title: The PARP inhibitors, veliparib and olaparib, are effective chemopreventive agents for delaying mammary tumor development in BRCA1-deficient mice.
abstract: Poly-ADP ribose polymerase (PARP) inhibitors are effective for the treatment of BRCA-deficient tumors. Women with these mutations have an increased risk of developing breast cancer and would benefit from effective chemoprevention. This study examines whether the PARP inhibitors, veliparib and olaparib, delay mammary gland tumor development in a BRCA1-deficient (BRCA1(Co/Co);MMTV-Cre;p53(+/-)) mouse model. In dose de-escalation studies, mice were fed with control, veliparib (100 mg/kg diet), or olaparib (200, 100, 50, or 25 mg/kg diet) continuously for up to 43 weeks. For intermittent dosing studies, mice cycled through olaparib (200 mg/kg diet) for 2 weeks followed by a 4-week rest period on control diet. To examine biomarkers, mice were fed with olaparib using the intermittent dosing regimen and mammary glands were evaluated by immunohistochemistry. In mice treated with veliparib or olaparib (200 mg/kg diet), the average age of the first detectable tumor was delayed by 2.4 and 6.5 weeks, respectively, compared with controls. Olaparib also increased the average lifespan of mice by 7 weeks. In dose de-escalation studies, lower concentrations of olaparib delayed tumor development but were less effective than the highest dose. When fed intermittently, olaparib delayed the onset of the first palpable tumor by 5.7 weeks and significantly reduced proliferation and induced apoptosis in hyperplastic mammary glands. In summary, veliparib and olaparib are effective for delaying tumor development and extending the lifespan of BRCA1-deficient mice, and intermittent dosing with olaparib was as effective as continuous dosing. These results suggest that the use of PARP inhibitors is a promising chemopreventive option.
authors.affiliation: Authors' Affiliations: Departments of Pharmacology, and.
authors.forename: Ciric
authors.initials: C
authors.lastname: To
authors.affiliation: Authors' Affiliations: Departments of Pharmacology, and.
authors.forename: Eun-Hee
authors.initials: EH
authors.lastname: Kim
authors.affiliation: Authors' Affiliations: Departments of Pharmacology, and.
authors.forename: Darlene B
authors.initials: DB
authors.lastname: Royce
authors.affiliation: Authors' Affiliations: Departments of Pharmacology, and.
authors.forename: Charlotte R
authors.initials: CR
authors.lastname: Williams
authors.affiliation: Authors' Affiliations: Departments of Pharmacology, and.
authors.forename: Ryan M
authors.initials: RM
authors.lastname: Collins
authors.affiliation: Authors' Affiliations: Departments of Pharmacology, and.
authors.forename: Renee
authors.initials: R
authors.lastname: Risingsong
authors.affiliation: Authors' Affiliations: Departments of Pharmacology, and.
authors.forename: Michael B
authors.initials: MB
authors.lastname: Sporn
authors.affiliation: Authors' Affiliations: Departments of Pharmacology, and Medicine, Dartmouth Medical School, Hanover, New Hampshire Karen.T.Liby@dartmouth.edu.
authors.forename: Karen T
authors.initials: KT
authors.lastname: Liby
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D019313:BRCA1 Protein / Q000502:physiology*; D001562:Benzimidazoles / Q000627:therapeutic use*; D015415:Biomarkers / Q000032:analysis; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D015674:Mammary Neoplasms, Animal / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D018345:Mice, Knockout; D010793:Phthalazines / Q000627:therapeutic use*; D010879:Piperazines / Q000627:therapeutic use*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D016159:Tumor Suppressor Protein p53 / Q000502:physiology
chemical_list: D000970:Antineoplastic Agents; D019313:BRCA1 Protein; D001562:Benzimidazoles; D015415:Biomarkers; D010793:Phthalazines; D010879:Piperazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D016159:Tumor Suppressor Protein p53; C521013:veliparib; C531550:olaparib