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)

Green tea, next to water, is the most popular and commonly consumed beverage in the world, especially in eastern countries. In prior studies we have shown that the polyphenolic fraction isolated from green tea (GTP) exerts antigenotoxic effects in various mutagenicity test systems (Mutat. Res., 223: 273-285, 1989) and that its topical application or oral feeding in drinking water protects against polycyclic aromatic hydrocarbon-induced skin tumor initiation and complete carcinogenesis in SENCAR and BALB/c mice [Cancer Lett., 42: 7-12, 1988; Carcinogenesis (Lond.), 10: 411-415, 1989] and UV B radiation-induced photocarcinogenesis in SKH-1 hairless mice [Carcinogenesis (Lond.), 12: 1527-1530, 1991]. In the present study we assessed the effect of skin application of GTP to SENCAR mice on 12-O-tetradecanoylphorbol-13-acetate (TPA) and other skin tumor promoter-caused induction of epidermal ornithine decarboxylase (ODC) activity. Topical application of GTP to mouse skin inhibited TPA-induced epidermal ODC activity in a dose-dependent manner. The inhibitory effect of GTP was also dependent on the time of its application relative to TPA treatment. Maximum inhibitory effect was observed when GTP was applied 30 min prior to topical application of TPA. GTP application to animals also inhibited the induction of epidermal ODC activity caused by several structurally different mouse skin tumor promoters. In order to identify which of the specific epicatechin derivatives present in GTP is responsible for these inhibitory effects, they were isolated from GTP and evaluated for their inhibitory effects against TPA-caused induction of epidermal ODC activity. Among these, (-)epigallocatechin-3-gallate (EGCG), which was the major constituent present in GTP by weight, exerted the maximum inhibition. EGCG also showed greater inhibitory effects against TPA-caused induction of epidermal ODC activity when compared with several other naturally occurring polyphenols. The results of this study suggest that GTP, specifically its epicatechin derivative EGCG, could provide anti-tumor-promoting effects against a wide spectrum of skin tumor promoters.
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PMID:Inhibition of skin tumor promoter-caused induction of epidermal ornithine decarboxylase in SENCAR mice by polyphenolic fraction isolated from green tea and its individual epicatechin derivatives. 161 28

Data generated in the new National Cancer Institute drug evaluation program, which are based on inhibition of cell growth in 60 human tumor cell lines, were probed with nine known antimitotic agents using the COMPARE algorithm. Cytotoxicity data were available on approximately 7000 compounds at the time of the analysis, and, based on the criteria used, 82 compounds were selected as positive by the computer search. Nine were the probe compounds themselves, and 41 were analogues of known antimitotic agents. Among the remaining 32 compounds there were 19 distinct chemical species. Agents in ten of these groups (containing 20 compounds) were effective inhibitors of in vitro tubulin polymerization and caused the mitotic arrest of cells grown in culture. Two compounds were related natural products binding in the Vinca domain of tubulin, and the others were synthetic agents which interfered with colchicine binding. The remaining 12 agents (one natural product, the remainder synthetic) fell into several groups: two compounds were weak inhibitors of tubulin polymerization, inhibited colchicine binding, and caused mitotic arrest; one compound weakly inhibited tubulin polymerization but did not cause an increase in the number of cells arrested in mitosis; two compounds caused mitotic arrest at micromolar concentrations, but thus far no in vitro interaction with tubulin has been observed; the remainder neither inhibited tubulin polymerization nor caused a rise in the number of cultured cells arrested in mitosis. Tubulin-dependent GTP hydrolysis was stimulated or inhibited by all agents which inhibited tubulin polymerization with the exception of one compound. The analysis of differential cytotoxicity data thus appears to have great promise for the identification of new antimitotic agents with antineoplastic potential.
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PMID:Identification of novel antimitotic agents acting at the tubulin level by computer-assisted evaluation of differential cytotoxicity data. 161 65

The intrinsic GTPase activity of the cellular protein p21ras is strongly increased by two cytosolic proteins, the GTPase-activating protein (GAP) produced by the neurofibromatosis type 1 gene (NF1-GAP) and a GAP of 120 kDa molecular mass (p120-GAP). The GAP-mediated stimulation of p21ras GTPase activity was measured in cytosol obtained from carcinogen-induced liver tumors and normal liver tissues of mice of two strains, namely C3H/He and C57BL/6J. For this purpose, cytosolic extracts were incubated with recombinant human p21ras complexed to [gamma-32P]GTP and the time-dependent decrease in p21ras bound radioactivity was measured. Liver cytosolic extracts mediated an increase in the GTPase activity of wild-type p21ras. There were great differences between tumor and normal tissues in the maximal velocity (Vmax) and in the apparent Michaelis constant (KM) of the p21ras GTPase reaction. Both Vmax and apparent KM were decreased in the liver tumors. Cytosolic extracts isolated from liver tumors that harbored point mutations in codon 61 of the c-H-ras gene did not differ in their activity from extracts obtained from non-mutated liver tumors. Since both GAP proteins are important cellular regulators of the ras signaling pathway and probably also effectors of p21ras, the observed differences in GAP activity may be of relevance for the tumorigenic process in mouse liver.
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PMID:Differences in GTPase-activating protein activity between liver tumors and normal liver tissue in mice. 162 May 52

A growth factor-stimulated protein kinase activity that phosphorylates the epidermal growth factor (EGF) receptor at Thr669 has been described (Countaway, J. L., Northwood, I. C., and Davis, R. J. (1989) J. Biol. Chem. 264, 10828-10835). Anion-exchange chromatography demonstrated that this protein kinase activity was accounted for by two enzymes. The first peak of activity eluted from the column corresponded to the microtubule-associated protein 2 (MAP2) kinase. However, the second peak of activity was found to be a distinct enzyme. We present here the purification of this enzyme from human tumor KB cells by sequential ion-exchange chromatography. The isolated protein kinase was identified as a 46-kDa protein by polyacrylamide gel electrophoresis and silver staining. Gel filtration chromatography demonstrated that the enzyme was functional in a monomeric state. A kinetic analysis of the purified enzyme was performed at 22 degrees C using a synthetic peptide substrate based on the primary sequence of the EGF receptor (KREL VEPLT669PSGEAPNQALLR). The Km(app) for ATP was 40 +/- 5 microM (mean +/- S.D., n = 3). GTP was not found to be a substrate for the purified enzyme. The Km(app) for the synthetic peptide substrate was 260 +/- 40 microM (mean +/- S.D., n = 3). The Vmax(app) for the isolated protein kinase was determined to be 400-900 nmol/mg/min. The purified enzyme was designated EGF receptor Thr669 (ERT) kinase. It is likely that the MAP2 and ERT kinases account for the phosphorylation of the EGF receptor at Thr669 observed in cultured cells. The marked stimulation of protein kinase activity caused by growth factors indicates that these enzymes may have an important function during signal transduction.
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PMID:Isolation and characterization of two growth factor-stimulated protein kinases that phosphorylate the epidermal growth factor receptor at threonine 669. 165 22

It is still undetermined which GTP-binding (G) protein is involved in the regulation of prolactin (PRL) release and through which effector. This study shows that, when compared to normal pituitary tissue, the levels of alpha o protein were very low in dopamine (DA)-resistant, PRL-secreting pituitary tumors 7315a and MtTW15, while alpha o mRNA was present in the two tumors. In the MtTW15 tumor alpha i1, alpha i2 and alpha i3 levels were decreased while those of alpha s42 and alpha s47 were increased, and in the 7315a tumor alpha i2, alpha i3 and beta levels were decreased and those of alpha s47 increased. In an estrone-induced, DA-sensitive prolactinoma the levels of alpha i3 were greatly reduced. DA was unable to inhibit basal PRL release by 7315a and MtTW15 and basal cAMP accumulation by adenomatous and MtTW15 cells. Vasoactive intestinal peptide (VIP) increased both cAMP accumulation and PRL release by all cell preparations which could be suppressed by DA with adenomatous and 7315a but not with MtTW15 cells. These and previously published results provide circumstantial evidence that alpha o, alpha i1 and alpha i3 are all involved in the transduction of the DA inhibitory message while alpha s47 transduces cAMP activating messages and alpha s42 is responsible for the constitutive activation of L-type Ca2+ channels, adenylate cyclase and baseline PRL release.
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PMID:G proteins in normal rat pituitaries and in prolactin-secreting rat pituitary tumors. 165 58

The discovery of isozymes (types I and II) of IMP dehydrogenase (IMPDH; EC 1.1.1.205), the rate-limiting enzyme of de novo GTP biosynthesis, has attracted attention as a possible novel approach to cancer diagnosis and selective tumor cell chemotherapy. To elucidate differences in expression and regulation of the two IMPDH isozymes, we examined the steady-state levels of these mRNAs in various types of leukemic cells from patients. Northern blot analysis revealed that type II IMPDH was more active transcriptionally (1.5- to 5.1-fold) in all the leukemic cells examined than in normal lymphocytes, whereas type I expression was similar. The increased expression of type II mRNA in leukemic cells was closely linked with the increase in total IMPDH activity (r = 0.92). When leukemic cells from a patient with chronic granulocytic leukemia in blast crisis were separated into blast-rich and mature leukocyte-rich fractions, the expression of type II mRNA correlated positively with the population of immature leukemic cells, whereas type I expression was unchanged. Treatment of leukemic blasts with 12-O-tetradecanoyl-phorbol-13-acetate for 5 days resulted in a 90% decrease in the expression of type II mRNA with macrophage-like differentiation, while the expression of type I mRNA was relatively stable. These observations suggest that expression of type II IMPDH is stringently linked with immature characteristics of leukemic cells; thus, it should be a selective target for antileukemic chemotherapy.
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PMID:Selective up-regulation of type II inosine 5'-monophosphate dehydrogenase messenger RNA expression in human leukemias. 167 9

The increased activity in cancer cells of inosine 5'-monophosphate dehydrogenase (IMP DH, EC 1.1.1.205), the rate-limiting enzyme of de novo GTP biosynthesis, was suggested as a sensitive target for chemotherapy. Tiazofurin (NSC 286193), through its conversion to the active metabolite, thiazole-4-carboxamide adenine dinucleotide (TAD), is a strong inhibitor of IMP DH. In our clinical trial, tiazofurin caused return to the chronic phase in patients with chronic granulocytic leukemia in blast crisis (Tricot, G.; Jayaram, H.N.; Weber, G.; Hoffman, R. Tiazofurin: Biological effects and clinical uses. Int. J. Cell Cloning 8:161-170; 1990). In K562 human leukemic cells, tiazofurin down-regulated the expression of c-Ki-ras and c-myc oncogenes, which was followed by induced differentiation. We now report down-regulation by tiazofurin of the c-Ki-ras oncogene in a patient with chronic granulocytic leukemia in blast crisis. A single tiazofurin infusion (2,200 mg/m2) on days one and two decreased IMP dehydrogenase activity (the apparent t1/2 was 30 min), GTP concentration (the apparent t1/2 was 6 hr), and expression of ras (the apparent t1/2 was 8 hr) and c-myc (the apparent t1/2 was 38.5 hr) oncogenes in the leukemic cells. No further tiazofurin was given, because on days three and four the chemotherapeutic impact became evident in a tumor-lysis syndrome and the blast cells were cleared from the periphery by day five. The decrease in IMP DH activity, GTP concentration, and expression of c-Ki-ras oncogene were early markers of the successful chemotherapeutic impact of tiazofurin in a patient with chronic granulocytic leukemia in blast crisis.
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PMID:Tiazofurin down-regulates expression of c-Ki-ras oncogene in a leukemic patient. 170 12

Hepatocarcinogenesis was initiated in rats with diethylnitrosamine (DEN) followed by a selection with 2-acetylamino-fluorene (2-AAF). Portacaval shunt was then performed in order to promote tumor development. Control rats were not submitted to the initiation--selection protocol and were sham-operated. In control rats, adenylate cyclase activity from crude liver membranes was stimulated 7- to 8-fold by maximal doses of glucagon (10(-6) M) or guanyl-5'-yl-imidophosphate [Gpp(NH)p] (10(-3) M), and 17-fold by a maximal (10(-5) M) dose of forskolin. Guanosine-5'-O-(2-thiodiphosphate) inhibited the response to forskolin (-38%) and to low doses of glucagon (-50%). The initiation--selection protocol increased the activity in basal conditions and in response to various stimuli. The portacaval shunt did not modify the activity of the enzyme with respect to basal activity or the response to glucagon. It significantly decreased the response to Gpp(NH)p (-45%) and to forskolin (-27%). The initiation--selection protocol increased the basal activity of the enzyme (+150%) and its response to Gpp(NH)p (+300%). When tumors developed, the activity of the cyclase further increased (+200%) and an inhibitory effect of GTP on the hormone-stimulated enzyme appeared (-40%). From these results, it is concluded that the promotion of hepatocarcinogenesis by portacaval shunt is coupled with modifications in the activity of adenylate cyclase in response to glucagon and guanylnucleotides.
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PMID:Adenylate cyclase activity in crude liver membranes during chemical hepatocarcinogenesis in portacaval shunted rats. 174 14

Chromosome studies were carried out after a 24-hour harvest of unstimulated bone marrow aspirate cell cultures from a 75-year-old male with a clinical diagnosis of acute myelomonocytic leukemia (FAB M4). Analysis of nine cells after trypsin-Giemsa banding (GTG) revealed two cell lines with a mosaic chromosome pattern, 46,XY/46,XY,t(7;19)(q22;p13.3). A review of the recent literature reveals one case of childhood ALL with a 46,XY/46,XY,t(7;19)(q11;q13) chromosome pattern [1] and a 46,XY,t(3q;11q),t(7q;19p),t(15;17)(q26;q22) in one patient with ANLL (FAB M3) [2]. The t(7;19)(q22;p13.3) seen in our case has not been reported as the sole specific clonal chromosome rearrangement in myeloid neoplasia. Interestingly, the plasminogen activator inhibitor type I, multi-drug resistance, and erythropoietin genes are located at band 7q22 and the insulin receptor gene is located at band 19p13.3. Both sites contain fragile site loci. The possible role of these fragile sites, genes, or other genes in the rearrangement can only be surmised.
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PMID:Atypical (7;19) translocation in acute myelomonocytic leukemia. 175 94

The gene responsible for neurofibromatosis type 1 (NF1), a common autosomal dominantly inherited disease, has been isolated. A region of NF1 gene product has been demonstrated to share structural and functional similarities with the mammalian GTPase activating protein (GAP) and the yeast IRA proteins. Thus, the NF1 protein is thought to play a role in signal transduction by stimulating the conversion of the Ras protein from a GTP-bound active form to a GDP-bound inactive form. The increased risk of malignant tumors in neuroectodermal tissues of NF1 patients may be caused by disruption of growth and differentiation regulatory functions of the NF1 gene. A second type of the NF1-GAP related domain (NF1-GRD) transcript, which has an extra 21-amino-acid insert in the center of the previously reported first type transcript, has been described. This insert significantly changes the hydrophilicity and secondary structure of the central region of NF1-GRD, therefore, suggesting it also changes its function. Alternative splicing is the most likely mechanism by which these two types of transcripts arise. The NF1-GRD alternative splicing has been shown to be intimately involved in differentiation of neuroectodermal tissues. Aberrant regulation of the alternative splicing may contribute to tumor formation in neuroectodermal tissue.
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PMID:Neurofibromatosis type 1 (NF1) gene: implication in neuroectodermal differentiation and genesis of brain tumors. 178 31


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