Inhibition of Poly(ADP-Ribose) Polymerase in Tumors from BRCA Mutation Carriers

• Published in: The New England journal of medicine Vol. 361; no. 2; pp. 123 - 134
• Main Authors: Fong, Peter C, Boss, David S, Yap, Timothy A, Tutt, Andrew, Wu, Peijun, Mergui-Roelvink, Marja, Mortimer, Peter, Swaisland, Helen, Lau, Alan, O'Connor, Mark J, Ashworth, Alan, Carmichael, James, Kaye, Stan B, Schellens, Jan H.M, de Bono, Johann S
• Format: Journal Article
• Language: English
• Published: Waltham, MA Massachusetts Medical Society 09.07.2009
• Subjects: Adult; Aged; Aged, 80 and over; Biological and medical sciences; Cancer; DNA repair; Dose-Response Relationship, Drug; Drug Design; Female; General aspects; Genes, BRCA1; Genes, BRCA2; Genetics; Germ-Line Mutation; Heterozygote; Humans; Male; Medical sciences; Middle Aged; Mutation; Neoplasms - drug therapy; Neoplasms - genetics; Phthalazines - adverse effects; Phthalazines - pharmacokinetics; Phthalazines - therapeutic use; Piperazines - adverse effects; Piperazines - pharmacokinetics; Piperazines - therapeutic use; Poly(ADP-ribose) Polymerase Inhibitors; Proteins; Rodents; Young Adult; Enzyme; Transferases; Glycosyltransferases; Medicine; NAD; ADP-ribosyltransferase; Genetics; Tumor; Inhibitor; Inhibition; Mutation; Carrier; Pentosyltransferases
• ISSN: 0028-4793; 1533-4406; 1533-4406
• DOI: 10.1056/NEJMoa0900212

Inhibition of poly(adenosine diphosphate [ADP]–ribose) polymerase (PARP), a key enzyme for the repair of breaks in DNA, can lead to the accumulation of breaks in double-stranded DNA. The BRCA1 and BRCA2 proteins help to repair such breaks. In this phase 1 trial, the PARP inhibitor olaparib was shown to lack the severe toxic effects of conventional chemotherapy and to result in objective responses in tumors with a BRCA mutation. In this phase 1 trial, the poly(ADP–ribose) polymerase inhibitor olaparib was shown to lack the severe toxic effects of conventional chemotherapy and to result in objective responses in tumors with a BRCA mutation. Cellular DNA is continually subject to damage, which coordinated pathways act to repair, thereby maintaining genomic integrity and cell survival. 1 – 3 The poly(adenosine diphosphate [ADP]–ribose) polymerases (PARPs) are a large family of multifunctional enzymes, the most abundant of which is PARP1. It plays a key role in the repair of DNA single-strand breaks through the repair of base excisions. 4 , 5 The inhibition of PARPs leads to the accumulation of DNA single-strand breaks, which can lead to DNA double-strand breaks at replication forks. Normally, these breaks are repaired by means of the error-free homologous-recombination double-stranded DNA repair pathway, 6 key components of . . .