PARP Inhibitors in Cancer Therapy: Promise, Progress, and Puzzles

Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA, 02114, USA.
Cancer cell (Impact Factor: 23.52). 02/2011; 19(2):165-7. DOI: 10.1016/j.ccr.2011.01.047
Source: PubMed


A recent article in the New England Journal of Medicine by O'Shaughnessy et al. provides evidence that a treatment strategy aimed at inducing DNA damage with chemotherapy while simultaneously disabling repair using a PARP inhibitor might offer hope for patients with a treatment-refractory form of breast cancer.

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Available from: Leif W Ellisen, May 18, 2015
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    • "Here, poly (ADP-ribose) polymerase (PARP) inhibitor sensitization of cells to MMS-induced killing is dependent on the presence of the 5′-dRP group [27]. The topic is timely as PARP inhibitors are currently being evaluated in cancer chemotherapy [28]. Although the budding yeast system does not contain the PARP enzyme, this system can nonetheless informs us about the metabolism of the 5′-dRP group in BER intermediates. "
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    ABSTRACT: To better understand alkylating agent-induced cytotoxicity and the base lesion DNA repair process in Saccharomyces cerevisiae, we replaced the RAD27(FEN1) open reading frame (ORF) with the ORF of the bifunctional human repair enzyme DNA polymerase (Pol) β. The aim was to probe the effect of removal of the incised abasic site 5'-sugar phosphate group (i.e., 5'-deoxyribose phosphate or 5'-dRP) in protection against methyl methanesulfonate (MMS)-induced cytotoxicity. In S. cerevisiae, Rad27(Fen1) was suggested to protect against MMS-induced cytotoxicity by excising multinucleotide flaps generated during repair. However, we proposed that the repair intermediate with a blocked 5'-end, i.e., 5'-dRP group, is the actual cytotoxic lesion. In providing a 5'-dRP group removal function mediated by dRP lyase activity of Pol β, the effects of the 5'-dRP group were separated from those of the multinucleotide flap itself. Human Pol β was expressed in S. cerevisiae, and this partially rescued the MMS hypersensitivity observed with rad27(fen1)-null cells. To explore this rescue effect, altered forms of Pol β with site-directed eliminations of either the 5'-dRP lyase or polymerase activity were expressed in rad27(fen1)-null cells. The 5'-dRP lyase, but not the polymerase activity, conferred the resistance to MMS. These results suggest that after MMS exposure, the 5'-dRP group in the repair intermediate is cytotoxic and that Rad27(Fen1) protection against MMS in wild-type cells is due to elimination of the 5'-dRP group.
    PLoS ONE 10/2012; 7(10):e47945. DOI:10.1371/journal.pone.0047945 · 3.23 Impact Factor
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    • "The prototype of these drugs are inhibitors of poly ADP(ribose) polymerase (PARP), enzymes required for single-strand break and base-excision repair [36]. Combinations of PARP inhibitors with DNA damaging chemotherapy are already showing early promise in the treatment of TNBC [37, 38]. Activation of TAp73 may be involved in the response to unrepaired DNA damage in at least a subset of these tumors. "
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    ABSTRACT: The p53 family transcription factors p53, p63 and p73 make diverse contributions in development and cancer. Mutation or deletion of p53 is observed in the majority of human cancers. In contrast, p63 and p73 are not lost in cancer but mediate distinct genetic roles in normal and tumor-specific contexts: p73 promotes genome stability and mediates chemosensitivity, while p63 largely lacks these p53-like functions and instead promotes proliferation and cell survival. We recently uncovered a mechanism which maintains p63/p73 homeostasis within the epithelium through direct transcriptional regulation of microRNAs (miRs). We discovered that several of the top p63-regulated miRs target p73 for inhibition, including miR-193a-5p, a direct p63/p73 transcriptional target which is repressed by p63 and activated by p73 both in vitro and in vivo. The resulting feed-forward circuit involving p63, miR-193a-5p and p73 controls p73 levels, cell viability and DNA damage susceptibility in certain cancers including squamous cell carcinoma. Here, we discuss the evolutionary implications of this regulatory circuit, which may point to a general mechanism of miR-mediated cross-talk within transcription factor gene families. Additionally, we suggest that inducible chemoresistance mediated by this miR-dependent mechanism might be an attractive target for therapeutic intervention.
    Oncotarget 03/2011; 2(3):259-64. DOI:10.18632/oncotarget.244 · 6.36 Impact Factor
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    ABSTRACT: This work proposes a fuzzy logic framework suitable for web page filtering. Web page classifiers are trained off-line using the directory structure of the Open Directory Project ( and are available to the user through an appropriate interface. These classifiers are considered as fuzzy membership functions which determine the membership degree of a web page to each class. The user selects a number of classes and formulates logical rules combining the classifiers. Fuzzy logic operators are used in order to filter the results of a query according to the specified rule providing different views (orderings) of the search results to the user.
    Neural Network Applications in Electrical Engineering, 2002. NEUREL '02. 2002 6th Seminar on; 02/2002
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