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

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.
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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.
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PMID:Hydride transfer stereospecificity of rat liver aldehyde dehydrogenases. 303 2

The presence in tumor cells and in normal cells of enzymes which metabolize and inactive alkylating agents appears to play a major role in determining the effectiveness of alkylating agents against human tumors and the toxicities of these agents to normal tissues. The enzyme aldehyde dehydrogenase appears to protect bone marrow and the gastrointestinal tract against toxicity from cyclophosphamide and other closely related oxazophosphorine agents. The presence of this enzyme in bone marrow stem cells facilitates the elimination of tumor cells from bone marrow suspensions, with preservation of the ability of the marrow suspension to reconstitute normal hematopoiesis in a patient. A variety of mouse and human tumors has been shown to be resistant to cyclophosphamide on the basis of an elevated aldehyde dehydrogenase content. The clinical significance of this type of resistance is currently being explored. Increased levels of glutathione-S-transferase have been shown to be associated with cellular resistance to a variety of alkylating agents. We have identified and characterized the conjugates of nitrogen mustards with glutathione. The formation of these conjugates is catalyzed by glutathione-S-transferase. The further study and characterization of these specific reactions should contribute to the understanding and quantitation of this type of alkylating agent resistance.
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PMID:Enzymatic mechanisms of resistance to alkylating agents in tumor cells and normal tissues. 307 28

Significant changes in aldehyde dehydrogenase (ALDH) activity occur during rat hepatocarcinogenesis in vivo. To compare the structure and expression of the tumor aldehyde dehydrogenase gene in rat hepatoma cell lines and normal rat liver, several rat hepatoma cell lines, including HTC, H4-II-EC3, JM2, McA-RH7777, and four lines established in this laboratory have been examined for T-ALDH gene expression using a tumor ALDH complementary DNA. Northern blot analysis of polyadenylate-containing RNA from log-phase cells and normal rat liver with T-ALDH complementary DNA indicates production of a single major 1.7-kilobase transcript in the high activity lines HTC, JM2, RLT-2M, RLT-3C, RLT-9F, and intermediate activity line RLT-5G. There is a direct correlation between expression of T-ALDH enzyme activity and the amount of 1.7-kilobase transcript. S1 nuclease protection experiments confirm that there is only one major T-ALDH transcript in the high activity lines. Thus, cell line differences in T-ALDH activity are reflected in the level of a single T-ALDH transcript. Southern analysis was used to identify the T-ALDH gene in genomic DNA. The results indicate that no significant amplification or rearrangement of the T-ALDH gene has occurred in these hepatoma cells. DNA methylation has been proposed to play an important role in gene expression. Genomic DNA from HTC, JM2, McA-RH7777, H4-II-EC3, RLT-2M, RLT-9F, RLT-3C, RLT-5G, rat embryo and normal rat liver were digested with MspI and HpaII to examine methylation patterns. A digestion pattern consistent with hypomethylation was detected only in DNA from the high T-ALDH activity cell lines HTC, JM2, RLT-2M, and RLT-9F. This suggests that constitutive expression of T-ALDH in the hepatoma cells is related to changes in DNA methylation patterns.
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PMID:Expression of tumor-associated aldehyde dehydrogenase gene in rat hepatoma cell lines. 326 98

The 0-24-h urinary metabolic profile of cyclophosphamide was investigated in a series of 14 patients with various malignancies receiving combination chemotherapy including i.v. cyclophosphamide. This was accomplished using combined thin-layer chromatography-photography-densitometry, which can quantitate cyclophosphamide and its four principal urinary metabolites (4-ketocyclophosphamide, nor-nitrogen mustard, carboxyphosphamide, and phosphoramide mustard). Recovery of drug-related metabolites was 36.5 +/- 17.8% (SD) dose, the most abundant metabolites being phosphoramide mustard (18.5 +/- 16.1% dose) and unchanged cyclophosphamide (12.7 +/- 9.3% dose). The most variable metabolite was carboxyphosphamide, with five patients excreting 0.3% dose or less. These patients were termed low carboxylators (LC) and could be distinguished from high carboxylators (HC) by a carboxylation index (relative percentage as carboxyphosphamide multiplied by 10). Mean carboxylation indices for the LC and HC phenotypes were 3.4 +/- 2.6 and 151 +/- 115, respectively. There were no associations between patient age, sex, body weight, tumor type, or concomitant drug therapy and carboxylation phenotype. Neither 4-ketocyclophosphamide nor nor-nitrogen mustard excretion differed between LC and HC phenotypes; however, HC patients had a greater excretion of cyclophosphamide (46.4 +/- 15.5 relative percentage) than LC patients (19.4 +/- 12.6%). The DNA cross-linking cytotoxic metabolite phosphoramide mustard was elevated more than 2-fold in the LC (76.5 +/- 13.9%) compared with the HC (33.0 +/- 12.2%) phenotype. It is concluded that these data represent the first evidence of a defect in cyclophosphamide metabolism, and it is proposed that this arises from a hitherto unrecognized aldehyde dehydrogenase genotype.
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PMID:Phenotypically deficient urinary elimination of carboxyphosphamide after cyclophosphamide administration to cancer patients. 340 42

The substrate preference of an aldehyde dehydrogenase induced in rat liver cytosol by 3-methylcholanthrene was examined. This enzyme, T-ALDH, is identical to the aldehyde dehydrogenase inducible in rat liver by 2,3,7,8-tetrachloro-dibenzo-p-dioxin and the tumor-associated aldehyde dehydrogenase found in rat hepatocellular neoplasms. With either NAD or NADP as coenzyme, the preferred substrates were the aliphatic aldehydes n-hexanal, n-nonanal, and isobutyraldehyde and the aromatic aldehydes 2,5-dihydroxybenzaldehyde, benzaldehyde, and 3-hydroxybenzaldehyde. The results indicate that T-ALDH may play a role in oxidizing a variety of aldehydes produced in physiological lipid metabolism. On the contrary, this isozyme does not seem to participate in the oxidation of small aliphatic aldehydes generated during lipid peroxidation. Similarly, no significant activity could be detected when the enzyme was tested with aldehydes produced in carbohydrate, amino acid, polyamine, steroid, and vitamin metabolism.
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PMID:Substrate preference of a cytosolic aldehyde dehydrogenase inducible in rat liver by treatment with 3-methylcholanthrene. 342 Jun 20

Diethylnitrosamine following partial hepatectomy followed by phenobarbital promotion was used to study changes in aldehyde dehydrogenase (ALDH) activity during rat hepatocarcinogenesis. Over a period of 350 days, animals were killed 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 NAD+ to detect normal liver ALDH activities, and benzaldehyde and NADP+ for tumor-associated ALDH. In contrast to previously tested protocols, no significant changes in ALDH activity were demonstrable by histochemistry or total activity assays in preneoplastic livers. However, nine of 16 (56%) of the hepatocellular carcinomas examined expressed the tumor-associated ALDH phenotype. The present results are integrated with previous observations as a hypothesis explaining the roles of initiation and promotion in expression of the tumor-associated aldehyde dehydrogenase phenotype.
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PMID:Changes in aldehyde dehydrogenase activity during diethylnitrosamine-initiated rat hepatocarcinogenesis. 360 75

The radiation modifying effect and toxicity of tetraethylthiuram disulfide (disulfiram) have been studied. Disulfiram (DSM) inhibits aldehyde dehydrogenase, dopamine-beta-oxygenase, microsomal mixed-function oxidases and cytochrome P-450 enzymes. It is widely used for aversion therapy in alcoholism. Disulfiram also inhibits tumor formation by several known carcinogens. A biphasic toxicity pattern of DSM is reported in the L-929 mouse fibroblast culture system. Disulfiram is 100 percent toxic at 2 X 10(-7) M (0.05 micrograms per ml), 23 percent toxic at 3 X 10(-7) M (0.1 microgram per ml), and 100 percent toxic again at 3.4 X 10(-6) M (1.0 microgram per ml). The pattern is similar to the biphasic toxicity pattern of DMS's major metabolite, sodium diethyldithiocarbamate (DTC). Reports of both radiation protection and radiation enhancement by DTC exist. Previously, a radioprotective effect by 2 X 10(-6) M DTC (dose modifying factor = 1.26) has been demonstrated in the L-929 cell system. To date, no radiation modifying properties of DSM have been reported. Our investigation of DSM as a radiation modifier at 3 X 10(-7) M (0.1 microgram per ml) did not show significant improvement in survival of irradiated cells treated with DSM relative to the irradiated control group, as determined by absence of a difference in the Do of the two groups. Considering DSM's close structural relationship to DTC, it is possible that DSM may exhibit a radioprotective effect when applied in a different concentration than what was used in our research.
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PMID:Disulfiram as a radiation modifier. 380 Mar

We have proposed developing rat hepatoma cell lines as an in vitro model for studying the regulation of changes in aldehyde dehydrogenase activity occurring during hepatocarcinogenesis. Aldehyde dehydrogenase purified in a single step from HTC rat hepatoma cells is identical to the aldehyde dehydrogenase isolated from rat hepatocellular carcinomas. HTC aldehyde dehydrogenase is a 100 kDa dimer composed of 54-kDa subunits, prefers NADP+ as coenzyme, and preferentially oxidizes benzaldehyde-like aromatic aldehydes but not phenylacetaldehyde. The substrate and coenzyme specificity, effects of disulfiram, pH profile and isoelectric point of HTC aldehyde dehydrogenase are also identical to these same properties of the tumor aldehyde dehydrogenase. In immunodiffusion, both isozymes are recognized with complete identity by anti-HTC aldehyde dehydrogenase antibodies. Having established that HTC aldehyde dehydrogenase is very similar, if not identical, to the aldehyde dehydrogenase found in hepatocellular carcinomas, simplifies the development of molecular probes for examination of the regulation of tumor aldehyde dehydrogenase activity in vivo and in vitro.
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PMID:Characterization of aldehyde dehydrogenase from HTC rat hepatoma cells. 393 72

The resistant hepatocyte model was used to study expression of tumor-associated aldehyde dehydrogenase (ALDH) activity during the course of rat hepatocarcinogenesis. The hepatic ALDH phenotype was determined at intervals over 280 days by histochemical analysis, total ALDH activity assays and gel electrophoresis, using propionaldehyde and NAD (P/NAD) to characterize normal liver ALDH activity or benzaldehyde and NADP (B/NADP) to determine tumor-associated ALDH activity. By total activity assays and gel electrophoresis, no significant changes in ALDH activity occurred until day 70. However, histochemical analysis clearly demonstrated changes in ALDH activity early in neoplastic development. Intense focal hepatocyte staining with P/NAD and/or B/NADP was first detectable at day 28. The number of P/NAD-positive foci increased until day 35 then declined until day 70. The number of B/NADP-positive foci also increased until day 35, but then remained relatively constant for the remainder of the experiment. GGT activity of serial sections indicated that early ALDH-positive lesions represent a small subpopulation (9%) of all GGT-positive foci. However, by day 168 a significant portion (80%) of persistent GGT-positive neoplastic nodules were also B/NADP-positive histochemically. In addition, virtually all hepatocellular carcinomas (96%) generated by this protocol possessed significantly elevated levels of tumor-associated ALDH by histochemical analysis, total ALDH activity and gel electrophoresis. These results indicate that early appearing ALDH-positive lesions may define one early subpopulation of all initiated cells that have a high probability of progressing to the ultimate neoplasm.
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PMID:Expression of tumor-associated aldehyde dehydrogenase during rat hepatocarcinogenesis using the resistant hepatocyte model. 614 20


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