Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Multiple lines of evidence show that oxidation products of ascorbic acid (vitamin C) are capable of inducing a variety of genetic alterations in microbial and mammalian cells. We have studied the inactivation kinetics in repair proficient and deficient Escherichia coli K12 cells treated with oxidized solutions of ascorbic acid, in the presence of catalytic amounts of copper. Our results suggest that the repair pathways controlled by the recA and uvrA gene products (the latter in a recA strain) contribute to cell survival. However, the lack of beta-galactosidase induction, in the SOS chromotest, implies a role for the RecA protein other than SOS induction. Catalase and thiourea suppress the toxic effects of oxidized ascorbate solutions, confirming that H2O2 and hydroxyl radicals are intermediate agents in the damaging action. Single-strand breaks were detected in DNA from treated cells.
Carcinogenesis 1986 Feb
PMID:Ascorbate-copper induced DNA lesions and repair in Escherichia coli K12 cells. 300 73

The superoxide dismutase (SOD) biomimetic copper(II) (3,5-diisopropylsalicylate)2 (CuDIPS) has been previously reported to inhibit the tumorigenicity of a polycyclic aromatic hydrocarbon (PAH) requiring metabolic activation. We have used the Ames Salmonella typhimurium revertant assay to survey the effects of CuDIPS and its analogs on the metabolic activation of the PAH benzo[a]pyrene (BP) by liver homogenates. Supplementation of homogenates from normal and Aroclor 1254-treated SENCAR mice with varied concentrations of CuDIPS resulted in a dose-dependent noncompetitive inhibition of BP mutagenesis. Cytochrome P-450 reductase activity in liver homogenates and microsomal preparations was also inhibited by concentrations of CuDIPS possessing antimutagenic activity. Neither DIPS nor ZnDIPS, analogs of CuDIPS lacking SOD activity, inhibited mutagenesis or P-450 reductase activity. CuSO4, which has SOD activity, was almost as effective as CuDIPS on a molar basis in inhibiting mutagenesis and P-450 reductase activity. The inhibitory effects of CuDIPS and CuSO4 could not be attributed to their SOD activity since bovine liver superoxide dismutase, at a 100-fold excess of CuDIPS-SOD activity, had no effect on their activity. Collectively these findings suggest that the in vitro antimutagenic activity of CuDIPS is independent of its salicylate structure and is mediated through a copper-dependent but non SOD-associated inhibition of P-450 reductase activity.
Carcinogenesis 1986 Oct
PMID:Inhibition of benzo[a]pyrene-dependent mutagenesis and cytochrome P-450 reductase activity by copper complexes. 309 13

A keratinocyte-mediated mutagenesis assay, and the murine skin multistage carcinogenesis tumor model were used to survey the chemopreventive properties of Cu(II)(3,5-diisopropylsalicylate)2 [CuDIPS] and its analogs. Supplementation of cocultures of newborn SENCAR keratinocytes and Chinese hamster lung fibroblasts (V79 cells) with CuDIPS, 3,5-diisopropylsalicylate (DIPS), and CuSO4 resulted in dose-dependent killings of V79 cells (LD50 of 34, 75, 960 microM, respectively), and inhibitions of benzo[a]pyrene (BP) and 7,12-dimethylbenz[a]anthracene (DMBA) mutagenesis (ED50 of 13, 95, 80 microM, and 40, 125, 110 microM, respectively). Analyses of dose-response curves suggest (i) CuDIPS preferentially inhibits BP mutagenesis; (ii) the antimutagenic activity of CuDIPS towards DMBA and the cytotoxicity of the copper complex are derived from the DIPS component of the chelate; (iii) the antimutagenic activity of CuDIPS towards BP requires both copper and DIPS; and (iv) DIPS and CuDIPS induced cytotoxicity is required for inhibition of mutagenesis. Inhibition of mutagenesis by CuDIPS was not mediated by modulation of promutagen metabolism because antimutagenic concentrations of the chelate had no significant effects on DMBA- and BP-dependent cytotoxicities. Topical pretreatment of SENCAR mice with CuDIPS (100-4000 nmol) 15 min prior to initiation with DMBA or BP resulted in small (38% maximum) non-dose-responsive reductions of papillomas/mouse following 20 weeks of promotion.
Carcinogenesis 1988 Apr
PMID:Survey of cytotoxicities and antimutagenic and antitumor initiating activities of Cu(II)(3,5-diisopropylsalicylate)2 and its analogs in a keratinocyte-mediated mutation assay and the murine skin multistage carcinogenesis model. 312 7

Oxidative stress has been suggested to play an integral role in the cancer process. It may be particularly significant during tumor progression, where there is likely to be a large amount of free radicals generated by infiltrating inflammatory cells and dying tumor cells. In order to test this hypothesis, a variety of free radical scavengers and antioxidants were assessed for their ability to inhibit tumor progression. The murine skin multistage carcinogenesis model was used to generate papillomas, which are a population of putative precancerous lesions. Various test agents were applied topically to papillomas in order to determine if they would decrease the incidence of the malignant lesion, squamous cell carcinoma. The agents tested included: reduced glutathione (GSH), butylated hydroxyanisole, vitamin E, copper(II) (3,5-diisopropylsalicylate)2, sodium benzoate, N-acetyl cysteine and disulfiram. Under the conditions of our experiments, only GSH and disulfiram inhibited tumor progression to a significant degree. Additional studies indicated that GSH prevented cancer development in a dose-dependent manner. Another experiment demonstrated that when papillomas received repeated topical applications of diethylmaleate, a GSH-depleting agent, tumor progression was enhanced. Collectively these data suggest that sufficient glutathione levels may be important in preventing cancer formation.
Carcinogenesis 1988 Sep
PMID:Effect of exogenous glutathione on tumor progression in the murine skin multistage carcinogenesis model. 313 44

Copper, zinc superoxide dismutase (Cu,ZnSOD) and manganese superoxide dismutase (MnSOD) activities were measured in mouse large intestinal mucosa during dimethylhydrazine (DMH) carcinogenesis. Mice were divided into five groups. Group A was subcutaneously injected with DMH (20 mg/kg) weekly and fed with a diet containing 0.2% cholic acid (C) and 0.8% indole (I). Group B was injected with DMH and given indole feeding. Group C was treated with DMH injection and cholic acid feeding. Group D was given DMH injection alone. Group E was an age-matched control group given 0.9% NaCl injection. The experiment last 21 weeks. The Cu, ZnSOD activity of intestinal mucosa in group A animals began to increase significantly at the 7th week of the experiment. In groups B, C and D, however, this enzyme was not elevated statistically until the 16th week, and then each of these groups kept an increased Cu,ZnSOD level the rest of the experimental period. MnSOD activity was elevated statistically in group C animals at the 7th week. The enzyme activity in group A and D animals increased at the 9th week, but the enzyme activity did not increase statistically until the 11th week in group B. After the 16th week of the experiment the increased activity of MnSOD in all experimental groups returned to the level of the control group. Large intestinal cancer tissues had increased Cu,ZnSOD activity and decreased MnSOD activity.
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PMID:Superoxide dismutase activity during dimethylhydrazine colon carcinogenesis and the effects of cholic acid and indole. 323 59

In light of recent studies implicating low catalase activities in the pathogenesis of the cancer-prone disease xeroderma pigmentosum (XP) we have measured catalase activity, protein levels, and mRNA concentrations in six XP fibroblast strains and three normal controls. Only one XP strain of complementation group A (XP1223) possessed significantly lower catalase by all three criteria. The other five XP strains (two XP variants, two strains of complementation group D, and one strain of complementation group C) possessed catalase levels which fell into the range of the interindividual variations of normal controls. We further assessed the total enzymatic antioxidant defense status by measuring the levels of copper, zinc, and manganese superoxide dismutase and glutathione peroxidase. None of these enzymes showed significant deviations from controls in XP cells. Our results do not support the notion that a deficient enzymatic antioxidant defense facilitates the establishment of a prooxidant state in XP upon exposure to near-UV. However, they do not argue against the participation of active oxygen in near-UV-induced carcinogenesis in XP.
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PMID:Antioxidant enzymes in xeroderma pigmentosum fibroblasts. 334 84

The present study was designed to compare the skin tumor promoting and epidermal ornithine decarboxylase (ODC) inducing activities of various structural analogs of anthralin (1,8-dihydroxy-9-anthrone) and chrysarobin (1,8-dihydroxy-3-methyl-9-anthrone). Groups of 30 SENCAR mice each were initiated with 7,12-dimethylbenz[a]anthracene and 2 weeks later promoted with once- or twice-weekly applications of various doses of these anthrone derivatives. Carbon-10 (C10)-acyl derivatives of anthralin were active skin tumor promoters in the range of 25-440 nmol per mouse. 10-Acetylanthralin was significantly more active than 10-myristoyl-anthralin at low doses (e.g. 25 and 50 nmol per mouse) and nearly as potent as the unsubstituted compound. Higher doses (greater than or equal to 100 nmol per mouse) of this derivative were toxic, hence, reducing the final papilloma response. On a relative activity scale where anthralin is 1.0, these derivatives had activities that were approximately 0.7 and 0.2, respectively. 10,10-Dipropylanthralin was totally inactive at the doses tested. C6-Substituted derivatives of chrysarobin demonstrated diverse tumor promoting activities when tested in the range of 25-440 nmol per mouse. On a relative activity scale where chrysarobin is 1.0, 6-methoxychrysarobin (physcion anthrone) was approximately 0.9, whereas 6-hydroxychrysarobin (emodin anthrone) had no activity. Chrysophanic acid (1,8-dihydroxy-3-methyl-9,10-anthraquinone) was also inactive as a tumor promoter at the doses tested. In general, the tumor promoting activities of these anthrone derivatives correlated very well with their ability to induce epidermal ODC after a single topical application indicating an important role for this enzyme in skin tumor promotion by anthones. The ability of C10-substituted derivatives of anthralin to undergo base catalyzed oxidation in vitro correlated with both ODC inducing and tumor promoting activities. In addition, copper(II)bis(diisopropylsalicylate) was found to inhibit both ODC induction and skin tumor promotion by chrysarobin. These latter data, when taken together, suggest a role for oxidation at C10 in skin tumor promotion by anthrone derivatives.
Carcinogenesis 1988 Aug
PMID:Structure-activity relationships for epidermal ornithine decarboxylase induction and skin tumor promotion by anthrones. 340 40

During a 2-yr study of carcinogenesis by CdCl2 in male Wistar [Crl:(WI)BR] rats, weekly clinical observations during the last 6 mo of the study revealed many cases of persistent tumor-like masses at the site of the metal identification tags in the ears of the animals. A total of 14 tumors (mostly compound osteosarcomas) was diagnosed in 168 rats. Histologically, almost 90% of the rats in this study (henceforth referred to as Study I) showed some significant lesion at the tag site including various degrees of chronic inflammation, chondrous hyperplasia, and osseous metaplasia of the pinnal cartilage. In marked contrast, only two tumors were detected in 193 animals in a second study (Study II) in the same strain of rats, and only 56% of the rats had lesions at the tag site. A high incidence (greater than 25%) of clinically severe inflammation at the tag site was seen early in Study I and persisted during the first 6 mo of the study, while the incidence of such reactions in Study II was never more than 1%. Elemental analysis of the tags provided no explanation for the differences between the two studies, as tags used in both studies were of the same composition, predominantly nickel and copper. Metallic internal prostheses have induced local malignancies in humans and animals, and the present observations provide further evidence of the hazard posed by such devices at the site of prolonged contact with tissues. These findings suggest that a persistent tissue reaction may be an important factor in tumor development.
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PMID:Inflammatory, proliferative, and neoplastic lesions at the site of metallic identification ear tags in Wistar [Crl:(WI)BR] rats. 356 30

Ten nickel oxides and nickel-copper oxides, which all contained NiO (bunsenite) as the predominant crystalline phase, were assayed as follows: in vitro dissolution tests in water and body fluids; in vitro phagocytosis tests in Chinese hamster ovary and C3H-10T1/2 cells; morphological transformation and cytotoxicity tests in cultured Syrian hamster embryo (SHE) cells; erythropoiesis stimulation assay by intrarenal administration to Fischer-344 rats; and scoring the renal histopathologic responses in rats killed 3 months post-injection. The test compounds differed substantially in their biological effects when tested in the various experimental systems. Based upon highly significant concordance of ranked results in the assays (P less than 0.001), six colligative biological attributes of the compounds were identified: (i) dissolution half-times in rat serum and renal cytosol; (ii) phagocytosis by C3H-10T1/2 cells; (iii) morphological transformation of SHE cells; (iv) erythropoiesis stimulation in rats; (v) induction of tubular hyperplasia in rat kidneys; and (vi) induction of arteriosclerosis in rat kidneys. Strong rank correlation (P less than 0.01) between results of the cell transformation and erythropoiesis stimulation assays is especially notable, since the compounds were tested by blind protocols in independent laboratories. The presence of high surface area and demonstrable Ni(III) were two physicochemical characteristics that were associated with the greatest biological effects of nickel oxides.
Carcinogenesis 1987 Feb
PMID:Physicochemical characteristics and biological effects of nickel oxides. 380 16

The effects of a selective detoxifier of the proximate oxygen radical, superoxide anion, on the induction of tumors in the skin of CD-1 mice by either the initiation-promotion regimen or the complete carcinogenesis process were investigated. The principle agent of interest, copper (II) (3,5-diisopropylsalicylate)2 (CuDIPS), is a low molecular weight, lipophilic copper coordination complex that catalytically disproportionates superoxide anion at a rate comparable to native Cu-Zn superoxide dismutase (SOD). The protocols used to elicit tumors were: (i) a single application of 0.2 mumol of 7,12-dimethylbenz[a]anthracene (DMBA) followed by twice-weekly applications of 12-O-tetradecanoylphorbol-13-acetate (TPA) in an initiation-promotion study, and (ii) either a single application of 3.6 mumol DMBA followed by no further treatment or weekly applications of 0.2 mumol DMBA in complete carcinogenesis protocols. Application of 2 mumol CuDIPS 15 min prior to the initiating dose of DMBA was without significant effect on tumor yield or incidence, whereas application prior to each dose of TPA substantially reduced tumor incidence and yield. This anti-promoting property of CuDIPS can be attributed to its SOD-mimetic activity in as much as the corresponding zinc coordination complex lacking in SOD activity, zinc (II) (3,5-diisopropylsalicylate)2, was non-inhibitory. Significant reductions in tumor yield were also observed when CuDIPS was applied prior to DMBA in either of the complete carcinogenesis protocols. Additionally, covalent binding of [3H]DMBA to epidermal DNA was markedly reduced by CuDIPS pre-treatment, suggesting that the anti-carcinogenic properties may reflect a perturbation in superoxide anion-dependent metabolic activation of DMBA. The induction by DMBA of ornithine decarboxylase activity, a biochemical marker of tumor promoter activity, was not affected by CuDIPS; however, induction of ornithine decarboxylase by TPA was potently blocked. Collectively, these effects of a biomimetic SOD further implicate reactive oxygen species at multiple stages in chemical carcinogenesis.
Carcinogenesis 1985 Aug
PMID:Effects of a biomimetic superoxide dismutase on complete and multistage carcinogenesis in mouse skin. 392 37


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