Potentiation of anti-cancer agent cytotoxicity by the potent poly(ADP-ribose) polymerase inhibitors NU1025 and NU1064

Bowman, Karen J.; White, Alex William; Golding, BT; Griffin, RJ; Curtin, Nicola J.

doi:10.1038/bjc.1998.670

Cited by 130 publications

(62 citation statements)

References 19 publications

(20 reference statements)

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“…Antibiotics-antimycotics (100 units/ml synergize with conventional genotoxic chemotherapies, including topoisomerase I inhibitors, ionizing radiation and DNA alkylating agents. [19][20][21][22][23][24][25][26] The present studies were designed to determine whether PARP1 and CHK1 inhibitors interacted to cause DNA damage and whether signaling by the ERK1/2 pathway regulated this process. PARP1 inhibitors interacted with CHK1 inhibitors to kill mammary carcinoma cells.…”

Section: Methodsmentioning

confidence: 99%

PARP and CHK inhibitors interact to cause DNA damage and cell death in mammary carcinoma cells

Booth

Cruickshanks

Ridder

et al. 2013

Cancer Biology & Therapy

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Section: Methodsmentioning

confidence: 99%

PARP and CHK inhibitors interact to cause DNA damage and cell death in mammary carcinoma cells

Booth

Cruickshanks

Ridder

et al. 2013

Cancer Biology & Therapy

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“…A significant window seems to exist between the ability of a PARP inhibitor to potentiate therapeutic benefit versus potentiation of undesirable side effects (39,49). PARP inhibitors have not potentiated agents that do not damage DNA (50).…”

Section: Parp Inhibitionmentioning

confidence: 99%

Current Development of Clinical Inhibitors of Poly(ADP-Ribose) Polymerase in Oncology

Ratnam¹,

Low

2007

Clinical Cancer Research

270

214

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Poly(ADP-ribose) polymerase (PARP) is a nuclear enzyme that signals the presence of DNA damage by catalyzing the addition of ADP-ribose units to DNA, histones, and various DNA repair enzymes and by facilitating DNA repair. PARP has been gaining increasing interest as a therapeutic target for many diseases and especially for cancer. Inhibition of PARP potentiates the activity of DNA-damaging agents, such as alkylators, platinums, topoisomerase inhibitors, and radiation in in vitro and in vivo models. In addition, tumors with DNA repair defects, such as those arising from patients with BRCA mutations, may be more sensitive to PARP inhibition. At least five different companies have now initiated oncology clinical trials with PARP inhibitors, ranging in stage from phase 0 to phase 2. This review summarizes the preclinical and clinical data currently available for these agents and some of the challenges facing the clinical development of these agents.

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“…NU1025 (8-hydroxy-2-methyl-quinazolin-4-[3H]one), which is approximately 50 × more potent than 3AB as a PARP inhibitor (Griffin et al, 1995b; has recently been evaluated as a resistance modifier. NU1025 can enhance the cytotoxicity of some classes of DNA-damaging agents (monofunctional DNAalkylating agents, γ-irradiation and bleomycin) but not others (antimetabolites) in L1210 cells (Bowman et al, 1998). In order to investigate the potential of PARP inhibitors as modulators of the activity of topoisomerase inhibitors, the effect of NU1025 on camptothecin-and etoposide-induced cytotoxicity, DNA strand breaks and PARP activity was investigated.…”

mentioning

confidence: 99%

Differential effects of the poly (ADP-ribose) polymerase (PARP) inhibitor NU1025 on topoisomerase I and II inhibitor cytotoxicity in L1210 cells in vitro

et al. 2001

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The potent novel poly(ADP-ribose) polymerase (PARP) inhibitor, NU1025, enhances the cytotoxicity of DNA-methylating agents and ionizing radiation by inhibiting DNA repair. We report here an investigation of the role of PARP in the cellular responses to inhibitors of topoisomerase I and II using NU1025. The cytotoxicity of the topoisomerase I inhibitor, camptothecin, was increased 2.6-fold in L1210 cells by co-incubation with NU1025. Camptothecin-induced DNA strand breaks were also increased 2.5-fold by NU1025 and exposure to camptothecin-activated PARP. In contrast, NU1025 did not increase the DNA strand breakage or cytotoxicity caused by the topoisomerase II inhibitor etoposide. Exposure to etoposide did not activate PARP even at concentrations that caused significant levels of apoptosis. Taken together, these data suggest that potentiation of camptothecin cytotoxicity by NU1025 is a direct result of increased DNA strand breakage, and that activation of PARP by camptothecin-induced DNA damage contributes to its repair and consequently cell survival. However, in L1210 cells at least, it would appear that PARP is not involved in the cellular response to etoposide-mediated DNA damage. On the basis of these data, PARP inhibitors may be potentially useful in combination with topoisomerase I inhibitor anticancer chemotherapy. © 2001 Cancer Research Campaign http://www.bjcancer.com

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Potentiation of anti-cancer agent cytotoxicity by the potent poly(ADP-ribose) polymerase inhibitors NU1025 and NU1064

Abstract: Summary The ability of the potent poly(ADP-rbose) polymerase (PARP) inhibitor. NU1025 (8-hydroxy-2-methyl-quinazolin-4-[3H] Cleaver and Morgan. 1991: Lautier et al. 1993: de Murcia and Menissier de Murcia. 1994: Lindahl et al. 1995

Cited by 130 publications

References 19 publications

PARP and CHK inhibitors interact to cause DNA damage and cell death in mammary carcinoma cells

PARP and CHK inhibitors interact to cause DNA damage and cell death in mammary carcinoma cells

Current Development of Clinical Inhibitors of Poly(ADP-Ribose) Polymerase in Oncology

Differential effects of the poly (ADP-ribose) polymerase (PARP) inhibitor NU1025 on topoisomerase I and II inhibitor cytotoxicity in L1210 cells in vitro

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