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

The ability of the potent poly(ADP-ribose) polymerase (PARP) inhibitor, NU1025 (8-hydroxy-2-methyl-quinazolin-4-[3H]one) to potentiate the cytotoxicity of a panel of mechanistically diverse anti-cancer agents was evaluated in L1210 cells. NU1025 enhanced the cytotoxicity of the DNA-methylating agent MTIC, gamma-irradiation and bleomycin 3.5-, 1.4- and 2-fold respectively. The cytotoxicities of the thymidylate synthase inhibitor, nolatrexed, and the cytotoxic nucleoside, gemcitabine, were not increased. Potentiation of MTIC cytotoxicity by a delayed exposure to NU1025 was equally effective as by a simultaneous exposure to NU1025, indicating that the effects of NU1025 were mediated by an inhibition of the cellular recovery. The recovery from potentially lethal gamma-irradiation damage cytotoxicity in plateau-phase cells was also inhibited by NU1025. Investigation of DNA strand breakage and repair in gamma-irradiated cells by alkaline elution demonstrated that NU1025 caused a marked retardation of DNA repair. A structurally different PARP inhibitor, NU1064 (2-methylbenzimidazole-4-carboxamide), also potentiated the cytotoxicity of MTIC, to a similar extent to NU1025. NU1064 potentiated a sublethal concentration of a DNA methylating agent in a concentration-dependent manner. Collectively, these data suggest that the most suitable cytotoxic agents for use in combination with PARP inhibitors are methylating agents, bleomycin and ionizing radiation, but not anti-metabolites.

• Publication year

  1998

• Venue

  British Journal of Cancer

• Publication date

  1998-11-01

• Fields of study

  Biology, Medicine, Chemistry

• Identifiers
  DOI 10.1038/bjc.1998.670PMID 9823965PMCID 2063197
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Fludarabine- and gemcitabine-induced apoptosis: incorporation of analogs into DNA is a critical event

  2004cited by this paper
• Temozolomide: a review of its discovery, chemical properties, pre-clinical development and clinical trials.

  1997cited by this paper
• Novel Benzimidazole and Quinazolinone Inhibitors of the DNA Repair Enzyme Poly(ADP‐ribose)polymerase*

  1996cited by this paper
• AG337, a novel lipophilic thymidylate synthase inhibitor: in vitro and in vivo preclinical studies

  1996cited by this paper
• Mice lacking ADPRT and poly(ADP-ribosyl)ation develop normally but are susceptible to skin disease.

  1995cited by this paper
• Molecular genetic systems to study the role of poly(ADP-ribosyl)ation in the cellular response to DNA damage.

  1995cited by this paper
• Post-translational modification of poly(ADP-ribose) polymerase induced by DNA strand breaks.

  1995cited by this paper
• Gemcitabine: metabolism, mechanisms of action, and self-potentiation.

  1995cited by this paper
• Novel potent inhibitors of the DNA repair enzyme poly(ADP-ribose)polymerase (PARP).

  1995cited by this paper
• Potentiation of temozolomide-induced cytotoxicity: a comparative study of the biological effects of poly(ADP-ribose) polymerase inhibitors.

  1995influential reference
• Poly(ADP-ribose) polymerase: a molecular nick-sensor.

  1994cited by this paper
• Cytotoxic mechanisms of 5-fluoropyrimidines. Relationships with poly(ADP-ribose) polymerase activity, DNA strand breakage and incorporation into nucleic acids.

  1993cited by this paper
• Overproduction of the poly(ADP‐ribose) polymerase DNA‐binding domain blocks alkylation‐induced DNA repair synthesis in mammalian cells.

  1993cited by this paper
• Specific proteolytic cleavage of poly(ADP-ribose) polymerase: an early marker of chemotherapy-induced apoptosis.

  1993cited by this paper
• Molecular and biochemical features of poly (ADP-ribose) metabolism

  1993cited by this paper
• Histone shuttle driven by the automodification cycle of poly(ADP‐ribose) polymerase

  1993cited by this paper
• Role of poly(ADP-ribose) formation in DNA repair

  1992cited by this paper
• Relation between carcinogenesis, chromatin structure and poly(ADP-ribosylation) (review).

  1991cited by this paper
• Poly(ADP-ribose)polymerase: a perplexing participant in cellular responses to DNA breakage.

  1991cited by this paper
• Effect of PD 128763, a new potent inhibitor of poly(ADP-ribose) polymerase, on X-ray-induced cellular recovery processes in Chinese hamster V79 cells.

  1991cited by this paper
• Mechanism of cell death following thymidylate synthase inhibition: 2'-deoxyuridine-5'-triphosphate accumulation, DNA damage, and growth inhibition following exposure to CB3717 and dipyridamole.

  1991cited by this paper
• Effects of PD 128763, a New Potent Inhibitor of Poly(ADP-Ribose) Polymerase, on X-Ray-Induced Cellular Recovery Processes in Chinese Hamster V79 Cells'

  1991cited by this paper
• Adenosine-diphosphoribosyltransferase inhibitors can protect against or potentiate the cytotoxicity of S-phase acting drugs.

  1988cited by this paper
• Enhancement of bleomycin activity by 3-aminobenzamide, a poly (ADP-ribose) synthesis inhibitor, in vitro and in vivo.

  1988influential reference
• Antitumor activity and pharmacokinetics in mice of 8-carbamoyl-3-methyl-imidazo[5,1-d]-1,2,3,5-tetrazin-4(3H)-one (CCRG 81045; M & B 39831), a novel drug with potential as an alternative to dacarbazine.

  1987cited by this paper
• Increased protein ADPribosylation in HeLa cells exposed to the anti-cancer drug methotrexate.

  1986influential reference
• Disturbances in DNA precursor metabolism associated with exposure to an inhibitor of poly(ADP-ribose) synthetase.

  1986cited by this paper
• Specificity of inhibitors of poly(ADP-ribose) synthesis. Effects on nucleotide metabolism in cultured cells.

  1985cited by this paper
• Inhibitors of poly(adenosine diphosphoribose) synthetase, examination of metabolic perturbations, and enhancement of radiation response in Chinese hamster cells.

  1985cited by this paper
• Potentiation of cell killing by inhibitors of poly(adenosine diphosphate-ribose) synthesis in bleomycin-treated Chinese hamster ovary cells.

  1985cited by this paper
• Differential toxicity of 3-aminobenzamide to wild-type and 6-thioguanine-resistant Chinese hamster cells by interference with pathways of purine biosynthesis.

  1984cited by this paper
• In situ detection of mycoplasma contamination in cell cultures by fluorescent Hoechst 33258 stain.

  1977cited by this paper

• Targeting DNA Topoisomerase I for the Treatment of Cancer: Past, Present and Future.

  2025cites this paper
• Antitumor activity of rucaparib plus PLX038A in serous endometrial carcinoma

  2025cites this paper
• Investigating the possible NU1025 drug delivery with graphene and boron nitride nanosheets using DFT and molecular docking computations

  2025cites this paper
• Schizocommunin-inspired heterocyclic hybrid molecules

  2024cites this paper
• Substitutions at the C-8 position of quinazolin-4-ones improve the potency of nicotinamide site binding tankyrase inhibitors

  2024cites this paper
• Editorial: DNA repair and nucleic acid therapeutics in cancer

  2023cites this paper
• Role of arachidonic acid metabolism in intervertebral disc degeneration: identification of potential biomarkers and therapeutic targets via multi-omics analysis and artificial intelligence strategies

  2023cites this paper
• TAF1D Functions as a Novel Biomarker in Osteosarcoma

  2023cites this paper
• A novel cuproptosis-related subtypes and gene signature associates with immunophenotype and predicts prognosis accurately in neuroblastoma

  2022cites this paper
• Expression level of long non-coding RNA colon adenocarcinoma hypermethylated serves as a novel prognostic biomarker in patients with thyroid carcinoma

  2021cites this paper
• PARP Inhibitors and Myeloid Neoplasms: A Double-Edged Sword

  2021cites this paper
• Poly(ADP-ribose) polymerase inhibition: past, present and future

  2020cites this paper
• The chromatin remodeler ALC1 underlies resistance to PARP inhibitor treatment

  2020cites this paper
• Mammalian DNA base excision repair: Dancing in the moonlight.

  2020cites this paper
• The Development of Rucaparib/Rubraca®: A Story of the Synergy Between Science and Serendipity

  2020cites this paper
• Poly(ADP-Ribose) Glycohydrolase (PARG) vs. Poly(ADP-Ribose) Polymerase (PARP) – Function in Genome Maintenance and Relevance of Inhibitors for Anti-cancer Therapy

  2020cites this paper
• A therapeutic update on PARP inhibitors: implications in the treatment of glioma.

  2020cites this paper
• NU1025 | MedChemExpress

  2020influential citation
• Poly(ADP-ribose) polymerase inhibition: past, present and future

  2020cites this paper
• Novel quinazolin-4-one derivatives as potentiating agents of doxorubicin cytotoxicity.

  2019cites this paper
• Topoisomerases and cancer chemotherapy: recent advances and unanswered questions

  2019cites this paper
• The Story of Rucaparib (Rubraca)

  2019cites this paper
• Poly (ADP-Ribose) Polymerases (PARPs) and PARP Inhibitor-Targeted Therapeutics.

  2018cites this paper
• Design and synthesis of 2-(4,5,6,7-tetrahydrothienopyridin-2-yl)-benzoimidazole carboxamides as novel orally efficacious Poly(ADP-ribose)polymerase (PARP) inhibitors.

  2018cites this paper
• Targeting DNA Damage Response Pathways in Cancer

  2017cites this paper
• The Use of PARP Inhibitors in Cancer Therapy: Use as Adjuvant with Chemotherapy or Radiotherapy, Use as a Single Agent in Susceptible Patients, and Techniques Used to Identify Susceptible Patients.

  2017cites this paper
• Lead Discovery of Dual G-Quadruplex Stabilizers and Poly(ADP-ribose) Polymerases (PARPs) Inhibitors: A New Avenue in Anticancer Treatment.

  2017cites this paper
• Total synthesis of penipanoid C, 2-(4-hydroxybenzyl)quinazolin-4(3H)-one and NU1025

  2016cites this paper
• Concepts and Molecular Aspects in the Polypharmacology of PARP‐1 Inhibitors

  2016cites this paper
• PARP inhibitor combination therapy.

  2016cites this paper
• Structural Requirements of Some 2-(1-Propylpiperidin-4-yl)-1H-benzimidazole-4-carboxamide Derivatives as Poly (ADP-Ribose) Polymerase (PARP) for the Treatment of Cancer: QSAR Approach

  2015cites this paper
• PARP Enzymes are Potential Targets for Cancer Chemotherapy

  2015cites this paper
• Efficacy of PARP Inhibitor Rucaparib in Orthotopic Glioblastoma Xenografts Is Limited by Ineffective Drug Penetration into the Central Nervous System

  2015cites this paper
• History of the Discovery of Poly (ADP-ribose)

  2015cites this paper
• InhibitorRucaparib inOrthotopic Glioblastoma Xenografts Is Limited by Ineffective Drug Penetration into the Central Nervous System

  2015cites this paper
• Rapamycin-resistant poly (ADP-ribose) polymerase-1 overexpression is a potential therapeutic target in lymphangioleiomyomatosis.

  2014cites this paper
• Targeted Molecular Therapy for Patients with Ovarian Cancer

  2014cites this paper
• Poly (ADP-ribose) Polymerase Inhibitors in Cancer Treatment

  2014cites this paper
• Structural Requirements of Some 2-(1-Propylpiperidin-4-yl)-1H-benzimidazole-4-carboxamide Derivatives as Poly (ADP-Ribose) Polymerase (PARP) for the Treatment of Cancer: QSAR Approach

  2014cites this paper
• Effect of DNA repair deficiencies on the cytotoxicity of drugs used in cancer therapy - a review.

  2014influential citation
• Design, synthesis and biological evaluation of novel imidazo[4,5-c]pyridinecarboxamide derivatives as PARP-1 inhibitors.

  2013cites this paper
• PARP and PARP Inhibitor Therapeutics

  2013cites this paper
• Base excision repair of radiation-induced DNA damage in mammalian cells

  2013cites this paper
• Bioinformatics analysis reveals potential candidate drugs for different subtypes of glioma

  2013cites this paper
• Therapeutic applications of PARP inhibitors: anticancer therapy and beyond.

  2013cites this paper
• Inhibiting the DNA damage response as a therapeutic manoeuvre in cancer

  2013influential citation
• Repair of DNA Strand Breaks in a Minichromosome In Vivo: Kinetics, Modeling, and Effects of Inhibitors

  2013cites this paper
• PARP and CHK inhibitors interact to cause DNA damage and cell death in mammary carcinoma cells

  2013cites this paper
• DNA repair dysregulation from cancer driver to therapeutic target

  2012cites this paper
• Poly(ADP-ribose) Polymerase 1 Modulates the Lethality of CHK1 Inhibitors in Mammary Tumors

  2012cites this paper
• Formation and repair of DNA double-strand breaks caused by ionizing radiation in the Epstein-Barr virus minichromosome

  2012cites this paper
• Poly(ADP-ribose) Polymerase 1 Modulates the Lethality of CHK1 Inhibitors in Mammary Tumors □ S

  2012cites this paper
• The potential of the PARP-1 inhibitor, AGO14699, in human cancers defective in homologous recombination DNA repair

  2012cites this paper
• Chapter 4 – The role of PARP in DNA repair and its therapeutic exploitation

  2012cites this paper
• Targeting DNA repair and the cell cycle in glioblastoma

  2012cites this paper
• Papel de Parp-1 en procesos de muerte celular inducida por el tratamiento con el antineoplásico Doxorrubicina

  2011cites this paper
• The role of poly adenosine diphosphate ribose polymerase inhibitors in breast and ovarian cancer: Current status and future directions

  2011cites this paper
• Strategies employed for the development of PARP inhibitors.

  2011cites this paper
• Modulación por la poli (ADP-Ribosa) polimerasa-1 de la expresión genética durante la carcinogénesis epidérmica

  2011cites this paper
• Towards Tailored Therapy of Glioblastoma Multiforme

  2011cites this paper
• Novel rational drug design strategies with potential to revolutionize malaria chemotherapy.

  2011cites this paper
• Función de PARP-1 en rutas de inestabilidad genómica e hipoxia: implicaciones en el control tumoral

  2011cites this paper
• Design, Development, and Evaluation of Tools to Study Cellular ADP-ribose Polymer Metabolism

  2011cites this paper
• Preclinical Development The Clinically Active PARP Inhibitor AG 014699 Ameliorates Cardiotoxicity but Does Not Enhance the Ef fi cacy of Doxorubicin , despite Improving Tumor Perfusion and Radiation Response in Mice

  2011cites this paper
• The Clinically Active PARP Inhibitor AG014699 Ameliorates Cardiotoxicity but Does Not Enhance the Efficacy of Doxorubicin, despite Improving Tumor Perfusion and Radiation Response in Mice

  2011cites this paper
• The use of PARP inhibitors in cancer therapy: use as adjuvant with chemotherapy or radiotherapy; use as a single agent in susceptible patients; techniques used to identify susceptible patients.

  2011cites this paper
• Inhibitors of DNA Repair and Response to Ionising Radiation

  2011cites this paper
• Molecular Determinants of Radiation Response

  2011cites this paper
• The role of PARP in DNA repair and its therapeutic exploitation

  2011cites this paper
• The emerging role of poly(ADP-Ribose) polymerase inhibitors in cancer treatment.

  2011cites this paper
• Evaluation of focal adhesion kinase as a novel radiosensitising target

  2010cites this paper
• Methylation of PARP-1 promoter involved in the regulation of benzene-induced decrease of PARP-1 mRNA expression.

  2010cites this paper
• Small‐molecule Inhibitors of DNA Base Excision Repair

  2010cites this paper
• Increased cytotoxicity of an unusual DNA topoisomerase II inhibitor compound C-1305 toward HeLa cells with downregulated PARP-1 activity results from re-activation of the p53 pathway and modulation of mitotic checkpoints.

  2010cites this paper
• Pre-clinical and clinical evaluation of PARP inhibitors as tumour-specific radiosensitisers.

  2010cites this paper
• Poly(ADP-ribosyl)ation polymerases: mechanism and new target of anticancer therapy

  2010cites this paper
• Epigenetic mediated transcriptional activation of PARP-1 participates in silica-associated malignant transformation of human bronchial epithelial cells.

  2010cites this paper
• Novel therapeutics in combination with radiotherapy to improve cancer treatment: rationale, mechanisms of action and clinical perspective.

  2010cites this paper
• Genetic polymorphisms in XRCC1 associated with radiation therapy in prostate cancer

  2010cites this paper
• Poly(ADP-ribose) polymerase inhibitors in cancer treatment: a clinical perspective.

  2010cites this paper
• Evolution of poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors. From concept to clinic.

  2010cites this paper
• Oral Poly(ADP-Ribose) Polymerase-1 Inhibitor BSI-401 Has Antitumor Activity and Synergizes with Oxaliplatin against Pancreatic Cancer, Preventing Acute Neurotoxicity

  2009cites this paper
• Novel role for the transient receptor potential channel TRPM2 in prostate cancer cell proliferation

  2009cites this paper
• In vitro and In vivo Radiosensitization of Glioblastoma Cells by the Poly ( ADP-Ribose ) Polymerase Inhibitor E 7016

  2009cites this paper
• DNA damage, signalling and repair after exposure of cells to the sulphur mustard analogue 2-chloroethyl ethyl sulphide.

  2009cites this paper
• A Phase IB Trial of Intravenous INO-1001 Plus Oral Temozolomide in Subjects with Unresectable Stage-III or IV Melanoma

  2009cites this paper
• PARP1 expression in pediatric central nervous system tumors

  2009cites this paper
• Synthesis of isoquinolinone-based tetracycles as poly (ADP-ribose) polymerase-1 (PARP-1) inhibitors.

  2009cites this paper
• Head and neck cancer radiosensitization by the novel poly(ADP‐ribose) polymerase inhibitor GPI‐15427

  2009cites this paper
• Effect of silicon dioxide on expression of poly (ADP‐Ribose) polymerase mRNA and protein

  2009cites this paper
• Inhibition of Poly ( ADP-ribose ) polymerase – PARP

  2009influential citation
• In vitro and In vivo Radiosensitization of Glioblastoma Cells by the Poly (ADP-Ribose) Polymerase Inhibitor E7016

  2009cites this paper
• Telomere Dysfunction and the DNA Damage Response

  2009cites this paper
• Synthesis of New 4(3H)-Quinazolinone Derivatives by Reaction of 3-Amino-2(1H)-thioxo-4(3H)-quinazolinone with Selected Chloroformates: Ammonolysis of 3-Ethoxycarbonylamino-2-ethoxycarbonylthio-4(3h)-quinazolinone, Part 21

  2009cites this paper
• Targeting the DNA damage response in cancer.

  2009cites this paper
• PARP inhibitors and cancer therapy - early results and potential applications.

  2008cites this paper
• Rapid regulation of telomere length is mediated by poly(ADP-ribose) polymerase-1

  2008cites this paper
• Mechanisms of Chemoresistance to Alkylating Agents in Malignant Glioma

  2008cites this paper
• Targeting poly (ADP) ribose polymerase I (PARP-1) and PARP-1 interacting proteins for cancer treatment.

  2008cites this paper
• INO-1001, a novel inhibitor of poly(ADP-ribose) polymerase, enhances tumor response to doxorubicin

  2008cites this paper