Anticarcinogenic potential of DNA-repair modulators

Boothman, David A.; Schlegel, Robert; Pardee, Arthur B.

doi:10.1016/0027-5107(88)90201-1

Cited by 43 publications

(24 citation statements)

References 112 publications

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“…All of the above models attempt to explain how cells with MMR defects acquire selective growth advantages, acquire mutations, and thus become tumorigenic, whereas MMR-competent cells respond to the same DNA lesions with lethal consequences. These MMR-dependent responses appear to support the theory that cell death, as opposed to survival with high mutagenic consequences, is evolutionarily preferable in multicellular organisms (Boothman et al, 1988).…”

Section: Mmr-mediated Futile Cyclingsupporting

confidence: 67%

“…Cell cycle arrests are postulated to allow cells greater time to repair DNA damage and/or allow the elimination of severely damaged cells to prevent tumor formation in mammalian cells (Boothman et al, 1988;Hartwell and Kastan, 1994). The responses of MMRcompetent cells to specific types of DNA-damaging agents appear to highlight both of these responses, and offer the best 'proof of principle' of these hypotheses in human cells.…”

Section: Mmr-mediated Signalingmentioning

confidence: 99%

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A role for DNA mismatch repair in sensing and responding to fluoropyrimidine damage

et al. 2003

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Section: Mmr-mediated Futile Cyclingsupporting

confidence: 67%

Section: Mmr-mediated Signalingmentioning

confidence: 99%

A role for DNA mismatch repair in sensing and responding to fluoropyrimidine damage

et al. 2003

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“…Surveillance mechanisms monitor the integrity of the genome; detection of DNA damage coordinately triggers checkpoint pathways and DNA repair systems (56). Activation of a DNA damage checkpoint results in cell cycle arrest, allowing time for DNA repair.Caffeine belongs to a class of chemicals that strongly enhance the cytotoxic effect of ionizing radiation and other DNAdamaging agents, at concentrations that are not otherwise toxic to cells (3,30,53). The molecular mechanisms underlying this caffeine effect are still not fully understood.…”

mentioning

confidence: 99%

“…Caffeine belongs to a class of chemicals that strongly enhance the cytotoxic effect of ionizing radiation and other DNAdamaging agents, at concentrations that are not otherwise toxic to cells (3,30,53). The molecular mechanisms underlying this caffeine effect are still not fully understood.…”

mentioning

confidence: 99%

Caffeine Inhibits Human Immunodeficiency Virus Type 1 Transduction of Nondividing Cells

Daniel

Marusich

Argyris

et al. 2005

J Virol

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Caffeine is an efficient inhibitor of DNA repair and DNA damage-activated checkpoints. We have shown recently that caffeine inhibits retroviral transduction of dividing cells, most likely by blocking postintegration repair. This effect may be mediated at least in part by a cellular target of caffeine, the ataxia telangiectasiamutated and Rad3-related (ATR) kinase. In this study, we present evidence that caffeine also inhibits efficient transduction of nondividing cells. We observed reduced transduction in caffeine-treated growth-arrested cells as well as caffeine-treated terminally differentiated human neurons and macrophages. Furthermore, this deficiency was observed with a human immunodeficiency virus type 1 (HIV-1) vector lacking Vpr, indicating that the effect is independent of the presence of this viral protein in the infecting virion. Finally, we show that HIV-1 transduction of nocodazole-arrested cells is reduced in cells that express an ATR dominant-negative protein (kinase-dead ATR [ATRkd]) and that the residual transduction of ATRkd-expressing cells is relatively resistant to caffeine. Taken together, these data suggest that the effect(s) of caffeine on HIV-1 transduction is mediated at least partly by the inhibition of the ATR pathway but is not dependent on the caffeine-mediated inhibition of cell cycle checkpoints.Cellular mechanisms that protect the integrity of chromosomal DNA are important for cell and organism survival. Surveillance mechanisms monitor the integrity of the genome; detection of DNA damage coordinately triggers checkpoint pathways and DNA repair systems (56). Activation of a DNA damage checkpoint results in cell cycle arrest, allowing time for DNA repair.Caffeine belongs to a class of chemicals that strongly enhance the cytotoxic effect of ionizing radiation and other DNAdamaging agents, at concentrations that are not otherwise toxic to cells (3,30,53). The molecular mechanisms underlying this caffeine effect are still not fully understood. However, it has been established that caffeine disrupts DNA damage-activated cell cycle checkpoints. For example, it has been shown that caffeine eliminates p53 activation and G 1 arrest, G 2 /M arrest, and S-phase delay in response to DNA damage (20, 23, 24, 26-28, 31, 34, 39, 42, 50-52). Nevertheless, it seems that not all caffeine effects are due to disruption of DNA damage checkpoints. It has been demonstrated that abrogation of a caffeinemediated checkpoint does not correlate with the level of caffeine-induced radiosensitization (40). It is therefore likely that caffeine acts on both cell cycle checkpoints and directly on DNA repair.DNA damage-activated cell cycle checkpoints are regulated by two related kinases, the ataxia telangiectasia-mutated (ATM) kinase and the ATM and Rad3-related (ATR) kinase, which belong to a family of phosphatidylinositol-3 kinase-related kinases (1,46). ATM is activated primarily by double-strand DNA breaks, whereas ATR also responds to replication stress (1,33,46). While ATM and ATR activate cell cycle checkpo...

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“…Unlike the defective DNA repair in cancer-prone diseases, however, some drugs (i.e., most notably caffeine and 3-aminobenzamide) have been reported to decrease carcinogenicity (6)(7)(8). Such drugs may have promise not only for increasing the efficacy of chemotherapy (9), but also for decreasing carcinogenicity (10). P-Lapachone (3,4-…”

mentioning

confidence: 99%