Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0006826 (cancer)
 1,092,456 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

31P nuclear magnetic resonance (NMR) spectra of cells and of cell extract revealed high levels of phosphorylcholine (PC) and phosphocreatine (PCr) in an adriamycin-resistant human small cell lung carcinoma cell line (GLC4/ADR) and the adriamycin-sensitive parental cell line (GLC4). PCr levels in extracts of GLC4/ADR were increased compared to extracts of GLC4. We estimated that 11% of the total intracellular ATP is not bound to Mg2+ in both cell lines. This value corresponded to an intracellular free Mg2+ of 0.30 mM. The effects of different adriamycin concentrations, 0.05, 1 and 30 microM for GLC4 and 1, 30 and 200 microM for GLC4/ADR, on the phosphorus metabolite levels in continuously perfused cells were monitored. Significant differences between GLC4 and GLC4/ADR included: (a) a strong increase in the beta ATP level in the presence of 30 microM adriamycin in GLC4 only, followed by a fast decrease after 5 h of perfusion. (b) a less dramatic increase in the PC level in GLC4/ADR and an unchanged ATP level in the presence of increasing adriamycin concentrations. (c) an increased GPC level in GLC4/ADR in the presence of adriamycin. The changes in PC and GPC levels in the presence of adriamycin suggested that the phospholipid turnover was increased in GLC4/ADR and could be stimulated in the presence of adriamycin. In both cell lines, PCr levels decreased faster than the ATP levels after adriamycin treatment. Thus, biochemical markers for adriamycin resistance can be detected with NMR spectroscopy. However, more studies are necessary to obtain parameters to distinguish drug-sensitive from drug-resistant tumours in patients by NMR spectroscopy.
Br J Cancer 1991 Feb
PMID:NMR spectroscopy analysis of phosphorus metabolites and the effect of adriamycin on these metabolite levels in an adriamycin-sensitive and -resistant human small cell lung carcinoma cell line. 184 46

The aim of our work was to investigate whether DNA topoisomerase II participates in the repair-specific incision of UV-irradiated genomic DNA. Therefore, the influence upon DNA incision of the topoisomerase II inhibitors (nalidixic and oxolinic acid, novobiocin and coumermycin A1) as well as the intercalating agent quinacrine has been measured in normal human fibroblasts using the alkaline elution technique. In addition, inhibition by novobiocin has been determined in fibroblast strains from 11 normal donors and from 16 xeroderma pigmentosum (XP) patients belonging to the complementation groups A, C, D, E, and XP variant. Nalidixic and oxolonic acid did not inhibit endonucleolytic cleavage, whereas novobiocin was a potent inhibitor of DNA incision. It was observed that in normal and in all XP strains 50% inhibition by novobiocin occurred on average in the dose range 315-590 microM. Since inhibition by novobiocin was not paralleled by that with the other topoisomerase II inhibitors nalidixic and oxolinic acid, it must be concluded that reduction of enzyme-catalysed breaks was not due to the participation of topoisomerase II in the incision step, but to the displacement of ATP at the binding site of the DNA-incising enzyme. This enzyme absolutely requires ATP as a cofactor for endonucleolytic cleavage. Quinacrine, however, inhibited DNA incision in normal fibroblasts at a mean Ki of 318 microM. Inhibition by this intercalating agent seems to be caused by structural perturbations in DNA, which render it a poor substrate for endonucleolytic cleavage.
J Cancer Res Clin Oncol 1991
PMID:The effects of inhibitors of topoisomerase II and quinacrine on ultraviolet-light-induced DNA incision in normal and xeroderma pigmentosum fibroblasts. 184

1,3 Dimethylthiourea (DMTU) has previously been shown by us to inhibit the growth of melanoma cells and to induce phenotypic alterations in these cells, including ultrastructural alterations of mitochondria. These findings raised the possibility that impaired mitochondrial function might be involved in mediating the effect of DMTU on cell growth and phenotypic expression. The present study indicates that DMTU as well as another growth inhibitory methylurea derivative, tetramethylurea (TMU) significantly decrease ATP content in the B16 melanoma cell line. 1,3 Dimethylurea (1,3DMU) and 1,1 dimethylurea (1,1DMU) which are poor growth inhibitors, do not reduce ATP content significantly. Altered energy metabolism in the DMTU-treated cells is reflected by inhibition of the activity of cytochrome c oxidase and by increased lactate levels. A cell line selected for resistance to growth inhibition by DMTU was shown to be completely resistant to induction of phenotypic alterations by DMTU. These cells possess high lactate levels, high ATP content and a somewhat decreased Na/K ATPase activity as compared to wild type B16 F10 cells. 1,3 DMTU treatment of the resistant cells leads to a decrease in the activity of the mitochondrial enzyme cytochrome c oxidase, similar to its effect on the wild type B16 F10 cells. DMTU also reduces ATP content moderately in the resistant cells. However, the levels of ATP do not decrease beyond those found in untreated B16 F10 wild type cells. Taken together the results suggest that decreased ATP content might be involved, at least partially, in mediating the effects of DMTU on B16 melanoma cell growth and phenotypic expression.
Br J Cancer 1991 Apr
PMID:Dimethylthiourea inhibition of B16 melanoma growth and induction of phenotypic alterations; relationship to ATP levels. 185 Jun 8

Cis-unsaturated fatty acids (c-UFAs) such as gamma-linolenic acid (GLA), arachidonic acid (AA) and eicosapentaenoic acid (EPA) can kill tumor cells selectively in vitro. As c-UFAs have the ability to augment free radical generation, the effect of antioxidants, free radical quenchers and augmentors of free radical generation such as iron and copper salts on fatty acid-induced tumor cell death was studied. In addition, the role of lipid peroxidation in the tumoricidal action of c-UFAs was also examined. Results indicate that vitamin E, uric acid, glutathione peroxidase, superoxide dismutase and ATP can block, whereas iron, copper and catalase enhance the tumoricidal action of GLA. The ability of GLA, AA and EPA to kill tumor cells correlated with the amount of lipid peroxidation these fatty acids can induce as measured by thiobarbituric acid test. It was also observed that 14C-labelled linoleic acid uptake was almost the same whereas that of 14C-labelled arachidonic acid and eicosapentaenoic acid were substantially less in tumor cells compared to normal cells. Tumor cells incorporated major portions of the fatty acids in the ether lipid and phospholipid fractions, whereas normal cells incorporated the fatty acids primarily in the phospholipid fraction. These results suggest that c-UFA-induced tumoricidal action is a free radical dependent process and that there are significant differences between normal and tumor cells in fatty acid uptake and distribution.
Cancer Lett 1991 Mar
PMID:Tumoricidal action of cis-unsaturated fatty acids and their relationship to free radicals and lipid peroxidation. 185 Jun 58

Several pharmaceutical agents, manufacturing chemicals, and environmental contaminants were found to act primarily as promoting agents in an initiation-promotion paradigm. The phenotypic distribution of four enzyme markers--placental glutathione-S-transferase (PGST), gamma-glutamyl transpeptidase (GGT), canalicular ATPase (ATPase), and glucose-6-phosphatase (G6Pase)--was analyzed in altered hepatic foci (AHF) by quantitative stereology. The number and volume distribution of AHF were determined for each promoter tested. For phenobarbital and 2,3,7,8-tetrachloro-p-dioxin, PGST and GGT together scored 100% of the AHF; for 1-(phenylazo)-2-naphthol (CI solvent yellow 14) and chlorendic acid, PGST alone marked 90% of the AHF; after chronic administration of WY-14,643, ATP and G6Pase were the predominant markers. In rats fed tamoxifen, G6P scored more than half of the AHF. Differences in the number of AHF promoted by each of these agents and in their phenotypic distributions may reflect the differentially responsive nature of individual initiated hepatocytes to the action of specific promoters. Since the chronic bioassay of suspected carcinogens does not allow one to differentiate between weak complete carcinogens and those carcinogenic agents that act in a reversible manner to promote the growth of previously initiated cells, the partial hepatectomy, altered-hepatic-focus model of cancer development is proposed as a supplement to the chronic bioassay for the identification of those carcinogenic agents that are primarily, if not exclusively, promoting agents in rat liver.
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PMID:An initiation-promotion assay in rat liver as a potential complement to the 2-year carcinogenesis bioassay. 185 24

Long-chain fatty acids inhibit glucuronidation of benzo(a)pyrene phenols in perfused liver; therefore, this study was designed to investigate interactions of fatty acids with beta-glucuronidase, glucuronosyl transferase, and energy supply. In beta-glucuronidase-deficient C3H/He mice, infusion of oleate (250 microM) increased the release of free benzo(a)pyrene phenols from 14 to 33 nmol/g/h and decreased release of glucuronides into the perfusate from 25 to 17 nmol/g/h. Rates of accumulation of glucuronides in the liver were also diminished from 11 to 4 nmol/g/h after infusion of oleate (250 microM). Fatty acids did not affect the release of benzo(a)pyrene metabolites into bile, and the ratio of free phenol to glucuronide production was increased from 0.57 to 1.30. A similar trend was observed in livers from DBA/2 mice that have beta-glucuronidase. Rates of hydrolysis of benzo(a)pyrene-O-glucuronide were not altered in isolated microsomes by addition of oleoyl coenzyme A (CoA) or octanoyl CoA (10- approximately 100 microM). Thus, we conclude that fatty acids do not alter glucuronidation by acting on beta-glucuronidase. The concentration of cofactors (UDP-glucuronic acid, UDP-glucose, and adenine nucleotides) involved in hepatic conjugation was not altered by infusion of concentrations of oleate (300 microM) that inhibited glucuronidation in perfused livers. When oleate concentrations were increased to 600 microM, UDP-glucuronic acid and UDP-glucose decreased 44 and 49%, respectively, and the ATP:ADP ratio declined concomitantly. Oleoyl CoA inhibited UDP-glucuronosyl transferase noncompetitively (half-maximal inhibition, 10 microM) in microsomes with 3-hydroxy-benzo(a)pyrene or p-nitrophenol as substrate. In contrast, octanoyl CoA was a very poor inhibitor of transferase activity. Inhibition of the transferase by oleoyl CoA was increased markedly by treatment with detergents (Triton X-100), i.e., half-inhibition of glucuronosyl transferase was obtained with about 2 microM oleoyl CoA. Inhibition of UDP-glucuronosyl transferase by oleoyl CoA was also increased in a dose-dependent manner by albumin, possibly due to increasing access of the CoA derivative to the enzyme. Collectively, these data indicate that fatty acids diminish glucuronidation via the formation of acyl CoA compounds that inhibit UDP-glucuronosyl transferase noncompetitively.
Cancer Res 1991 Sep 01
PMID:Inhibition of glucuronidation of benzo(a)pyrene phenols by long-chain fatty acids. 190 48

Arterial blood pressure and relevant parameters of the arterial blood (O2 and CO2 tensions, pH, haematocrit, serum electrolytes and osmolality) were determined in tumour-bearing rats upon local hyperthermia (HT) and/or hyperglycaemia (HG). Tumour heating was performed in a saline bath (44 degrees C) for 120 min; hyperglycaemia was induced by i.v. infusion of 40% glucose solution for 150 min [blood glucose levels: 35-40 mM during heating; total amount of glucose: 1.19 g/100 g body wt.; infusion rates: 0.31 ml (100 g body wt.)-1 min-1 for 2 min, 0.02 ml (100 g body wt.)-1 min-1 for 88 min, and 0.01 ml (100 g body wt.)-1 min-1 for 60 min]. Immediately after treatment, glucose, lactate and ATP levels were determined in tumour and muscle specimens and compared to these values under normothermic (NT) and/or normoglycaemic (NG) conditions. In all groups (NT/NG, NT/HG, HT/NG, HT/HG) there were only minor but characteristic changes in blood parameters, which were mainly due to the volume and type of the infused fluids (glucose solution, saline). During hyperglycaemia, tumour glucose levels rose 13- to 17-fold, whereas muscle glucose concentrations exhibited only a 3- to 5-fold increase; lactate levels were 1.9-2.5 times higher in tumours than in muscle, indicating an increase in the metabolic differences between normal and malignant tissues. Despite an increased glucose availability, tumours did not show an improved energy status and, thus, would not be expected to develop a decrease in thermal sensitivity or stimulation in growth rate. The good systemic tolerability of the combined treatment (HT/HG) and the differential changes in malignant and normal tissue occurring under these conditions, support further attempts to manipulate tumour metabolic environment by glucose in order to achieve better therapeutic results.
J Cancer Res Clin Oncol 1991
PMID:Acute changes of systemic parameters in tumour-bearing rats, and of tumour glucose, lactate, and ATP levels upon local hyperthermia and/or hyperglycaemia. 190 97

Neuroblastoma cells accumulate ascorbic acid and iron. It was hypothesized that these features could be exploited for sensitizing neuroblastoma cells for therapy in combination with reactive oxygen intermediates. In the present study the effects of 6-hydroxydopamine (6-OHDA) and H2O2 on metabolic parameters critical for cell survival were investigated in cells with low and high ferritin content in the presence and absence of ascorbate. Human neuroblastoma SK-N-SH cells were pretreated with 100 microM FeSO4 and 10 microM desferrioxamine, respectively, for 24 h yielding cells with different ferritin contents. The effects of 6-OHDA and H2O2 (25 microM-250 microM) in the absence and presence of 1 mM ascorbic acid on DNA strand break formation, activation of poly(ADP-ribose) polymerase, and finally decrease in NAD+ and ATP concentration were investigated. All these parameters were influenced by 6-OHDA and H2O2 in a concentration-dependent manner in a similar way. The effects were most pronounced in ferritin-rich cells and in the presence of ascorbic acid. Using isolated CCC PM2 DNA, 6-OHDA and ascorbic acid caused strand breaks that were prevented in the presence of mannitol or desferrithiocine. H2O2-mediated strand breaks were observed only in the presence of ascorbic acid. Based on these data and data published by others a model explaining the deleterious effects of ascorbic acid on neuroblastoma cells is presented. It is suggested that continuous application of a high dosage of ascorbic acid might be a useful approach in neuroblastoma therapy.
Cancer Res 1991 Nov 15
PMID:Ascorbic acid enhances the effects of 6-hydroxydopamine and H2O2 on iron-dependent DNA strand breaks and related processes in the neuroblastoma cell line SK-N-SH. 193 70

Diarylsulfonylureas are novel oncolytic agents shown to have therapeutic activity against both rodent solid tumors and xenografts of human tumors in mice. Previous studies have shown that diarylsulfonylureas localize in mitochondria and cause morphological changes in these organelles. We have investigated the mechanism of action of diarylsulfonylureas, namely, N-(5-indanylsulfonyl)-N'-(4-chlorophenyl)urea (ISCU) and the N-4-methyl analogue (MPCU), by studying their effect on mitochondrial morphology and uptake of rhodamine 123 in GC3/c1 cells in culture and the oxidative phosphorylation in isolated mitochondria from mouse liver, using pyruvate-malate and succinate as substrates. Morphometric analysis of mitochondria in GC3/c1 cells exposed to ISCU showed that ISCU (165 microM) doubled the mitochondrial size after 24-h exposure in culture. Also, ISCU (100 microM), like 40 microM carbonylcyanide p-trifluoromethoxyphenylhydrazone, significantly reduced the rhodamine 123 uptake by GC3/c1 cells studied by flow cytometry. In isolated mitochondria both ISCU and MPCU uncoupled oxidative phosphorylation at 50 microM, with pyruvate-malate as substrate, as was indicated by a significant increase in the State 4 oxygen consumption. This resulted in the loss of ADP phosphorylation and, therefore, the ADP/oxygen ratio was reduced to zero and the respiratory control ratio to one. The succinate oxidation was also significantly impaired by ISCU, causing some decrease in ADP phosphorylation. On the other hand, MPCU did not exhibit any significant effect on the oxidation of succinate. At concentrations of lower than 50 microM, both of these compounds exhibited a deleterious effect, causing damage to mitochondrial functions in the presence of pyruvate-malate as substrates. These data confirm, through morphometric analysis, our previous qualitative observations of abnormal mitochondrial morphology observed in GC3/c1 cells grown in the presence of high concentrations of ISCU and MPCU and further suggest that diarylsulfonylureas, by uncoupling mitochondrial oxidative phosphorylation, may lower cellular ATP. It is probable that this mechanism contributes, at least partially, to cytotoxicity in GC3/c1 cells exposed to high concentrations of ISCU for relatively brief periods (2 to 4 h) and possibly contributes to cytotoxicity at drug concentrations that can be achieved in rodents.
Cancer Res 1991 Dec 01
PMID:Effect of antitumor diarylsulfonylureas on in vivo and in vitro mitochondrial structure and functions. 193 89

HL60 cells isolated for resistance to Adriamycin are multidrug resistant and defective in the cellular accumulation of drug. These cells do not however overexpress mdr1 and do not contain detectable levels of P-glycoprotein. In the present study we have prepared antisera against synthetic peptides that correspond to various sequence domains of P-glycoprotein and have examined by Western blot analysis the reactivity of these antisera with proteins contained in membranes of HL60/Adr cells. All antisera are highly reactive with a Mr 180,000 (p180) P-glycoprotein contained in membranes of HL60 cells isolated for resistance to vincristine (HL60/Vinc). In contrast, of 13 antisera tested 12 do not react with any resistance-associated protein in the HL60/Adr isolate. One antiserum (ASP14) is however highly reactive with a Mr 190,000 protein (p190) contained in HL60/Adr membranes. This protein is not detected in drug-sensitive cells. ASP14 also reacts with proteins p195 and p50 contained in a second independent HL60/Adr isolate. Analysis of membrane subfractions shows that p190 is located primarily in the endoplasmic reticulum with only low levels contained in plasma membranes. Additional studies demonstrate that endoplasmic reticulum of HL60/Adr cells contain a major Mr 190,000 protein that is capable of binding the photoaffinity agent 8-azido[alpha-32P]ATP. p195 contained in a second HL60/Adr isolate is also labeled with 8-azido[alpha-32P]ATP. These results thus demonstrate that antiserum against a specific P-glycoprotein sequence detects a p190 (p195) resistance-associated membrane protein in two independent HL60/Adr isolates. p190 (p195) and P-glycoprotein thus contain a minor sequence homology and based on the specificity of ASP14 this occurs in a region which may be involved in nucleotide binding. Possibly this sequence is common to and essential for the functionality of proteins which contribute to resistance by reducing cellular drug levels.
Cancer Res 1990 Mar 01
PMID:Mechanisms of multidrug resistance in HL60 cells: detection of resistance-associated proteins with antibodies against synthetic peptides that correspond to the deduced sequence of P-glycoprotein. 196 79


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