine-19 NMR spectrometry was used to monitor the metabolism of two antineoplastic fluoropyrimidines, 5-fluorouracil (5FU) and 5'-deoxy-5-fluorouridine (5'dFUrd), in cell cultures of human pancreatic (Capan-1) and colon (HT-29) adenocarcinoma. The preliminary results showed, for the two tumor cell lines treated with 5FU, the presence in nonperfused cells of three signals corresponding to intracellular metabolites: 5FU, F-nucleotides and F-nucleosides. When the cells were perfused only the signals of F-nucleotides and 5FU were present. The F-nucleosides observed during the analysis of the nonperfused cells came from the conversion of F-nucleotides. During the NMR recording of Capan-1 cells at 37 degrees C the first metabolite of the catabolic pathway of 5FU, 5,6-dihydro-5-fluorouracil, occurred. At the beginning of the NMR recording of Capan-1 cells treated with 5'dFUrd, two signals corresponding to F-nucleotides and F-nucleosides (consistent with 5'dFUrd) were observed; during the analysis, a supplementary signal corresponding to 5FU appeared. Even after pretreatment with methotrexate the signal of 5FU incorporated into RNA was not detected. Our experiments, performed in attempts to observe the signal of the ternary complex between thymidylate synthetase (TS), 5-fluoro-2'-deoxyuridine-5'-monophosphate (FdUMP) and 5,10-methylene-tetrahydrofolate (5,10-CH2FH4), allowed detection in some cases of a broad signal, whose chemical shift was similar to that reported in the literature following incubation of TS with FdUMP and 5,10-CH2FH4, but our results were not always reproducible.
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PMID:Noninvasive fluorine-19 NMR study of fluoropyrimidine metabolism in cell cultures of human pancreatic and colon adenocarcinoma. 294 69

The carbohydrate antigen termed Lex (Gal beta 1----4[Fuc alpha 1----3]GlcNAc beta 1----R), its di- or trimeric form, and their sialylated antigens have been characterized as developmentally regulated, tumor-associated antigens in human gastrointestinal epithelia. In this paper, remarkable changes of these antigens, defined by respective monoclonal antibodies FH3, FH4, and FH6, in fetal kidney (mesonephros and metanephros) and other urogenital organs, as well as in various types of kidney tumors, have been investigated. During the development of each organ and tissue, the antigens were found to be maximally expressed at a defined period of organogenesis, and a shifting of expression from one locus to another was observed. Each antigen showed a slightly but clearly different stage of maximum expression. The following changes in metanephros development are of particular interest. Expression of the antigen defined by FH3 followed by the antigen defined by FH4 appeared only after six weeks of gestation in the convoluted tubuli at the central region of metanephros, and propagated rapidly into those at the peripheral cortex region with a simultaneous regression at the central region. The regression of FH4 antigen was more rapid than that of FH3. All three antigens were expressed in the medullar thin tubuli, which develop into the thin-limb of Henle's loop, in which only the antigens defined by FH3 and FH4 persisted and FH6 antigen disappeared. Well-differentiated, but not undifferentiated, renal adenocarcinomas strongly expressed the antigens defined by FH4 and FH6, although the antigen defined by FH6 was expressed in more differentiated tumor cells than the antigen defined by FH4. Well-differentiated cells organized into tubular structures showed a strong expression of these differentiation antigens. However, some tumor cells that were organized into tubular structures, but were characterized by undifferentiated cytomorphology (larger nucleus and smaller volume of cytoplasm), did not express FH4 and FH6 antigens. Thus, cytodifferentiation and histotypic differentiation proceed independently within kidney tumors. The fucosylated type 2 chain structures defined by these three monoclonal antibodies are useful markers that indicate the degree of tumor differentiation.
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PMID:Changes of Lex and dimeric Lex haptens and their sialylated antigens during development of human kidney and kidney tumors. 300 81

5-Fluorouracil (FUra) has been administered to mice bearing xenografts of human colon adenocarcinomas. In two tumor lines, HxGC3 and HxVRC5, intrinsically resistant to FUra, 2'-deoxyuridylate (dUMP) accumulated 13.4- and 23.9-fold above basal levels. In HxELC2 xenografts, which demonstrated some sensitivity to FUra, there was a decrease in dUMP concentration after drug administration. Maximal intratumor levels of 5-fluoro-2'-deoxyuridylate (FdUMP) were found at 1 hr, but decreased in all tumor lines by 4 hr after administration of FUra. Data derived in tumor cytosols suggested that FdUMP levels in situ were not rate-limiting for formation of covalent ternary complex, but that accumulation of dUMP would retard the rate of complex formation. Subsequent to administration of FUra, thymidylate synthase activity was reduced greater than 75% in all tumors, but it recovered rapidly in tumors resistant to FUra. In addition, the pretreatment level of activity of thymidylate synthase was 12.7-fold greater in HxVRC5 tumors than in HxELC2 tumors. This elevated activity in HxVRC5 tumors appears not to be a consequence of gene amplification. Formation of FdUMP or the accumulation of dUMP did not correlate with the activity of phosphatases measured at pH 5.8 or pH 9.2 in each tumor line. Further, inhibition of phosphatase activity did not alter, significantly, the net rate of dissociation of the FdUMP-thymidylate synthase-[6R]-CH2-H4PteGlu complex.
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PMID:Relationship between 5-fluoro-2'-deoxyuridylate, 2'-deoxyuridylate, and thymidylate synthase activity subsequent to 5-fluorouracil administration, in xenografts of human colon adenocarcinomas. 300 60

The B16/C3 murine melanoma is a pigmented tumor that is rich in the copper-containing enzyme, tyrosinase. This enzyme, which converts tyrosine to melanin precursors, is largely associated with membrane fractions of cells and exists in a number of discrete isozymic forms ranging in molecular mass from 58,000 to 150,000 daltons and pI from 3.4 to 5.2. One of these isozymes (Mr = 58,000, pI 3.4) has been purified to homogeneity. The purified enzyme catalyzes the hydroxylation of L-tyrosine to L-dihydroxyphenylalanine (L-DOPA) and the conversion of L-DOPA to dopaquinone. Ascorbic acid, tetrahydrofolate, and dopamine can serve as cofactors in the hydroxylase reaction. The Michaelis constants for the purified enzyme were 7 X 10(-4) M for L-tyrosine and 6 X 10(-4) M for L-DOPA. The Vmax for L-DOPA was much greater than the Vmax for L-tyrosine indicating that tyrosine hydroxylation is rate-limiting in melanin precursor biosynthesis. Two putative copper chelators, phenylthiourea and diethyldithiocarbamide inhibited both the tyrosine hydroxylase and L-DOPA oxidase activities of the enzyme. Phenylthiourea was a noncompetitive inhibitor while diethyldithiocarbamide was a competitive inhibitor indicating that these agents act by different mechanisms. When digested with proteases and glycosidases, higher molecular weight forms of tyrosinase co-migrated with the purified enzyme in isoelectric focusing and sodium dodecyl sulfate-polyacrylamide gel electrophoresis suggesting that the isozyme was derived from larger precursors. Thus, post-translational processing of tyrosinase may underlie isozyme diversity and this may be important in the control of melanogenesis in this tumor model.
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PMID:Tyrosinase isozyme heterogeneity in differentiating B16/C3 melanoma. 309 4

The activity of thymidylate synthetase in the liver of the ddY strain male mouse increased transitorily according to the increase in tumor cell number at maximum 7-9 days after ip transplantation of Ehrlich ascites tumor. The enzyme was able to be purified from the tumor host mouse liver or from the normal mouse liver in the same manner as from tumor cells using Affi-Gel blue and methotrexate-Sepharose 4B affinity column chromatography. The three enzyme preparations obtained were purified at 27,000-38,000-, and 8,000-fold, and yielded total activities of 11, 3, and 16% of these homogenates, respectively. These preparations were similar in molecular weight to the whole enzyme (67,000) and its subunit (34,000), optimum pH, and Km values either for deoxyuridine 5'-monophosphate or tetrahydrofolate in the presence of formaldehyde. Furthermore, the amount of 5-fluoro-2'-deoxyuridine 5'-monophosphate forming the ternary complex with the enzyme and tetrahydrofolate paralleled the enzyme activities in the cytosol fractions of the three tissues. The characteristics of the tumor host liver enzyme were similar to those of the proliferating tissues, the Ehrlich ascites tumor.
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PMID:Purification and characterization of thymidylate synthetase in the liver of the mouse bearing Ehrlich ascites tumor. 321 80

Plasma pharmacokinetics of high-dose (500 mg/m2) leucovorin calcium (dl-5-formyltetrahydrofolic acid [dl-CF]) and fluorouracil (FUra) have been evaluated in patients with advanced colorectal cancer treated with the combination of FUra and dl-CF by two different intravenous (IV) schedules: (A) In patients with no prior chemotherapy, dl-CF was administered by a two-hour IV infusion and FUra by rapid IV injection one hour after the start of the dl-CF infusion and (B) in previously treated patients, dl-CF and FUra were administered by five-day continuous IV infusion (CI). Following the two-hour infusion of dl-CF, mean peak plasma concentration and elimination half-life of I-5-formyltetrahydrofolic acid (I-CF) were 24 +/- 6 mumol/L and 0.8 +/- 0.1 hour, respectively. CI of dl-CF over five days yielded a mean steady-state plasma level of I-CF of only 1.2 +/- 0.5 mumol/L. Peak and steady-state plasma concentrations of the metabolite 5-methyl tetrahydrofolic acid were comparable in the two schedules (17 +/- 8 mumol/L for the two-hour infusion and 12 +/- 5 mumol/L for the CI). Areas under the concentration v time curve (AUC) of total reduced folates were significantly greater under conditions of CI: 89.0 v 16.7 mmol/L/min for the two-hour infusion. In tumor tissue, 5,10-methylenetetrahydrofolate increased eight-fold two to four hours following the two-hour infusion and two-fold during the CI of dl-CF and FUra. Inhibition of thymidylate synthase (dTMP-S) by the two-hour and CI infusion schedules were 66% v 39%, respectively. The observed differences in the intracellular dTMP-S folate cofactor pools and the degree of inhibition of dTMP-S achieved in patients treated by two different schedules may be due to differences in the biochemical properties and/or to differences in the modulation of FUra metabolism by folate of tumor tissues obtained from newly diagnosed and previously treated patients.
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PMID:Plasma and tumor tissue pharmacology of high-dose intravenous leucovorin calcium in combination with fluorouracil in patients with advanced colorectal carcinoma. 326 Jun 21

The method for measuring polyglutamate forms of CH2-H4PteGlu and H4PteGlu, by entrapment in ternary complexes with [6-3H]5-fluoro-2'-deoxyuridylate and Lactobacillus casei thymidylate synthase has been characterized. Results demonstrated that (a) the relationship between concentration of CH2-H4PteGlu and complex isolated on nondenaturing gels was dependent upon the number of glutamyl residues, and an alternative method for data analysis has been presented, (b) the relationship was linear over a 100-fold change in concentration, (c) formation of isolatable complex was time dependent, (d) noncovalent complexes formed with PteGlu2-5 could be isolated only at concentrations considerably higher than those required for CH2-H4PteGlu1-6, and (e) endogenous deoxyuridylate would be unlikely to interfere significantly with the assay. The distribution of polyglutamates of CH2-H4PteGlu and the combined pools of CH2-H4PteGlu plus H4PteGlu were subsequently examined in three human colon adenocarcinoma xenografts. In each tumor, the pentaglutamate of CH2-H4PteGlu and H4PteGlu was the most prominent species, followed by the hexaglutamate, constituting 68 to 92% of the CH2-H4PteGlu pool, and greater than 93% of the combined pools. A small percentage of di-, tri-, and tetraglutamates were also detected. Using a catalytic assay, the combined pool of CH2-H4PteGlu and H4PteGlu was estimated in the range of 0.5 to 2.7 microM in cell water, and for CH2-H4PteGlu, from 185 nM to 1.7 microM. Using thymidylate synthase purified from colon adenocarcinoma HxVRC5, CH2-H4PteGlu5 (where the subscript digit attached to the glutamate portion equals the number of glutamate residues) stabilized the covalent ternary complex at greater than 200-fold lower concentration in comparison to CH2-H4PteGlu1. Data indicated that in each colon tumor, the concentrations of CH2-H4PteGlun or CH2-H4PteGlun plus H4PteGlun were suboptimal for the interaction of 5-fluoro-2'-deoxyuridylate with thymidylate synthase, and would predict for relatively transient inhibition of thymidylate synthase after treatment with 5-fluorouracil. These data support therapeutic modulation to increase the concentration of CH2-H4PteGlun in the treatment of colon adenocarcinomas with 5-fluorouracil.
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PMID:Characterization of the pools of 5,10-methylenetetrahydrofolates and tetrahydrofolates in xenografts of human colon adenocarcinoma. 336 96

The human ovarian cell line A2780 was exposed to either cisplatin (10 microM) or 5-fluorouracil (5FUra) (5 microM) for 1 hr. Cytotoxicity was less than 14% with either agent alone. Cisplatin (10 microM) and 5FUra (5 microM) in combination for 1 hr caused a 76% reduction in cell growth. Thymidine (dThd, 10 microM), if given concomitantly with the combination of cisplatin and 5FUra, completely protected the tumor cells. A 30-min exposure to cisplatin increased the intracellular pools of 5,10-methylenetetrahydrofolate and tetrahydrofolate 2.5-fold. The capacity of intact cells to form 5-fluorodeoxyuridylate (FdUMP)-thymidylate (dTMP) synthase complex when incubated with fluorodeoxyuridine (FdUrd) was enhanced 2.5-fold when the cells were pretreated with cisplatin. These experiments demonstrate that cisplatin can increase the availability of the reduced folate necessary for tight binding of FdUMP to dTMP synthase, thus enhancing the cytotoxicity of the cisplatin and 5FUra combination.
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PMID:Biochemical basis for cisplatin and 5-fluorouracil synergism in human ovarian carcinoma cells. 346 65

The term "high molecular weight substances" used in this paper implies mostly nucleic acids of certain molecular weight and protein, and the genetic aspects of anti-cancer chemotherapy were discussed. Studies on the mechanism of action of 5-FU have been focused on the inhibition of DNA synthesis, and it has been reported that 5-FU inhibits the growth of thymidylate synthesis deleted FM3A Thy 21 cells even in the presence of thymidine, and that the level of TTP is equal to that in control cells. On the other hand, the active metabolite of 5-FU, FdUMP, is known to bind to synthesized thymidylate and 5, 10-methylene-tetrahydrofolic acid to form a ternary complex. Recently, the cytocidal effect of 5-FU was observed in thymidylate synthetase-deficient cells in the presence of a sufficient amount of thymidine, suggesting that the cytocidal effect of 5-FU might be caused by inhibition of the RNA pathway. In this laboratory, the effect of 5-FU on polysomal patterns and the incorporation of 3H-UR into polysomes was studied in L1210 cells, but no significant difference was observed between normal and 5-FU-treated cells. Ribosomal RNA extracted from the polysomes of 5-FU treated cells appeared to contain a smaller 28S rRNA in comparison to 18S rRNA, indicating that the processing might be inhibited. Expression of mouse H-2Dd mRNA was not influenced by 5-FU at 10(-5) M up to 6 h. Methotrexate (MTX) has a chemical structure similar to folic acid, and is known to bind to DHFR (dihydrofolate reductase), and inhibit the synthesis of TMP. The cellular PRPP content is known to be increased by MTX, which inhibits purine synthesis. The level of PRPP content was found to be increased approximately 25 fold at 3 h after 10(-6) M MTX although normal bone marrow cells showed no increase even after MTX. This increased level of PRPP thus obtained in cancer cells was thought to be used for the phosphorylation of 5-FU. Clinically, sequential chemotherapy using MTX and 5-FU was employed successfully for solid tumors on the basis of the experimental evidence. In order to minimize the adverse effects of anti-cancer drugs, a technique involving the incorporation of the drug-resistant gene into normal bone marrow cells has been designed in this laboratory, and the MTX-resistant cells thus obtained are transplanted into the tumor-bearing mice.
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PMID:[The metabolism of high-molecular-weight substances in cells and the effect of anticancer drugs]. 356 94

The formation and stability of the covalent ternary complex formed between thymidylate synthase (E.C. 2.1.1.45), 5-fluoro 2'-deoxyuridylate (FdUMP) and 5,10-methylenetetrahydrofolate (CH2-H4PteGlu) has been examined in cytosols derived from xenografts of human colon adenocarcinomas. The rate of association (ka) for FdUMP was low being between 3.4 +/- 0.9 and 10.2 +/- 2.6 X 10(6) M-1 min-1, with the lowest ka value being determined in cytosols from a tumor (HxELC2) which has demonstrated some sensitivity to 5-fluoropyrimidines. Relative to reported ka values for human leukemic cells, the rate of association of FdUMP was 20- to 59-fold lower. This difference is not a consequence of FdUMP catabolism, or metabolism of CH2-H4PteGlu. In cytosols the apparent Km values for dUMP (3.6-4.2 microM) and and [6RS]- CH2-H4PteGlu (25-26.7 microM) were similar to reported values for human enzyme. Data derived from cytosols were similar to those derived using affinity purified enzyme from HxVRC5 colon adenocarcinoma xenografts. The net dissociation of [6-3H] FdUMP from the covalent ternary complex was 31-33 min in the absence of added CH2-H4PteGlu, and the rate of dissociation was dependent upon the concentration of cofactor. The concentration of [6RS]-CH2-H4PteGlu required to stabilize ternary complex derived from HxELC2 cytosols was slightly lower than that required for the same degree of stabilization of complex formed in cytosols from resistant tumors (HxGC3,HxVRC5). Addition of 5-CHO-H4PteGlu, 5-CH3-H4PteGlu, H2PteGlu, and PteGlu did not stabilize the covalent complex, but H4PteGlu substituted for CH2-H4PteGlu.
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PMID:Binding of 5-fluorodeoxyuridylate to thymidylate synthase in human colon adenocarcinoma xenografts. 373 54

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