[On the prospects of using the DNA repair inhibitors in radiotherapy of tumors].

Abstract

The cellular DNA repair systems sufficiently provide the resistance of tumors to ionizing radiation, and thus contribute to reducing the effectiveness of their radiotherapy. Therefore, suppression of the activity of critical DNA repair enzymes in tumor cells is considered one of the promising directions to overcome this resistance. As can be seen from the literature analysis, the use of many inhibitors of DNA repair enzymes have not yet yielded the results, which can be extrapolated to preclinical models or clinical trials. However, experimental studies show that the inhibitors of the enzyme family of poly(ADP-ribose) polymerases (PARP) are able to inhibit the growth of various human tumor cells. Pre-clinical and clinical trials of the PARP inhibitors also show promising results in terms of the possibility of their wide practical application. The effect of the PARP inhibitors consists in the blockage of the most important DNA repair systems. This leads to the accumulation of DNA single-strand breaks, the collapse of replication forks and to generation of lethal double-strand breaks (DSB). The PARP inhibitors can be used to suppress breast cancer and ovarian cancer with mutations in BRCA-1/2 genes ("BRCAness" cancer) without combination with radiotherapy or chemotherapy. In the tumor cells deficient in BRCA-1/2 genes DSB repair by homologous recombination pathway does not function. Therefore, the process of DNA DSB repair is switched to the non-homologous end-joining pathway, which operates with formation of the chromosomal rearrangements leading to cell death. Thus, the analysis results show that DNA repair inhibitors have the potential to improve the efficiency of cancer radiotherapy. Further research in this direction is very promising.

• Authors: A I Gaziev
• Journal: Radiatsionnaia biologiia, radioecologiia (Radiats Biol Radioecol) 2014 May-Jun Vol. 54 Issue 3 Pg. 229-40 ISSN: 0869-8031 [Print] Russia (Federation)
• PMID: 25764827 (Publication Type: English Abstract, Journal Article)

Chemical References

• BRCA1 Protein
• BRCA2 Protein
• BRCA2 protein, human
• Enzyme Inhibitors
• Poly(ADP-ribose) Polymerase Inhibitors
• Poly(ADP-ribose) Polymerases
• DNA Repair Enzymes

Topics

• BRCA1 Protein (genetics)
• BRCA2 Protein (genetics)
• Breast Neoplasms (drug therapy, genetics, pathology, radiotherapy)
• DNA Repair (drug effects)
• DNA Repair Enzymes (antagonists & inhibitors)
• Enzyme Inhibitors (therapeutic use)
• Female
• Humans
• Mutation
• Poly(ADP-ribose) Polymerase Inhibitors
• Poly(ADP-ribose) Polymerases (genetics)
• Radiation, Ionizing