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    • Amyloid β-peptide (10-35), amide There are however concerns

    2023-01-04

    There are however, concerns of potential side-effects that should also be taken into account. Even though some studies pointed towards a potentially greater radiosensitising effect in p53-deficient tumours, ATM inhibition radiosensitises Amyloid β-peptide (10-35), amide in general, which raises the concern of normal tissue toxicity. It should also be noted that pharmacological ATM inhibition appears to cause a different cellular phenotype than lack of ATM protein expression. Choi et al. showed that following exposure to IR, repair of damaged DNA replication forks is normal in A–T cells, which lack ATM protein, but is defective in wild-type cells when ATM is inhibited by KU-55933 or KU-60019. This effect of ATM inhibitor treatment was not observed in A–T cells (White et al., 2010). The authors hypothesised that “kinase-inhibited ATM” presents a physical impediment to sister chromatid exchange, a mechanism of homologous recombination repair (HRR), at DSBs at damaged replication forks (Choi et al., 2010, White et al., 2010). Interestingly, it has been shown recently that the expression of kinase dead (kd) ATM protein is more detrimental to cells than loss of ATM expression (Yamamoto et al., 2012). While ATM knockout mice have long been known to be viable, yet recapitulating many of the symptoms characteristic for A–T (Barlow et al., 1996, Elson et al., 1996), expression of physiological levels of kd ATM led to early embryonic lethality in mice. It has been suggested that this is due to the binding of catalytically inactive ATM to sites of DNA DSBs, thereby blocking those sites for proteins mediating alternative routes of DNA damage repair, and causing disturbance of the DDR and persistence of DNA damage (Yamamoto et al., 2012). ATP-competitive ATM inhibitors like KU-55933 might act in a similar way as kd ATM protein, which, upon prolonged exposure, may cause greater side effects in vivo than a loss of ATM protein expression would. Further studies will need to address this question, but the possibility should be considered for future clinical development of ATM inhibitors. However, given the observations that (i) transient inhibition of ATM is sufficient to achieve radiosensitisation in vitro (Rainey et al., 2008) and (ii) ATM must be inhibited at the time of etoposide administration (Batey et al., 2013) to achieve chemosensitisation in vivo, there is strong indication that short-term treatment with optimally-scheduled ATM inhibitors might be sufficient to achieve chemo- or radiosensitisation. In addition to the clinical use of ATM inhibitors as radiosensitisers, ATM deficiency in tumours might be exploitable as an “intrinsic radiosensitiser”. As mentioned earlier, ATM is frequently mutated in a variety of cancer types (Cancer Genome Atlas Research Network, 2012a, Cancer Genome Atlas Research Network, 2012b, Cancer Genome Atlas Research Network, 2012c, Cancer Genome Atlas Research Network, 2014). However, the large size of the ATM gene renders routine DNA sequencing a challenging diagnostic tool and a large proportion of the ATM mutations reported to date are missense variants, which occur across the entire length of the ATM protein, with no apparent hotspots. Predicting the consequences of such mutations on protein stability and activity is challenging without functional studies. Studies on ATM missense mutations found in ataxia–telangiectasia (A–T) patients have shown, however, that missense changes can lead to a reduction in ATM protein expression and that loss of ATM activity is often associated with reduced ATM protein levels (Sandoval et al., 1999, Lavin et al., 2004, Mitui et al., 2009, Jacquemin et al., 2012). In our own studies we have demonstrated that cancer-associated ATM mutations can lead to a reduction or loss of ATM protein expression and consequently impairment of the ATM signalling pathway. Furthermore we were able to show that analysis of ATM protein expression by immunohistochemistry may be a valuable clinical tool to identify a patient subgroup with low or absent ATM protein levels (Weber et al., 2014). Furthermore, studies in locally advanced breast cancer have demonstrated that the ATM gene is a potential target for epigenetic silencing (Vo et al., 2004). Hypermethylation of the ATM promoter resulting in decreased protein levels and increased radiosensitivity has been described for colorectal and glioma cell lines (Kim et al., 2002, Roy et al., 2006). A report by Tribius et al. suggested a correlation between ATM protein levels and radiosensitivity in primary glioblastoma cells in culture (Tribius et al., 2001).