Overcoming Resistance of Glioblastoma to Conventional Cytotoxic Therapies by the Addition of PARP Inhibitors
Anthony J. Chalmers.
This article will present the rationale for combining chemical inhibitors of the DNA repair enzyme poly(ADP-ribose) polymerase (PARP) with conventional cytotoxic agents to improve the treatment of glioblastoma. After a brief review of the current therapeutic options for these aggressive tumours, the possible reasons for their resistance to radiation and chemotherapy will be discussed, highlighting the important role of DNA damage response pathways in many key resistance mechanisms. The dose-limiting toxicities associated with radiation and chemotherapy treatment will be described in order to illustrate the importance of tumour specificity in any attempt to increase the effectiveness of conventional treatments. There will then be a summary of the reasons why targeting DNA repair pathways might achieve tumour specific sensitization. After a brief summary of the key DNA damage response pathways, the biology, biochemistry and pharmacology of PARP and the existing PARP inhibitors will be presented. The major part of the review will cover the effects of combining PARP inhibitors with radiation and chemotherapy in vitro and in vivo, commenting on the underlying mechanisms and indicating where the data are predictive of tumour specific sensitization. Finally, we will consider specific scenarios where PARP inhibitors might contribute to the treatment of glioblastoma patients, discuss the challenges and opportunities associated with early phase clinical testing of these agents, and describe the clinical trials that are either underway or in development.
Keywords: Glioblastoma, poly(ADP-ribose) polymerase, DNA repair, PARP inhibitors, radiosensitizers, chemosensitizers, Cytotoxic Therapies, surgical debulking, nitrosourea compounds, methylguanine, radioresistant, genetic aberrations, Downregulation, critical cytoprotective pathways, neurotoxicity, radiosensitization, Non-homologous, carmustine, lomustine, MGMT repairs, Carcinogenesis, ataxia telangiectasia mu-tated (ATM), genomic instability, PARP, post-mitotic, ADP-ribosylation, pharmacokinetics, apoptosis, neurotoxic, NAD+ depletion, thrombocytopenia, synergistic, Rat orthotopic, optimistic, camp-tothecin, multimodality approaches, Homozygous
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