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

Significant changes in aldehyde dehydrogenase (ALDH) activity occur during chemically induced rat hepatocarcinogenesis. We have developed a procedure for the histochemical localization of hepatic ALDH which has proven extremely useful as an additional probe for studying changes in this enzyme during hepatocarcinogenesis. Frozen sections of fresh tissue were stained for ALDH using either propionaldehyde-NAD to detect normal liver ALDH or benzaldehyde-NADP to detect tumor ALDH. Histochemically, normal liver ALDH activity is strongly centrilobular with only slight periportal activity and produces a characteristic staining pattern. During hepatocarcinogenesis, ALDH staining patterns in grossly normal liver range from normal-appearing to patterns of distinct, intense focal hepatocyte staining with propionaldehyde-NAD and/or benzaldehyde-NADP. ALDH-positive foci are found both in normal regions of tumor-bearing livers and prior to the appearance of gross neoplasms. Neoplastic nodules and carcinomas possess a wide variety of ALDH staining patterns between and within lesions. Neoplasms with elevated ALDH activity with propionaldehyde-NAD and/or benzaldehyde-NADP, as well as with no detectable ALDH, have been observed. Changes in ALDH can be identified histochemically at a time in hepatocarcinogenesis when other analytical methods cannot detect significant changes. Moreover, considerable heterogeneity in expression of tumor ALDH is demonstrable by histochemistry.
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PMID:Histochemical localization of aldehyde dehydrogenase during rat hepatocarcinogenesis. 619 10

The effect of separate and combined administration of 15% ethanol and 0.2% CsCl solution on life span of rats with Novikoff hepatoma implants was studied as a function of time of initiation of treatment. Pretreatment with CsCl alone or combined with ethanol resulted in earlier onset on morbidity compared to the ethanol-treatment or to controls. As high as 87.5% of Cs-treated animals died 16 days post tumor implantation compared to 33% of rats receiving CsCl and ethanol combined. This protective action of ethanol against Cs-evoked toxicity in tumor-bearing rats persisted through the experiment. Animals subjected to drug treatment immediately after tumor transplantation displayed delayed onset of morbidity compared to drug pretreated rats. In both cases the Cs-treatment enhanced morbidity by approximately 2 folds from corresponding controls. Animals sacrificed 18 days post tumor inoculation showed an induction of hepatic alcohol dehydrogenase and an increase in Vmax without changes in the apparent Km by the Cs-treatment. There was an increase in liver mitochondrial aldehyde dehydrogenase of hepatoma-bearing rats from tumor-free controls which was associated with an increase in the apparent Km value. The results indicate potentiation of the hepatoma toxicity by CsCl which may be minimized by ethanol. A role for hepatic enzymes determined in the pathogenesis of tumor line studied and/or their use as a biochemical correlate is suggested.
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PMID:Effect of cesium and ethanol on tumor bearing rats. 639 34

The interrelationship between certain dehydrogenases and a hepatic tumor was studied in mice. A rapidly growing hepatoma, Novikoff hepatoma, was transplantable from rats to mice after serial passages in Sprague-Dawley albino mice. Mice inoculated with viable tumor cell suspension were sacrificed 14, 18, 21 or 34 days thereafter. Hepatic cytoplasmic and mitochondrial aldehyde dehydrogenase (ALDH) were measured in addition to liver alcohol dehydrogenase (ADH) and testicular ALDH. Hepatic cytoplasmic and mitochondrial ALDH were markedly inhibited from controls at all time periods studied. Likewise, testicular ALDH was inhibited from respective controls in Novikoff hepatoma-bearing mice. No changes were measurable in hepatic ADH of hepatoma-bearing mice. The enzyme kinetics studied show a reduction in Vmax and an alteration in the apparent Km 34 days after tumor inoculation. Further analyses of hepatic mitochondrial ALDH showed that the inhibition was similarly present in the enzyme with the low and the high Km property. The results suggest that changes in the specific activity and property of ALDH may be a useful tool as a biochemical concomitant to both development and progression of the hepatoma studied.
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PMID:Hepatic and testicular aldehyde dehydrogenase in tumor-bearing mice. 639 79

The purification and properties of 4 inducible cytosolic rat liver aldehyde dehydrogenase isozymes are described. Based on their behavior during purification and their properties, the activities can be grouped into 2 classes. The isozyme inducible in normal liver by 2,3,7,8-tetrachlorodibenzo-p-dioxin and the tumor-specific isozyme found in hepatocellular carcinomas have apparent molecular weights of 110,000, prefer NADP+ as coenzyme, and preferentially oxidize benzaldehyde-like aromatic aldehydes, but not phenylacetaldehyde. They also have identical pH profiles and responses to effectors. These isozymes differ slightly in isoelectric point and thermal stability. The normal liver phenobarbital-inducible isozyme and the isozyme appearing during the promotion phase of hepatocarcinogenesis appear to be identical. Both have apparent molecular weights of 165,000, are NAD-specific and prefer aliphatic aldehydes. They can oxidize phenylacetaldehyde, but not benzaldehyde-like aromatic aldehydes. They also have identical pH and thermal stability profiles and responses to effectors. While the 4 inducible isozymes share identical subunit molecular weights (54,000) with the normal liver millimolar Km aldehyde dehydrogenases, they are distinctly different enzymatic species. The interrelationships of the various normal liver and inducible rat liver aldehyde dehydrogenases are discussed.
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PMID:Rat liver aldehyde dehydrogenase. II. Isolation and characterization of four inducible isozymes. 648 May 94

A cyclophosphamide-resistant L1210 cell line has been shown to have unusually high aldehyde dehydrogenase activity. The sensitivity of this cell line to 4-methylcyclophosphamide and phosphoramide mustard in vivo and corresponding sensitivities in vitro indicate that 4-hydroxycyclophosphamide and/or aldophosphamide is the form in which cyclophosphamide reaches these tumor cells in mice and that intracellular aldehyde dehydrogenase activity is an important determinant of cyclophosphamide sensitivity in these leukemia cell lines.
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PMID:Role of aldehyde dehydrogenase in cyclophosphamide-resistant L1210 leukemia. 648 75

Significant changes in aldehyde dehydrogenase (ALDH) activity occur during rat hepatocarcinogenesis in vivo. An NADP-dependent tumor ALDH isozyme has been studied extensively. To better understand the nature, origin, and importance of this tumor-associated phenotypic change, we have examined the ALDH activity of five well-established rat hepatoma cell lines, H4-II-EC3, HTC, McA-RH7777, JM1, and JM2. HTC, JM1, and JM2 express the tumor ALDH phenotype, as indicated by elevated NADP-dependent, benzaldehyde-oxidizing activity, the appearance of new isozymes by electrophoresis, and characteristic histochemical localization of ALDH activity in situ. The tumor ALDH phenotype is not detected in McA-RH7777 cells. H4-II-EC3 has intermediate tumor ALDH activity. Thus, the 5 cell lines provide a spectrum of tumor ALDH activities representative of the range of activities seen in vivo. Benzo(a)pyrene, 3-methylcholanthrene, and phenobarbital induce hepatic ALDH activity after treatment in vivo. The ability of these compounds to induce ALDH in vitro was assessed in H4-II-EC3, McA-RH7777, HTC, JM1, and JM2. Treatment of cell cultures for 72 hr with 3-methylcholanthrene (1.0 mM) increases the NADP-dependent ALDH activity in H4-II-EC3 and McA-RH7777 cell lines up to 34- and 11-fold, respectively. Treatment with benzo(a)pyrene (1.0 mM) also increases the NADP-dependent ALDH activity in both lines up to 17- and 48-fold, respectively. Treatment with 3-methylcholanthrene or benzo(a)pyrene increases ALDH activity 2-fold in HTC and JM2 but does not increase NADP-dependent ALDH activity in JM1. Only marginal increases in NADP-dependent ALDH are observed after phenobarbital treatment in 4 of 5 cell lines. The induction of ALDH is blocked by actinomycin D, alpha-amanitin, and cycloheximide. These studies support our hypothesis that changes in ALDH activity observed in vivo are due to mutational events occurring in initiated cells. It appears that rat hepatoma cell lines will provide an in vitro model for studying genetic regulation of the tumor ALDH.
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PMID:Regulation of aldehyde dehydrogenase activity in five rat hepatoma cell lines. 648 82

The synthesis of poly-gamma-glutamyl derivatives of 7-hydroxymethotrexate (7-OH-4-NH2-10-CH3-pteroyl-glutamic acid (PteGlu1] was evaluated by direct hydroxylation of the tetraglutamyl derivative of methotrexate (4-NH2-10-CH3-PteGlu4) by a cell-free preparation of rabbit liver aldehyde oxidase and by polyglutamylation of 7-OH-methotrexate in Ehrlich ascites tumor cells in vitro. The polyglutamyl derivatives of 7-OH-methotrexate rapidly accumulate in cells to the 7-OH-4-NH2-10-CH3-PteGlu4. While 7-OH-methotrexate monoglutamate does not bind to dihydrofolate reductase, 7-OH-4-NH2-10-CH3-PteGlu4 does bind to the enzyme as established by gel filtration analysis of cell extracts and by use of purified dihydrofolate reductase from Ehrlich cells. Within cells, the rate of formation of 7-OH-methotrexate polyglutamyl derivatives exceeds that for methotrexate by a factor of 2.7 at comparable free monoglutamyl substrate levels, suggesting that 7-OH-methotrexate may be a better substrate than methotrexate for the folylpolyglutamate synthetase. 7-OH-methotrexate slows the rate of methotrexate polyglutamylation in cells, a consequence of the inhibition of methotrexate transport with reduced methotrexate substrate available for polyglutamylation. When 7-OH-methotrexate polyglutamyl derivatives were accumulated inside the cells following which extracellular 7-OH-methotrexate was removed, the monoglutamate, and to a lesser extent the diglutamate, exited the cells whereas the majority of the longer polyglutamyl derivatives were retained and continued to be metabolized to higher forms. These studies suggest that 7-OH-methotrexate and its polyglutamyl derivatives may play a role in modulating methotrexate action, either by their own inhibitory effects on folate-dependent enzymes or by their effects on methotrexate transport and metabolism within cells.
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PMID:Synthesis and properties of 7-hydroxymethotrexate polyglutamyl derivatives in Ehrlich ascites tumor cells in vitro. 671 37

In aromatic amine-induced rat hepatomas, the aldehyde dehydrogenase (AIDH) phenotype is qualitatively and quantitatively different from that of normal liver. To identify the mechanism(s) underlying the expression of the tumor-specific AIDHs, we have followed the time course of appearance of the new phenotype during hepatoma formation in Sprague-Dawley rats following brief dietary exposures to 2-acetylaminofluorene (0.02%; 32 days). Tumor promotion by phenobarbital (0.05% in the diet) was also used to compare the effects of a variety of tumor induction protocols on the AIDH phenotype. No change in the AIDH phenotype is detectable by total activity assay, gel electrophoresis, isoelectric focusing, or immunochemical methods during or following exposure to carcinogen or promoter until tumors are grossly observed in liver. Concomitant with tumor appearance, the tumor-specific AIDH phenotype appears. The phenotypic change is limited to the tumor; morphologically and histologically normal liver directly adjacent to the tumor and normal lobes of a tumor-bearing liver do not possess the tumor AIDH phenotype. No correlation exists between tumor size and the degree of deviation of the AIDH phenotype from normal. Nor is there any correlation between the degree of AIDH phenotype deviation and the histology of the various tumors observed. We conclude that the tumor-specific AIDH phenotype is not associated with altered liver metabolism due directly to carcinogen or promoter exposure. Rather, the mechanism of this phenotypic change requires that transformation-associated, stable genetic changes occur in the cells affected by carcinogen that are later expressed as the altered AIDH phenotype.
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PMID:Expression of the tumor aldehyde dehydrogenase phenotype during 2-acetylaminofluorene-induced rat hepatocarcinogenesis. 705 5

A significant change in hepatic aldehyde dehydrogenase activity has been observed in normal Sprague-Dawley rat liver during the promotion phase of hepatocarcinogenesis induced by brief feeding of 2-acetylaminofluorene (2-AAF) followed by tumor promotion using dietary phenobarbital (PB) exposure. Animals receiving only 2-AAF or PB do not possess this new aldehyde dehydrogenase activity. The phenotype is characterized by the appearance of a new cytosolic isozyme kinetically, electrophoretically and immunochemically distinct from the normal liver aldehyde dehydrogenase isozymes and from aldehyde dehydrogenases inducible in 2-AAF-induced hepatomas. The new isozyme is NAD-dependent, disulfiram-sensitive and cross-reacts with antiserum to a normal liver aldehyde dehydrogenase inducible in several lines of rats by PB. However, the population of animals used in this study has been shown previously to be non-responsive to aldehyde dehydrogenase induction by dietary PB. Since no animals receiving only PB express this new isozyme, the carcinogen must play a significant role in its induction. Moreover, that not all animals receiving carcinogen and promoter possess the phenotype suggests this carcinogen/promoter interaction has a genetic basis.
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PMID:Sequential 2-acetylaminofluorene--phenobarbital exposure induces a cytosolic aldehyde dehydrogenase during rat hepatocarcinogenesis. 709 12

Fourteen phosphorylated acetals and aldehydes were synthesized for testing in vitro as inhibitors or substrates of aldehyde oxidase, an enzyme involved in the conversion of aldophosphamide to inactive carboxyphosphamide, and for concurrent in vivo administration with cyclophosphamide to mice bearing L1210 ascites tumor cells. Five phosphorus derivatives gave Ki values of 0.1--0.3 mM compared to 0.03 mM for pyridoxal, as determined in aldehyde oxidase assays using N-methylnicotinamide as the substrate. The most active phosphorus inhibitor, ethyl phenyl(2-formylethyl)phosphinate (2b), and pyridoxal were further shown to give competitive and mixed inhibition, respectively. Three aldehydes, administered concurrently with cyclophosphamide, produced greater increases in life span of L1210-implanted mice than did pyridoxal. All four agents gave an average increase in life span greater than 50% over that shown by cyclophosphamide alone.
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PMID:Cyclophosphamide potentiation and aldehyde oxidase inhibition by phosphorylated aldehydes and acetals. 736 45


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