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

The effects of certain in vivo inducers of tumor-associated aldehyde dehydrogenase (aldehyde:NAD+ oxidoreductase, EC 1.2.1.3; ALDH) activity on the expression of tumor-associated ALDH (T-ALDH) in vitro have been investigated using cultured rat hepatocytes and hepatoma cell lines. Two distinct groups of T-ALDH inducers have been identified. Three hepatocarcinogenic initiators 2-acetylaminofluorene, diethylnitrosamine and ethionine, which cause changes in T-ALDH in vivo, do not induce T-ALDH activity in cultured rat hepatocytes or hepatoma cell lines following either short-term or long-term exposures. In contrast, polycyclic aromatic hydrocarbons, such as 3-methylcholanthrene, benzo[a]pyrene and 7,12-dimethylbenz[a]anthracene, induce an immediate increase of T-ALDH activity in both cultured rat hepatocytes and hepatoma cell lines. Synthesis and degradation rates of T-ALDH mRNA and protein have also been determined. The synthesis of T-ALDH protein is coupled with the increased synthesis of T-ALDH mRNA when the T-ALDH gene is constitutively expressed or activated by an inducer. Both T-ALDH mRNA (t1/2 = 25 - 34 h) and protein (t1/2 = 88 - 95 h) in high T-ALDH activity cell lines or low-activity cell lines treated with an inducer are relatively stable. Combined with previous studies, the results suggest that at least two different mechanisms are involved in T-ALDH gene expression; events occurring during initiation as well as during promotion appear to be involved in the genetically stable changes in T-ALDH gene expression which occur in vivo. The results also indicate that the lack of T-ALDH activity in normal hepatocytes or low-activity hepatoma cell lines is due to repression of the T-ALDH gene rather than to the differential stability of T-ALDH mRNA or protein.
 ...
PMID:Effects of hepatocarcinogenic initiators on aldehyde dehydrogenase gene expression in cultured rat hepatic cells. 237 65

Aldophosphamide, the penultimate cytotoxic metabolite of cyclophosphamide, can be detoxified by an oxidation reaction catalyzed by certain aldehyde dehydrogenases. The selective toxicity of cyclophosphamide is due, at least in part, to a greater expression of the relevant aldehyde dehydrogenase activity in normal cells relative to that expressed in certain tumor cells. Not known at the onset of this investigation was which of the several known mouse aldehyde dehydrogenases catalyze this reaction. Twelve enzymes that catalyze the NAD(P)-linked oxidation of aldophosphamide, acetaldehyde, benzaldehyde, and/or octanal were chromatographically resolved from mouse liver. Four of these appear to be novel; four others were determined to be betaine aldehyde dehydrogenase, succinic semialdehyde dehydrogenase, glutamic gamma-semialdehyde dehydrogenase, and xanthine oxidase (dehydrogenase). An additional aldehyde dehydrogenase, namely AHD-4, was semipurified from stomach. The stomach enzyme and nine of the hepatic enzymes catalyze the oxidation of aldophosphamide. Km values for these reactions range from 16 microM to 2.5 mM. The relevant aldehyde dehydrogenase of major importance varies with the tissue. In the liver, the major cytosolic aldehyde dehydrogenase, namely AHD-2, accounts for greater than 60% of total hepatic aldehyde dehydrogenase-catalyzed aldophosphamide (160 microM) detoxification. Succinic semialdehyde dehydrogenase (AHD-12) and three of the novel hepatic aldehyde dehydrogenases, namely AHD-8, AHD-10, and AHD-13, also contribute significantly to total hepatic aldehyde dehydrogenase-catalyzed aldophosphamide detoxification. In the stomach, AHD-4 and AHD-8 account for approximately 86% of total aldehyde dehydrogenase-catalyzed aldophosphamide (160 microM) detoxification. AHD-2 was not found in this tissue. Of all the aldehyde dehydrogenases examined, AHD-2 and AHD-8 were estimated to be the most efficient catalysts of aldophosphamide oxidation. Thus, these enzymes would seem most likely to be operative when tumor cells acquire aldehyde dehydrogenase-mediated cyclophosphamide resistance.
 ...
PMID:Identification of the mouse aldehyde dehydrogenases important in aldophosphamide detoxification. 237 64

4-amino-4-methyl-2-pentyne-1-al (AMPAL), a new irreversible inhibitor of aldehyde dehydrogenase (ALDH) has been assayed for its in vitro and in vivo antitumor activity. In vitro, AMPAL inhibits the proliferation and the ALDH activity of L1210 and RBL5 cell lines. In vivo, AMPAL significantly increases the mean survival time of mice i.p. grafted with leukemia (L1210, P815, MBL2, EL4, RBL5 cell lines) or carcinoma cells (Krebs cell line), without haematopoetic toxicity. No carcinostatic effect was observed against the P388 leukemia and the 3LL Lewis lung carcinoma. A possible relationship between the ALDH isoenzyme activity of the tumor and its sensitivity to AMPAL is discussed in the light of previous reports concerning the role of aldehydes in cell growth control.
 ...
PMID:In vivo antitumor activity of 4-amino 4-methyl 2-pentyne 1-al, an inhibitor of aldehyde dehydrogenase. 251 73

Aldehyde dehydrogenase has been purified from rat cornea in a single step. The enzyme is a class 3 aldehyde dehydrogenase. Cornea aldehyde dehydrogenase is a 100-kDa dimer composed of 51-kDa subunits, prefers NADP+ as coenzyme, and preferentially oxidizes benzaldehyde-like aromatic aldehydes as well as medium chain length (4-9 carbons) aliphatic aldehydes. The substrate and coenzyme specificity, immunochemical properties, effect of disulfiram, pH profile, and isoelectric point of cornea aldehyde dehydrogenase are identical to those of tumor-associated aldehyde dehydrogenase, the prototype class 3 enzyme. The substrate and coenzyme preferences are consistent with a role for cornea aldehyde dehydrogenase in the oxidation of a variety of aldehydes generated by lipid metabolism, including lipid peroxidation.
 ...
PMID:Characterization of rat cornea aldehyde dehydrogenase. 280 24

To study the mechanism(s) controlling expression of the tumor-associated aldehyde dehydrogenase (tumor ALDH), which appears during rat hepatocarcinogenesis, cDNAs encoding this isozyme were cloned and identified with an antibody probe. Poly(A)-containing RNA from HTC rat hepatoma cells, which have been shown to possess high levels of tumor ALDH, was used as template to synthesize double-stranded cDNA. The cDNA was methylated to protect internal sites. Two different synthetic DNA linkers were added sequentially to the cDNA to insure correct orientation for expression from the lac promoter of pUC8. A library of 100,000 independent members carrying inserts greater than 1 kilobase was obtained. From this library, two apparently identical tumor ALDH clones, differing only in size, were identified with an indirect immunological probe. The larger of the cDNA clones identified, pTALDH, was chosen for further study. Interestingly, since tumor ALDH is a dimeric enzyme, pTALDH directs synthesis of a functional tumor ALDH in the bacterial cell. The cDNA sequence has been confirmed by comparison to the amino acid sequence of tumor ALDH purified from HTC cells.
 ...
PMID:Cloning and complete nucleotide sequence of a full-length cDNA encoding a catalytically functional tumor-associated aldehyde dehydrogenase. 283 37

Chronic exposure to ethionine (0.05%) combined with dietary choline deficiency was used to study changes in aldehyde dehydrogenase (ALDH) activity during hepatocarcinogenesis in male Sprague-Dawley rats. Over a period of 43 weeks, animals were sacrificed at intervals and the ALDH phenotype of normal liver and any lesions was characterized by histochemical analysis, total activity assays, and gel electrophoresis, using propionaldehyde and nicotinamide adenine dinucleotide (NAD+) to detect normal liver ALDH activity and benzaldehyde and nicotinamide adenine dinucleotide phosphate (NADP+) for tumor-associated ALDH. In animals receiving ethionine plus choline deficiency, significant changes in ALDH were observed histochemically by 9 weeks, when there was a distinct shift in activity from its normal centrilobular pattern to a periportal distribution. The first NAD+- and NADP+-dependent ALDH-positive enzyme-altered foci were also seen at 9 weeks. There was no correlation between the ALDH and gamma-glutamyl transpeptidase phenotypes of an individual focus. Areas of cholangiofibrosis, cystic degeneration, and bile duct proliferation were distinctly ALDH negative. No significant changes in benzaldehyde and NADP+ ALDH activity were detectable by total activity assays or gel electrophoresis prior to the appearance of overt neoplasms at 26 weeks. No significant changes in ALDH activity occurred in animals receiving either ethionine or choline deficient diet alone. By histochemistry, total activity assays and gel electrophoresis, only 7 of the 28 (25%) of the hepatic neoplasms examined expressed the tumor-associated ALDH phenotype. An additional five neoplasms had barely detectable levels of benzaldehyde and NADP+ ALDH activity. These results are in striking contrast to changes in ALDH activity occurring during hepatocarcinogenesis induced by other protocols we have tested previously in which from 50 to 96% of all neoplasms were ALDH positive.
 ...
PMID:Changes in aldehyde dehydrogenase occurring during rat hepatocarcinogenesis induced by ethionine combined with dietary choline deficiency. 287 26

Recent studies in our laboratory have shown that five established rat hepatoma cell lines provide a wide spectrum of tumor-associated aldehyde dehydrogenase (ALDH) activity representative of the range of activities of this enzyme seen in primary rat hepatocellular carcinomas. Four newly established rat hepatoma cell lines, RLT-2M, RLT-3C, RLT-9F, and RLT-5G, were derived from a primary hepatocellular carcinoma. The primary tumor was induced by a single injection of diethylnitrosamine (15 microM/g body weight) to a 1-d-old female S-D rat followed at weaning by chronic phenobarbital treatment. RLT-2M was established from outgrowths of minced tumor pieces. RLT-3C, RLT-9F, and RLT-5G were cloned from RLT-2M by the serial endpoint dilution. All four lines have been maintained in culture for over 100 passages. The ALDH phenotype in both the primary tumor and the four new cell lines was determined by total activity assay, gel electrophoresis, and histochemistry. By total activity assay, the primary tumor did not possess significant tumor-ALDH activity. In contrast, the four new cell lines expressed tumor-ALDH activity. However, they differed in their basal ALDH activities and in ALDH inducibility by 3-methylcholanthrene, benzo(a)pyrene, and phenobarbital. Additionally, significant decreases in tumor-ALDH activity occurred when cells from each line were passaged in vivo. The four lines have been characterized by light and electron microscopic morphology, tumorigenicity, chromosome number, doubling time, and colony formation efficiency in soft agar.
 ...
PMID:Characteristics and aldehyde dehydrogenase activity of four rat hepatoma cell lines produced by diethylnitrosamine-phenobarbital treatment. 287

An aldehyde dehydrogenase (ALDH) with properties identical to those of the NADP+-dependent, tumor-associated aldehyde dehydrogenase appearing during rat hepatocarcinogenesis has been identified in normal rat urinary bladder. Like the tumor-associated aldehyde dehydrogenase, bladder NADP+-ALDH is cytosolic and preferentially oxidizes benzaldehyde-like aromatic aldehydes. Bladder ALDH is also extremely sensitive to the aldehyde dehydrogenase inhibitor disulfiram. Additionally, the electrophoretic mobility of bladder ALDH is identical to that of the NADP+-dependent, tumor-associated aldehyde dehydrogenase. Finally, antibodies to the tumor-associated ALDH cross-react with bladder aldehyde dehydrogenase. Histochemically, bladder aldehyde dehydrogenase is localized to the very active epithelial lining and to the inner and outer smooth muscle layers. The observation that normal urinary bladder possesses an enzyme activity very similar to one expressed during hepatocarcinogenesis, but not in normal liver, is consistent with the hypothesis that derepression of a gene normally repressed in liver is responsible for expression of the tumor-associated aldehyde dehydrogenase phenotype.
 ...
PMID:Identification of hepatocarcinogenesis-associated aldehyde dehydrogenase in normal rat urinary bladder. 300 91

The ex vivo sensitivity of human multipotent and committed hematopoietic progenitor cells and several cultured human malignant blood cell lines to analogues of "activated" cyclophosphamide, namely, 4-hydroperoxycyclophosphamide and mafosfamide, and to phosphoramide mustard was quantified with and without concurrent exposure to an inhibitor of aldehyde dehydrogenase activity, namely, disulfiram, cyanamide, diethyldithiocarbamate, or ethylphenyl(2-formylethyl)phosphinate. Inhibitors of aldehyde dehydrogenase activity potentiated the cytotoxic action of 4-hydroperoxycyclophosphamide and mafosfamide toward all of the hematopoietic progenitors; they did not potentiate the cytotoxic action of phosphoramide mustard toward these cells. Potentiation of the cytotoxic action of mafosfamide toward cultured human malignant blood cells was minimal. Spectrophotometric assay revealed little NAD-linked aldehyde dehydrogenase activity present in the cultured human tumor cell lines as compared to that found in normal mouse liver or oxazaphosphorine-resistant L1210 cells. Cellular aldehyde dehydrogenases are known to catalyze the oxidation of 4-hydroxycyclophosphamide/aldophosphamide, the major intermediate in cyclophosphamide bioactivation, to the relatively nontoxic acid, carboxyphosphamide. Thus, our findings indicate that human multipotent hematopoietic progenitor cells contain the relevant aldehyde dehydrogenase activity, the relevant activity is retained upon differentiation to progenitors committed to the megakaryocytoid, granulocytoid/monocytoid, and erythroid lineages, and the relevant activity may be lost or diminished upon transformation of hematopoietic progenitors to malignant cells.
 ...
PMID:Effect of aldehyde dehydrogenase inhibitors on the ex vivo sensitivity of human multipotent and committed hematopoietic progenitor cells and malignant blood cells to oxazaphosphorines. 303 2

The stereospecificity of hydride transfer to NAD+ by several forms of rat liver aldehyde dehydrogenase was determined by a nuclear magnetic resonance method. The forms included several mitochondrial and microsomal isozymes from normal liver, as well as isozymes from xenobiotic-treated and tumor cells. The proton added to NAD+ comes exclusively from the aldehyde substrate and in all cases was A (pro-R)-stereospecific.
 ...
PMID:Hydride transfer stereospecificity of rat liver aldehyde dehydrogenases. 303 2


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>