PARP Inhibitors
نویسندگان
چکیده
Poly (ADP-ribose) polymerase (PARP) is a novel therapeutic target in cancer. Preclinical studies demonstrate that PARP inhibitors selectively kill BRCAdeficient cells and potentiate the effects of DNA-damaging agents. There are several PARP inhibitors in clinical development, including olaparib, iniparib, veliparib, PF01367338, and MK-4827. Phase II studies of single-agent olaparib demonstrate activity in BRCA-associated cancers. A randomized phase II trial showed that the addition of iniparib to gemcitabine and carboplatin in patients with metastatic triple-negative breast cancer (TNBC) improved progression-free survival and overall survival. A phase III trial evaluating this combination in metastatic TNBC has completed accrual. Phase III studies of olaparib in BRCAassociated breast cancer and veliparib in breast cancer are being planned. This article reviews the clinical studies to date that have evaluated PARP inhibitors as a single agent or in combination with chemotherapy in patients with breast cancer, including BRCA-associated breast cancer and TNBC.
منابع مشابه
Non-NAD-Like poly(ADP-Ribose) Polymerase-1 Inhibitors effectively Eliminate Cancer in vivo
The clinical potential of PARP-1 inhibitors has been recognized >10years ago, prompting intensive research on their pharmacological application in several branches of medicine, particularly in oncology. However, natural or acquired resistance of tumors to known PARP-1 inhibitors poses a serious problem for their clinical implementation. Present study aims to reignite clinical interest to PARP-1...
متن کاملTrapping of PARP1 and PARP2 by Clinical PARP Inhibitors.
Small-molecule inhibitors of PARP are thought to mediate their antitumor effects as catalytic inhibitors that block repair of DNA single-strand breaks (SSB). However, the mechanism of action of PARP inhibitors with regard to their effects in cancer cells is not fully understood. In this study, we show that PARP inhibitors trap the PARP1 and PARP2 enzymes at damaged DNA. Trapped PARP-DNA complex...
متن کاملRationale for poly(ADP-ribose) polymerase (PARP) inhibitors in combination therapy with camptothecins or temozolomide based on PARP trapping versus catalytic inhibition.
We recently showed that poly(ADP-ribose) polymerase (PARP) inhibitors exert their cytotoxicity primarily by trapping PARP-DNA complexes in addition to their NAD(+)-competitive catalytic inhibitory mechanism. PARP trapping is drug-specific, with olaparib exhibiting a greater ability than veliparib, whereas both compounds are potent catalytic PARP inhibitors. Here, we evaluated the combination of...
متن کاملTrapping Poly(ADP-Ribose) Polymerase.
Recent findings indicate that a major mechanism by which poly(ADP-ribose) polymerase (PARP) inhibitors kill cancer cells is by trapping PARP1 and PARP2 to the sites of DNA damage. The PARP enzyme-inhibitor complex "locks" onto damaged DNA and prevents DNA repair, replication, and transcription, leading to cell death. Several clinical-stage PARP inhibitors, including veliparib, rucaparib, olapar...
متن کاملINVITED COMMENTARY Biomarkers of PARP inhibitor sensitivity
The PARP inhibitors represent one of the most exciting recent developments in cancer therapy. Substantial efficacy has been shown with PARP inhibitors in the treatment of hereditary BRCA1/2 related Breast and Ovarian cancer as single agents [1–3] and in combination with temozolomide [4]. Similarly, encouraging activity has been shown in sporadic ovarian cancer with a PARP inhibitor as a single ...
متن کاملVirtual screening for plant PARP inhibitors – what can be learned from human PARP inhibitors?
The functions of Poly(ADP-ribose) polymerase enzymes (PARPs) in general are best studied based on human PARP-1 (HsPARP-1). HsPARP-1 is well investigated because pharmacological modulation of its activity modulates DNA-binding of antitumor drugs [1]. In contrast to human PARP enzymes, the exact role of PARPs in plants remains to be elucidated. Different stresses activate plant PARP enzymes to me...
متن کامل