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)

Biopsy samples and cultured cells derived from them were obtained from 39 patients with malignant glioma and were analyzed for 1) glutathione (GSH) content; 2) sensitivity to 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and/or nitrogen mustard (HN2) treatment and 3) the effect of buthionine sulfoximine (BSO) treatment on BCNU and/or HN2 cytotoxicity. The average GSH concentration of biopsy specimens was lower than those of cultured cells (2.36 +/- 0.44 vs. 11.42 +/- 2.32 nmol/10(6) cells). While some of the tumor specimens were sensitive to either BCNU or HN2, the majority were resistant to both. However, 8 of 23 tumors tested showed enhanced sensitivity to BCNU following treatment with BSO. Five of 17 tumors were similarly sensitized to HN2 by BSO. These results suggest that BSO chemosensitization may be of value for certain patients and that screening assays may help identify treatment-sensitive individuals.
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PMID:Glutathione levels and chemosensitizing effects of buthionine sulfoximine in human malignant glioma cells. 174 83

PCR is widely employed to amplify short segments of genomic DNA to determine if a specific change has occurred. But some investigators need to sequence the entire coding region of mammalian genes to determine what specific changes have occurred. In 1989, we [Yang et al: Gene 83:347-354] described a method to copy mRNA of the hypoxanthine (guanine) phosphoribosyl transferase (HPRT) gene directly from the lysate of a clone of 6-thioguanine-resistant mutant diploid human fibroblasts without the need for RNA extraction or DNA template purification. To avoid detecting random changes introduced by polymerases, 100 to 500 cells from an individual clone, each containing the identical mutation, are lysed and the cDNA is amplified 10(10)-to 10(11)-fold to obtain 5 to 10 micrograms of DNA. The consensus sequence of the cDNA is determined by direct nucleotide sequencing. Using this method, we have investigated the kinds of mutations induced by carcinogens in the coding region of the HPRT gene and their location in the gene and examined the role of DNA repair in this process. Normal repair-proficient human cells and cells deficient in DNA repair were exposed to mutagens in exponential growth or synchronized and exposed at the beginning of S phase or in G1 phase several hr prior to DNA replication. The kinds and location of mutations in the HPRT gene were determined and knowledge of the nature of the DNA lesions formed by the various mutagens allowed assignment of the DNA strand in which the premutagenic lesion that gave rise to the mutation had been located. Related assays involving PCR have been used to determine the nature of mutations in the coding region of the H-, N-, or K-ras genes of tumor-derived malignant human cells and to determine whether or not such cells express specific growth factor genes.
Environ Mol Mutagen 1991
PMID:Use of PCR amplification of cDNA to study mechanisms of human cell mutagenesis and malignant transformation. 174 85

In order to study the mechanisms responsible for resistance to CDDP, 5 human tumor cell lines were made resistant to CDDP by repeated in vitro exposures. After cloning it was found that the cell lines developed were between 3.3-fold and 17-fold more resistant to CDDP than the parental cell lines at the IC90. These lines were also resistant to carboplatin and tetraplatin; however, resistance to tetraplatin was lower than to the other platinum complexes. Sensitivity was also assessed to Adria, MTX, 5-FU, chlorambucil, 4-HC, 4-HIF, BCNU, Thiotepa, HN2, Mito C and L-PAM, and no consistent cross-resistance was observed. As compared with the parental lines, non-protein sulfhydryl content was elevated in 3 resistant lines, and protein sulfhydryl was elevated in all 5 lines, as was glutathione-S-transferase activity. Measurements of platinum in whole cells and nuclei after exposure of the cultures to 25 microM CDDP for either 1 or 6 hr showed that nuclear levels reflected those in whole cells and that, per mg protein, platinum levels were lower in resistant cells at both time points. Formation of DNA cross-links, determined by alkaline elution, was lower in resistant cell lines than in parental cell lines, but did not correlate with the absolute cell kill observed. These results indicate that cellular resistance to CDDP often involves decreases in drug accumulation and increases in protein sulfhydryl content. Possible strategies for overcoming these mechanisms are discussed.
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PMID:Characteristics of five human tumor cell lines and sublines resistant to cis-diamminedichloroplatinum(II). 184 50

Primary cultures of mouse epidermal keratinocytes from SENCAR mice were treated with 7,12-dimethylbenz(a)anthracene (DMBA), benzo(a)pyrene [B(a)P], (+/-)7 beta-8 alpha-dihydroxy-9 alpha, 10 alpha-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene [(+/-)anti-BPDE], and (+/-)7 beta, 8 alpha-dihydroxy-9 beta, 10 beta-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene [(+/-)syn-BPDE] to examine the relationship between DNA adduct formation and the induction of unscheduled DNA synthesis (UDS). DNA adducts were measured as pmol hydrocarbon bound per mg of DNA, and UDS was quantitated autoradiographically as net grains per nucleus. A good correlation was observed between the levels of UDS detected and the amount of DNA adducts present in the cell population when comparing similar compounds within the linear dose-response range of 0.005 micrograms/ml-0.25 micrograms/ml. A higher rate of UDS for a given level of DNA adducts was interpreted as an increased efficiency of DNA repair. In some cases, an increase in the efficiency of DNA excision repair correlated with lower tumor-initiating activity. For this family of PAH, the concentration below which UDS could no longer be detected was approximately 0.01 microgram/ml. However, DNA adducts were measurable at concentrations of 0.01 and 0.005 micrograms/ml. The limits of detection of the current UDS assay in the SENCAR MEK culture system occurred at hydrocarbon adduct levels of approximately 10 pmol/mg DNA, or approximately 1 adduct per 3 x 10(5) bases. Additionally, the UDS assay was unable to detect DNA repair induced by the weakly carcinogenic PAHs, dibenz(aj)anthracene and 7-methyl-dibenz(aj)anthracene. The UDS assay did detect DNA repair by the more strongly carcinogenic PAH, 6-methylcholanthrene. These results suggest that the present UDS assay with MEKs is a useful assay for the rapid screening of potential genotoxic agents. However, the limits of sensitivity are such that the current assay may be unable to detect a low level of DNA damage induced by some weakly genotoxic (carcinogenic) agents. In addition, while the limits of sensitivity determined in these experiments apply to the polycyclic aromatic hydrocarbon class, other classes of genotoxic compounds such as alkylating agents or crosslinking agents may exhibit different thresholds of detection.
Environ Mol Mutagen 1991
PMID:Relationship between DNA adduct formation and unscheduled DNA synthesis (UDS) in cultured mouse epidermal keratinocytes. 191 14

Murine susceptibility to ethyl carbamate-induced carcinogenesis is strain dependent. In vivo sister chromatid exchange (SCE) responses to ethyl carbamate were evaluated in bone marrow cells of gravid adenoma-susceptible (ICR/Jcl), and resistant (C57Bl/6J) and (DBA/2J) murine dams, as well as in liver cells of their respective ICR/Jcl, C57Bl/6J X DBA/2J (BDF1), and DBA/2J X C57Bl/6J (BDF), fetuses following a single intravenous injection of 1.1, 2.2, or 3.3 mmol/kg of ethyl carbamate on gestation day 13/14. Bone marrow tissues of C57Bl/6J and DBA/2J, but not ICR/Jcl dams, demonstrated greater sensitivity to SCE induction than liver cells of their respective fetuses. Furthermore, relative SCE responses in bone marrow among dams indicated greater sensitivity of the more tumor-susceptible ICR/Jcl and C57Bl/6J strains to SCE induction by ethyl carbamate relative to the more tumor-resistant DBA/2J strain. In addition, concurrent alterations (stimulation or inhibition) of bone marrow cell cycle kinetics by ethyl carbamate were consistent with hormone-related, strain-dependent hematopoietic stress during pregnancy.
Teratog Carcinog Mutagen 1990
PMID:Comparative in vivo sister chromatid exchange induction by ethyl carbamate in maternal and fetal tissues of tumor-susceptible and -resistant murine strains. 197 64

Tumor promotion is defined operationally from two-stage models of experimental carcinogenesis. It is, therefore, in a strict sense, possible to identify tumor promoters only from such models. The development and use of in vitro two-stage cell transformation assays was a logical extension toward in vitro short-term testing for tumor promoters. Another approach is to apply mechanistic knowledge of the tumor promotion process in developing end points for such assays. In this context, we have been examining the role of blocked gap-junctional intercellular communication (GJIC) in tumor promotion, using in vitro and in vivo systems. Many promoters have been shown to block GJIC in vitro; our studies support the idea that inhibition of GJIC does play an important role in the promotion stage of BALB/c 3T3 cell transformation. In animal studies, we have shown that the rat liver tumor promoter phenobarbital can decrease the level of expression of the 32 Kd gap junction protein gene specifically in liver upon systemic exposure in rats. Further examination of the role of GJIC in tumor promotion is indeed warranted. Also, deployment of in vitro GJIC and transformation assay systems should provide useful short-term tests for detecting tumor promoting activity of environmental chemicals.
Teratog Carcinog Mutagen 1990
PMID:Tumor promotion: models and assay systems. 197 58

The relationship between mutagenesis and carcinogenesis was investigated in T x HT crossbred mice using diaplacental application of ethylnitrosourea (ENU) at different stages of embryonal development. Mutagenesis was detected by induction of coat color spots, and the carcinogenic response was investigated in a long-term follow-up study of the F1-generation. The animals were particularly sensitive to induction of tumors at the central nervous system (CNS)-skull/vertebra interface (30% and 20% in ENU-treated male and female offspring, respectively, compared with less than 1% in controls). There was a correlation between the appearance of these tumors and the presence of color spots. This correlation was low but statistically significant in female offspring. Three other types of tumors showed a correlation with the presence of coat color spots. Liver tumors were significantly increased in color spot-positive females but unchanged in males. Lung tumors were reduced in color spot-positive males and appeared earlier in color spot-positive females. There was a lower incidence of lymphoma/leukemia in all spot-positive mice. The reduction in tumor incidence beyond the spontaneous rate in spot-positive animals might be caused by a high cytolethal response to ENU in the relevant organs and tissues.
Teratog Carcinog Mutagen 1990
PMID:Simultaneous induction of mutagenic and cancerogenic effects in T x HT mice with transplacental ethylnitrosourea treatment. 198 33

Enhanced cytogenetic damage by the homo-aza-steroidal ester of p-bis(2-chloroethyl)-aminophenylacetic acid (ASE) was observed when human lymphocytes in vitro or Ehrlich ascites tumor (EAT) cells in vivo were exposed to nontoxic concentrations of 3-amino-benzamide (3-AB). 3-AB at these concentrations was found to enhance synergistically the cytogenetic damage induced in vivo by cyclophosphamide (CP), a metabolically activated chemotherapeutic, or chlorambucil (CBC) in EAT cells. One hour before i.p. injection of 5-bromodeoxyuridine (BrdUrd) adsorbed to activated charcoal, EAT-bearing mice treated i.p. with ASE or CP showed a dose-dependent increase in sister chromatid exchange (SCE) rates and cell division delays. The treatment of human lymphocytes in vitro with ASE led to the depletion of cellular NAD, and addition of 3-AB, a potent inhibitor of poly(ADP-ribose)polymerase [P(ADPR)polymerase], to ASE-treated human lymphocytes prevented the drop of NAD, which remained at approximately control levels. Also, the in vivo treatment of EAT cells with CBC, ASE, or CP led to the depletion of NAD, whereas addition of 3-AB to CBC-, ASE- or CP-treated cells prevented the drop of NAD, which remained at nearly control levels. 3-AB in conjunction with CBC, ASE, or CP increased the survival time of the EAT-bearing mice and markedly reduced the ascitic volume. Thus cytogenetic damage induced by ASE plus 3-AB in vitro and by CBC, ASE, or CP plus 3-AB in vivo correlates well with 1) the prevention of NAD depletion in the presence of 3-AB in cells treated with the same alkylating agents in vitro or in vivo and 2) the in vivo antitumor effect by ASE, CBC, or CP in combination with 3-AB.
Teratog Carcinog Mutagen 1990
PMID:Effects of alkylating antineoplastics alone or in combination with 3-aminobenzamide on genotoxicity, antitumor activity, and NAD levels in human lymphocytes in vitro and on Ehrlich ascites tumor cells in vivo. 198 34

Bacterial ancestry of mitochondria and plastids is now generally accepted. Both organelles contain their own DNA and transcription-translation apparatus of a prokaryotic type. Due to this fact these systems carry bacteria-like properties. Thus organellar DNA and ribosomes are essentially different from nuclear DNA and cytoplasmic ribosomes in physical as well as in functional respects. Due to the bacterial character of both types of organelles they are susceptible to various antibacterial chemicals. Inhibitors of bacterial protein synthesis inhibit mitochondrial (plastidial) biogenesis. Therefore the cellular content of mitochondria (plastids)-made proteins decreases during cytoplasmic turnover or cell division in the presence of these drugs. Such drug activity consequently leads to a reduced capacity for oxidative phosphorylation or photosynthesis. Organellar genomes are less stable and more sensitive to mutagenesis as compared to nuclear genome. It means also that genotoxic agents induce various disorders of mitochondrial (plastidial) functions. Impairments in the respiratory chain are associated with structural as well as functional abnormalities of mitochondria. These are clinically expressed mostly in tissues with a high demand for ATP: brain, heart, skeletal muscle, and retina. On the other hand, some antibacterial inhibitors of mitochondrial biogenesis (e.g., tetracyclines) inhibit selectively tumor cell proliferation. Therefore they may be considered for use in anticancer therapy. The article summarizes the response of mitochondria and plastids in various organisms to drugs and environmental xenobiotics. Various model organisms suitable for detection of xenobiotic effect on mitochondria (plastids) are presented as well as the possible consequences of such interaction.
Teratog Carcinog Mutagen 1990
PMID:Interaction of drugs with extranuclear genetic elements and its consequences. 198 11

Carcinogenicity results are presented for 114 long-term rodent studies carried out by the National Toxicology Program. Tumor rates are given for each positive or equivocal effect observed in 67 studies judged to show carcinogenic effects and in the 17 studies that show equivocal effects. The liver was found to be the most common site of carcinogenicity for both mice and rats; other frequent target sites included the lung, kidney, hematopoietic system, forestomach, thyroid gland, and mammary gland. The evaluative approach used in reaching decisions regarding the carcinogenicity of chemicals is discussed. No rigid statistical decision rules were employed, and biological as well as statistical factors were considered in the overall evaluation of the data. These long-term studies were utilized in a comprehensive evaluation of the ability of four in vitro genetic toxicity tests to predict rodent carcinogenicity. Details concerning these procedures and the results of this investigation are given elsewhere [Zeiger E, Haseman JK, Shelby MD, Margolin BH, Tennant RW 1990: Environ Mol Mutagen 16 (Supp. 18):1-14]. Interestingly, those chemicals evaluated at relatively low doses in the rodent experiments (because of the underlying toxicity of the chemicals) were far more likely to be positive in each of the four genetic toxicity assays than were "less toxic" chemicals evaluated in higher doses in the rodent studies.
Environ Mol Mutagen 1990
PMID:Carcinogenicity results for 114 laboratory animal studies used to assess the predictivity of four in vitro genetic toxicity assays for rodent carcinogenicity. 209 22


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