ABT-888 Confers Broad<i>In vivo</i>Activity in Combination with Temozolomide in Diverse Tumors

Palma, Joann P.; Wang, Yichun; Rodrı́guez, Luis E.; Montgomery, Debra; Ellis, Paul; Bukofzer, Gail; Niquette, Amanda; Liu, Xuesong; Shi, Yan; Lasko, Loren; Zhu, Gui‐Dong; Penning, Thomas D.; Giranda, Vincent L.; Rosenberg, Saul H.; Frost, David J.; Donawho, Cherrie K.

doi:10.1158/1078-0432.ccr-09-1245

Cited by 129 publications

(96 citation statements)

References 43 publications

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“…In addition, the doses of veliparib that are sufficient to produce antitumor activity have been shown to be pharmacodynamically active, leading to significant inhibition of PAR levels in vivo (8,31,35,36). Consistent with our previous reports, temozolomide monotherapy at 50 mg/kg/d (i.p., once daily for 5 days) produced significant tumor growth inhibition (45% TGI at day 14) when compared with the vehicle group (Fig.…”

Section: Activity In Xenograft Tumor Modelssupporting

confidence: 89%

“…We and other researchers have shown previously that PARP inhibitors can effectively potentiate the activity of temozolomide in various xenograft models (7,8,31,34). In addition, the doses of veliparib that are sufficient to produce antitumor activity have been shown to be pharmacodynamically active, leading to significant inhibition of PAR levels in vivo (8,31,35,36).…”

Section: Activity In Xenograft Tumor Modelsmentioning

confidence: 92%

“…Numerous preclinical studies have shown the ability of PARP inhibitors to potentiate the activity of temozolomide in both in vitro and in vivo model settings (7,8,11). This activity is particularly pronounced when used in tumors defective in DSB repair (8,31).…”

Section: Combination Activity With Temozolomidementioning

confidence: 99%

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Iniparib Nonselectively Modifies Cysteine-Containing Proteins in Tumor Cells and Is Not a Bona Fide PARP Inhibitor

Liu

Shi

Maag

et al. 2012

Clinical Cancer Research

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168

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Purpose: PARP inhibitors are being developed as therapeutic agents for cancer. More than six compounds have entered clinical trials. The majority of these compounds are b-nicotinamide adenine dinucleotide (NAD þ )-competitive inhibitors. One exception is iniparib, which has been proposed to be a noncompetitive PARP inhibitor. In this study, we compare the biologic activities of two different structural classes of NAD þ -competitive compounds with iniparib and its C-nitroso metabolite.Experimental Design: Two chemical series of NAD þ -competitive PARP inhibitors, iniparib and its C-nitroso metabolite, were analyzed in enzymatic and cellular assays. Viability assays were carried out in MDA-MB-436 (BRCA1-deficient) and DLD1À/À (BRCA2-deficient) cells together with BRCA-proficient MDA-MB-231 and DLD1 þ/þ cells. Capan-1 and B16F10 xenograft models were used to compare iniparib and veliparib in vivo. Mass spectrometry and the 3 H-labeling method were used to monitor the covalent modification of proteins.Results: All NAD þ -competitive inhibitors show robust activity in a PARP cellular assay, strongly potentiate the activity of temozolomide, and elicit robust cell killing in BRCA-deficient tumor cells in vitro and in vivo. Cell killing was associated with an induction of DNA damage. In contrast, neither iniparib nor its C-nitroso metabolite inhibited PARP enzymatic or cellular activity, potentiated temozolomide, or showed activity in a BRCA-deficient setting. We find that the nitroso metabolite of iniparib forms adducts with many cysteine-containing proteins. Furthermore, both iniparib and its nitroso metabolite form protein adducts nonspecifically in tumor cells. Conclusions: Iniparib nonselectively modifies cysteine-containing proteins in tumor cells, and the primary mechanism of action for iniparib is likely not via inhibition of PARP activity. Clin Cancer Res; 18(2); 510-23. Ó2011 AACR.

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Section: Activity In Xenograft Tumor Modelssupporting

confidence: 89%

Section: Activity In Xenograft Tumor Modelsmentioning

confidence: 92%

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Iniparib Nonselectively Modifies Cysteine-Containing Proteins in Tumor Cells and Is Not a Bona Fide PARP Inhibitor

Liu

Shi

Maag

et al. 2012

Clinical Cancer Research

Self Cite

168

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“…1) is a novel and potent inhibitor of PARP-1 and PARP-2 enzymes (K i of 5 and 2 nM, respectively) and has demonstrated excellent in vivo efficacy in a broad spectrum of preclinical tumor models in combination with a variety of cytotoxic agents such as temozolomide (TMZ), cisplatin, cyclophosphamide, and radiation (Donawho et al, 2007;Palma et al, 2009;Penning et al, 2009). Preclinical pharmacokinetic profiles of veliparib were characterized by high plasma clearance, high volumes of distribution, and high oral bioavailability across species (Donawho et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Disposition and Drug-Drug Interaction Potential of Veliparib (ABT-888), a Novel and Potent Inhibitor of Poly(ADP-ribose) Polymerase

Li¹,

Delzer²,

Voorman³

et al. 2011

Drug Metab Dispos

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ABSTRACT:The Veliparib absorption was high. Dosed radioactivity was widely distributed in rat tissues. The majority of drug-related material was excreted in urine as unchanged drug (approximately 54, 41, and 70% of the dose in rats, dogs, and humans, respectively). A lactam M8 and an amino acid M3 were two major excretory metabolites in animals. In the circulation of animals and humans, veliparib was the major drug-related component, and M8 was one of the major metabolites. Monooxygenated metabolite M2 was significant in the rat and dog, and M3 was also significant in the dog. Veliparib biotransformation occurred on the pyrrolidine moiety via formation of a lactam, an amino acid, and an N-carbamoyl glucuronide, in addition to oxidation on benzoimidazole carboxamide and sequential glucuronidation. In vitro experiments using recombinant human cytochrome P450 (P450) enzymes identified CYP2D6 as the major enzyme metabolizing veliparib with minor contributions from CYP1A2, 2C19, and 3A4. Veliparib did not inhibit or induce the activities of major human P450s. Veliparib was a weak P-glycoprotein (P-gp) substrate, showing no P-gp inhibition. Taken together, these studies indicate a low potential for veliparib to cause clinically significant P-gp or P450-mediated drug-drug interactions (DDIs). Overall, the favorable dispositional and DDI profiles of veliparib should be beneficial to its safety and efficacy.

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“…It has been shown that PARP inhibitors might function as sensitizing agents for chemotherapy and radiotherapy that cause DNA damage [26]. Palma et al have shown what they called "potent antitumor efficacy" of the PARP inhibitor, ABT-888 with temozolomide (TMZ) in orthotopic and metastatic implantation models across a spectrum of histologic types.Their results are worth noting, because the efficacy was independent of TMZ activity and overcame both inherent and acquired TMZ resistance [27]. Japanese investigators found that adding olaparib to SN-38 or irinotecan potentiated S-phase double-strand breaks, producing a synergistic effect in cells that were MSI-H and non-MSI-H [28].…”

Section: Discussionmentioning

confidence: 98%

Phase II Study of Olaparib (AZD-2281) After Standard Systemic Therapies for Disseminated Colorectal Cancer

et al. 2016

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Background. Effective new agents for patients with colorectal cancer (CRC) with disease progression during standard therapy regimens are needed. We hypothesized that poly ADP ribose polymerase (PARP) inhibitor therapy in patients with CRC and inefficient tumor DNA repair mechanisms, such as those with high-level microsatellite instability (MSI-H), would result in synthetic lethality. Methods.This was an open-label phase II trial testing olaparib 400 mg p.o. b.i.d. for patients with disseminated, measurable CRC failing standard therapies with centrally confirmed tumor MSI status. The primary endpoint was the tumor response, assessed by RECIST, version 1.0.The secondary endpoints were safety/toxicity, progression-free survival (PFS), and overall survival (OS). Results. Thirty-three patients (20 microsatellite stable [MSS], 13 MSI-H) were enrolled. The median age for all

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ABT-888 Confers BroadIn vivoActivity in Combination with Temozolomide in Diverse Tumors

Cited by 129 publications

References 43 publications

Iniparib Nonselectively Modifies Cysteine-Containing Proteins in Tumor Cells and Is Not a Bona Fide PARP Inhibitor

Iniparib Nonselectively Modifies Cysteine-Containing Proteins in Tumor Cells and Is Not a Bona Fide PARP Inhibitor

Disposition and Drug-Drug Interaction Potential of Veliparib (ABT-888), a Novel and Potent Inhibitor of Poly(ADP-ribose) Polymerase

Phase II Study of Olaparib (AZD-2281) After Standard Systemic Therapies for Disseminated Colorectal Cancer

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