A phase I study of ABT-888 (A) in combination with metronomic cyclophosphamide (C) in adults with refractory solid tumors and lymphomas.

Kummar, Shivaani; Chen, A. P.; J, Ji; Allen, Deborah; Egorin, Merrill J.; Gandara, David R.; Lenz, H.; Morgan, Rachael; Newman, Edward M.; Doroshow, James H.

doi:10.1200/jco.2010.28.15_suppl.2605

Cited by 12 publications

(10 citation statements)

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“…At least 6 PARP compounds are in various stages of clinical development for oncology, with several other compounds in preclinical development (6). Promising preliminary clinical data has been reported in combination with temozolomide, topoisomerase inhibitors, and cytoxan in phase I studies (12,37,38). In addition, evidence for singleagent activity has been reported in BRCA-deficient tumors in phase I/II studies with both olaparib and MK4827 (15,16,39,40).…”

Section: Discussionmentioning

confidence: 88%

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

167

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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: Discussionmentioning

confidence: 88%

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

167

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“…Two patients exhibited >95% reduction in PAR within the tumors. [125] Two patients with BRCA 2 ovarian cancer achieved PR. Both patients achieved PRs in the second dose level consisting of oral cyclophosphamide at 50 mg q d days 1–21 and veliparib 30 mg q day × 7 days on a 21 day cycle.…”

Section: Clinical Development Of Parp Inhibitorsmentioning

confidence: 99%

PARP Inhibitor Treatment in Ovarian and Breast Cancer

Weil

Chen²

2011

Current Problems in Cancer

136

108

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“…Several studies have suggested that veliparib was effective in combination with chemotherapy for gynecologic cancers (56)(57)(58). An open-label, multicenter, single-arm phase I combination study of ABT-888 and metronomic oral cyclophosphamide in patients with advanced malignancies was recently published by Kummar et al The study included 11 patients affected by advanced ovarian cancer, treated with a dose escalation design of the combined drugs.…”

Section: Clinical Developmentmentioning

confidence: 99%

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et al. 2015

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Ovarian cancer is burdened by the highest mortality rate among gynecological cancers. Gold standard is represented by the association of platinum-taxane-based chemotherapy and radical surgery. Despite several adjustments occurred in cytotoxic drug in last decades, most patients continue to relapse, and no significant enhancement has been reached in the overall survival. The development of drug resistance and the recurrence of disease have prompted the investigations of other targets that can be used in the treatment of ovarian cancers. Among such targets, polyadenosine diphosphate-ribose polymerase (PARP) represents a novel way to target specific patways involved in tumor growth. PARP accelerates the reaction of the polyADP-ribosylation of proteins implicated in DNA repair. PARP inhibitors have shown activity in cancers with BRCA mutations, with other deficient DNA repair genes or signaling pathways that modulate DNA repair, or in association with DNA damaging agents not involved in DNA repair dysfunction. A number of inhibitors for PARP has been developed, and such drugs are under investigation in clinical trials to identify their impact in the treatment of ovarian cancers. This review aims to summarize the recent researches and clinical progress on PARP inhibitors as novel target agents in ovarian cancer.

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A phase I study of ABT-888 (A) in combination with metronomic cyclophosphamide (C) in adults with refractory solid tumors and lymphomas.

Cited by 12 publications

References 0 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

PARP Inhibitor Treatment in Ovarian and Breast Cancer

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