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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The inhibitory effect of selenium on the genesis of spontaneous mammary tumors in C3H mice is statistically significant even at toxic levels of selenium (5 and 15 ppm of Se in form of selenite added to the supply water), no evidence for stimulation of tumor growth by selenium has been obtained. Arsenite lowers the tumor incidence at higher dosage (80 ppm of As in supply water) as well, but animals developing tumors under these conditions demonstrate significantly enhanced tumor growth rates. The addition of subtoxic concentrations of zinc (200 ppm in form of ZnCl2) to supply water containing 5 ppm of Se abolishes the cancer-protecting effect of selenium. The latter result is of possible importance with respect to the human breast cancer mortality experience: The calculated dietary zinc intakes of average adults in 28 countries correlate with the female age-corrected mortalities from breast cancer directly, with P less than 0.005. The zinc concentrations in whole blood from donors in different parts of the U.S.A. are also directly correlated with the female breast cancer mortalities.
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PMID:Inhibition of the genesis of spontaneous mammary tumors in C3H mice: effects of selenium and of selenium-antagonistic elements and their possible role in human breast cancer. 105 16

Gene amplification contributes to carcinogenesis by enhancing proto-oncogene activity and causing chromosomal instability. The ease of detecting amplified tumor-virus sequences has encouraged use of this system as a surrogate for studying the molecular events involved in endogenous gene amplification. We report here a new system for studying carcinogen-induced amplification of both endogenous and viral sequences in the SV40-transformed human keratinocyte line AG06. Treatment with carcinogens induced a transient dose-dependent amplification of the integrated SV40 sequences. The amplified sequences appeared in the extrachromosomal fraction. Treatment of these cells with carcinogens prior to methotrexate (MTX) selection increased the frequency of MTX-resistant colonies, 67% of which exhibited dihydrofolate reductase (dhfr) amplification. The abilities of five carcinogens with different DNA-damaging activities (the DNA-damaging agents N-methyl-N-nitro-N-nitrosoguanidine, mitomycin C (MMC), ultraviolet light C, and X-rays and the non-DNA-damaging agent arsenite) to induce SV40 and dhfr amplification at concentrations that result in 50% clonal survival were compared. All four DNA-damaging carcinogens (as well as growth arrest) were able to elicit some SV40 amplification, but responses varied markedly, from 1.8-fold for X-rays to sevenfold to eightfold for MMC. There was no correlation between the ability to elicit the two amplification responses. Arsenite, which did not induce SV40 amplification, was the best inducer of MTX resistance. These results point to different controls involved in the induction of viral and dhfr amplification. The signal for amplification of viral genes may be triggered by DNA damage and growth arrest, whereas amplification of dhfr, and perhaps other endogenous sequences, seems to be triggered by other signals as well.
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PMID:Differential susceptibility to carcinogen-induced amplification of SV40 and dhfr sequences in SV40-transformed human keratinocytes. 133 30

P-glycoproteins, encoded by families of evolutionarily conserved genes, can confer a multidrug-resistant phenotype to mammalian tumor cells. To obtain more information on their functions in normal cells we have cloned genomic and complementary DNA sequences of four P-glycoprotein gene homologs of the genetically well-characterized nematode Caenorhabditis elegans, termed pgp-1, pgp-2, pgp-3 and pgp-4, respectively. The genes were physically mapped on chromosome IV (pgp-1), I (pgp-2) and X (pgp-3 and pgp-4). Phenotypic mutants corresponding to these loci have not yet been described. Two of the genes, pgp-1 and pgp-3, were analyzed in detail. They are predicted to encode ATP-binding membrane-spanning proteins of 1321 and 1254 amino acid residues, respectively, with the characteristic features shared by most P-glycoproteins described thus far. Intra-species divergence of P-glycoprotein genes is more pronounced in C. elegans than in mammals. Only 40% of the amino acids of pgp-1 and pgp-3 are identical, in contrast to 77% identity between human MDR1 and MDR3. pgp-1 consists of 14 exons, pgp-3 of 13. The two genes share only one intron position, whereas they share four (pgp-1) and five (pgp-3) intron positions with mammalian P-glycoprotein genes. pgp-1, pgp-2, and pgp-3 are transcribed into low abundance mRNAs in wild-type nematodes. pgp-1 and pgp-3 mRNAs have the trans-spliced leader SL1 at their 5' ends. Arsenite, emetine and actinomycin D drugs did not increase the steady state levels of pgp mRNA, unlike in some mammalian cell types. Heat shock disturbed trans as well as cis-splicing of pgp-1 and led to the accumulation of partially processed pgp-1 RNA. Thus, in C. elegans these genes are not induced in the context of a general stress response, as has been proposed for mammalian P-glycoprotein genes in certain tissues.
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PMID:The P-glycoprotein gene family of Caenorhabditis elegans. Cloning and characterization of genomic and complementary DNA sequences. 136 May 40

The anticarcinogenic activity of selenium in animal models is well established. The active forms of selenium involved have not been identified to date, but conversion of selenium via hydrogen selenide (H2Se) to methylated forms such as dimethylselenide and trimethylselenonium ion is an important metabolic fate. By controlling the entry of selenium into various points within this pathway through selection of appropriate starting compounds, it is possible to pinpoint more closely the form(s) of selenium responsible for its anticarcinogenic activity. Selenobetaine in the chloride form [(CH3)2Se+CH2COOH] and its methyl ester are extensively metabolized in the rat to mono-, di-, and trimethylated selenides, largely bypassing the inorganic H2Se intermediary pool. The chemopreventive efficacy of these selenobetaines was determined at 1 and 2 ppm selenium supplemented in the diet throughout the duration of the experiment using the dimethylbenz(a)anthracene induced mammary tumor model in rats. There was a dose-dependent inhibitory response to both compounds, and they appeared to be slightly more active than selenite. These doses were without any adverse effects on the animals. Coadministration of selenobetaine with arsenite (5 ppm arsenic) enhanced the tumor-suppressive effect of selenobetaine, although arsenic by itself was totally inactive. Arsenite is known to inhibit certain steps in selenium methylation. The substantial prophylactic efficacy of methylated selenides and the enhancement by arsenite suggest that partially methylated forms of selenium may be directly involved in the anticarcinogenic action of selenium.
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PMID:Activity of methylated forms of selenium in cancer prevention. 210 64

A number of toxic chemical and physical agents elicit the induction of a series of protein species, some of which react with the agents and render them nontoxic. A few of the induced species (such as metallothionein) are rich in thiol groups that might be expected to react with alkylating agents and render them nontoxic. If a safe means could be found for selectively enhancing the synthesis of alkylating-agent-reactive species in normal but not tumor cells, such a procedure would have ramifications in the area of cancer chemotherapy. In this report, we have utilized a variety of trace elements (Zn, Se, Cu, As) as inducers of synthesis of protective species in line CHO Chinese hamster cells and in a number of derived variants to determine whether this type of approach can be utilized to increase resistance to alkylating-agent toxicity. Our results indicate that Zn, Se and Cu elicit a protective response (increased survival, monitored by colony-forming ability) against the toxic effects of iodoacetate or melphalan, and, at least in the case of zinc, at levels that are physiologically reasonable. Arsenite appears to be a marginally effective inducer in the CHO cell and an ineffective inducer in the Cdr20F4 variant cell. The increased survival is not attributable to metallothionein inducibility, decreased availability of the alkylating agent in the medium, or decreased uptake of the drug into the trace-element-pretreated cells. The protective responses induced by zinc or selenite alone are additive in cells receiving both trace elements prior to exposure to alkylating agent, which suggests that different domains of response are elicited by the two metals. In view of reported differences in inducibility of protective proteins between normal and tumor cells, a possibility is raised for a novel approach to alkylating-agent chemotherapy that is somewhat analogous to the protocol utilized in high-dose methotrexate therapy.
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PMID:Inducible protective proteins: a potentially novel approach to chemotherapy. 696 46

Although arsenite is an established carcinogen, the mechanisms underlying its tumor-promoting properties are poorly understood. Previously, we reported that arsenite treatment leads to the activation of the extracellular signal-regulated kinase (ERK) in rat PC12 cells through a Ras-dependent pathway. To identify potential mediators of the upstream signaling cascade, we examined the tyrosine phosphorylation profile in cells exposed to arsenite. Arsenite treatment rapidly stimulated tyrosine phosphorylation of several proteins in a Ras-independent manner, with a pattern similar to that seen in response to epidermal growth factor (EGF) treatment. Among these phosphorylated proteins were three isoforms of the proto-oncoprotein Shc as well as the EGF receptor (EGFR). Tyrosine phosphorylation of Shc allowed for enhanced interactions between Shc and Grb2 as identified by coimmunoprecipitation experiments. The arsenite-induced tyrosine phosphorylation of Shc, enhancement of Shc and Grb2 interactions, and activation of ERK were all drastically reduced by treatment of cells with either the general growth factor receptor poison suramin or the EGFR-selective inhibitor tyrphostin AG1478. Down-regulation of EGFR expression through pretreatment of cells with EGF also attenuated ERK activation and Shc tyrosine phosphorylation in response to arsenite treatment. These results demonstrate that the EGFR and Shc are critical mediators in the activation of the Ras/ERK signaling cascade by arsenite and suggest that arsenite acts as a tumor promoter largely by usurping this growth factor signaling pathway.
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PMID:Tumor promoter arsenite activates extracellular signal-regulated kinase through a signaling pathway mediated by epidermal growth factor receptor and Shc. 971 Jun 2

Arsenic is a human carcinogen whose mechanism of action is unknown. Previously, this laboratory demonstrated that arsenite acts as a comutagen by interfering with DNA repair, although a specific DNA repair enzyme sensitive to arsenite has not been identified. A number of stable arsenite-sensitive and arsenite-resistant sublines of Chinese hamster V79 cells have now been isolated. In order to gain understanding of possible targets for arsenite's action, one arsenite-resistant subline, As/R28A, was chosen as a donor for a cDNA expression library. The library from arsenite-induced As/R28A cells was transfected into arsenite-sensitive As/S5 cells, and transfectants were selected for arsenite-resistance. Two cDNAs, asr1 and asr2, which confer arsenite resistance to arsenite-hypersensitive As/S5 cells as well as to wild-type cells, were isolated. asr1 shows almost complete homology with the rat fau gene, a tumor suppressor gene which contains a ubiquitin-like region fused to S30 ribosomal protein. Arsenite was previously shown to inhibit ubiquitin-dependent proteolysis. These results suggest that the tumor suppressor fau gene product or some other aspect of the ubiquitin system may be a target for arsenic toxicity and that disruption of the ubiquitin system may contribute to the genotoxicity and carcinogenicity of arsenite.
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PMID:Expression cloning for arsenite-resistance resulted in isolation of tumor-suppressor fau cDNA: possible involvement of the ubiquitin system in arsenic carcinogenesis. 1006 70

Trivalent arsenic (arsenite, As3+) is a human carcinogen, which is associated with cancers of skin, lung, liver, and bladder. However, the mechanism by which arsenite causes cancer is not well understood. In this study, we found that exposure of Cl 41 cells, a well characterized mouse epidermal cell model for tumor promotion, to a low concentration of arsenite (<25 microM) induces cell transformation. Interestingly, arsenite induces Erk phosphorylation and increased Erk activity at doses ranging from 0.8 to 200 microM, while higher doses (more than 50 microM) are required for activation of JNK. Arsenite-induced Erk activation was markedly inhibited by introduction of dominant negative Erk2 into cells, while expression of dominant negative Erk2 did not show inhibition of JNK and MEK1/2. Furthermore, arsenite-induced cell transformation was blocked in cells expressing the dominant negative Erk2. In contrast, overexpression of dominant negative JNK1 was shown to increase cell transformation even though it inhibits arsenite-induced JNK activation. Our results not only show that arsenite induces Erk activation, but also for the first time demonstrates that activation of Erk, but not JNK, by arsenite is required for its effects on cell transformation.
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PMID:Requirement of Erk, but not JNK, for arsenite-induced cell transformation. 1032 51

It is accepted that inorganic arsenic trioxide is an inducer of apoptosis for many types of cancer. Our previous studies have demonstrated that arsenic trioxide induces apoptosis of esophageal carcinoma cells. Administration of arsenic trioxide results in the inhibition of growth and survival of tumor cells. Esophageal carcinoma cells treated with arsenic trioxide for 3 days demonstrated a typical morphological appearance of apoptosis. To further examine molecular mechanism of arsenic trioxide induced apoptosis of esophageal carcinoma cells, we have investigated the early changes of the apoptotic cell induced by arsenic trioxide. Our results indicated that arsenic trioxide induced apoptosis of esophageal carcinoma cells occurs as early as 2 h after treatment. Annexin-v staining has further proved that the phosphatidylserine is exposed at 2 h. The early morphological change of arsenic trioxide treated cells was in the mitochondria. Arsenic trioxide treated cells displayed aggregated mitochondria. It induces accumulation of high electron-density amorphous substances, swollen and disruption of mitochondria in oesophageal carcinoma cells after 2 h treatment. The alteration of mitochondria induced by arsenic trioxide seems to occur before the condensation of chromatin. Thus, our data demonstrated that the primary target of arsenic trioxide induced apoptosis of esophageal carcinoma cells may be the mitochondria. It is possible that arsenic trioxide is a mitochondriotoxic agent.
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PMID:The alteration of mitochondria is an early event of arsenic trioxide induced apoptosis in esophageal carcinoma cells. 1063 94

Arsenic trioxide (As2O3) was recently identified as a very potent agent against acute promyelocytic leukemia (APL). Intravenous infusion of 10 mg As2O3 daily for one to two months can induce significant complete remission (CR) of APL, and there is no cross drug-resistance between As2O3 and other antileukemic agents, including all-trans retinoic acid (ATRA). The CR rate of relapsed and/or refractory APL patients who received As2O3 treatment ranged from 52.3% to 93.3%. The median duration to CR ranged from 38 to 51 days, with accumulative As2O3 dosage of 340-430 mg. Although most adverse reactions of As2O3 treatment were tolerable, certain infrequent but severe toxicities related to As2O3 were observed, including renal failure, hepatic damage, cardiac arrhythmia and chronic neuromuscular degeneration, which should be monitored carefully. As2O3 can induce partial differentiation and subsequent apoptosis of APL cells through degradation of wild type PML and PML/RAR alpha chimeric proteins and possible anti-mitochondrial effects. Like the treatment of ATRA in APL, early relapses from As2O3 treatment within a few months were not infrequently seen, indicating that rapid emerging resistance to As2O3 can occur. Nevertheless, the PML/RAR alpha fusion protein was reported to disappear in some APL patients who received As2O3, and who might earn long-survival. However, the follow-up is still too short to draw the conclusion. Intriguingly, it has been shown that As2O3 can also induce apoptosis of other non-APL tumor cells with clinical achievable concentrations. However, the detailed molecular mechanisms are not yet fully understood. Further studies regarding to the pharmacological characters, clinical efficacies, toxicities, apoptogenic mechanisms, and spectrum of anti-tumor activity of As2O3 are warranted.
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PMID:Arsenic trioxide therapy for relapsed acute promyelocytic leukemia: an useful salvage therapy. 1083 Jul 35


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