ArticleBritish journal of cancer2010
Central nervous system penetration and enhancement of temozolomide activity in childhood medulloblastoma models by poly(ADP-ribose) polymerase inhibitor AG-014699.
Article in British journal of cancer, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
32 citing papers in PubMed, 55 citations in OpenAlex.
- Phase II study of irinotecan in combination with temozolomide (TEMIRI) in children with recurrent or refractory medulloblastoma: a joint ITCC and SIOPE brain tumor study.Neuro-oncology · 2013Trial
- Combination of PARP and WEE1 inhibitorsOncology reports · 2023Article
- The Role of PARP Inhibitors in Patients with Primary Malignant Central Nervous System Tumors.Current treatment options in oncology · 2022Review
- Article
- Small Molecule Inhibitors in Adult High-Grade Glioma: From the Past to the Future.Frontiers in oncology · 2022Review
- Medulloblastoma and the DNA Damage Response.Frontiers in oncology · 2022Review
- Application of Regulatory Cell Death in Cancer: Based on Targeted Therapy and Immunotherapy.Frontiers in immunology · 2022Review
- Understanding and overcoming resistance to PARP inhibitors in cancer therapy.Nature reviews. Clinical oncology · 2021Review
- Veliparib Is an Effective Radiosensitizing Agent in a Preclinical Model of Medulloblastoma.Frontiers in molecular biosciences · 2021Article
- Rucaparib: A Review in Ovarian Cancer.Targeted oncology · 2019Review
- Article
- The germline variants in DNA repair genes in pediatric medulloblastoma: a challenge for current therapeutic strategies.BMC cancer · 2017Article
- Rucaparib: First Global Approval.Drugs · 2017Review
- Delineation of MGMT Hypermethylation as a Biomarker for Veliparib-Mediated Temozolomide-Sensitizing Therapy of Glioblastoma.Journal of the National Cancer Institute · 2016Article
- Efficacy of PARP Inhibitor Rucaparib in Orthotopic Glioblastoma Xenografts Is Limited by Ineffective Drug Penetration into the Central Nervous System.Molecular cancer therapeutics · 2015Article
- Poly(ADP-ribose) polymerase inhibitors in Ewing sarcoma.Current opinion in oncology · 2014Review
- Molecular profiling of childhood cancer: Biomarkers and novel therapies.BBA clinical · 2014Review
- Overcoming multiple drug resistance mechanisms in medulloblastoma.Acta neuropathologica communications · 2014Article
- Tumour cell retention of rucaparib, sustained PARP inhibition and efficacy of weekly as well as daily schedules.British journal of cancer · 2014Article
- The rationale for targeted therapies in medulloblastoma.Neuro-oncology · 2014Review
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
12 authors at 2 institutions in 2 countries.
Funding
Abstract
backgroundTemozolomide shows activity against medulloblastoma, the most common malignant paediatric brain tumour. Poly(ADP-ribose) polymerase (PARP) inhibitors enhance temozolomide activity in extracranial adult and paediatric human malignancies.
methodsWe assessed the effect of AG-014699, a clinically active PARP inhibitor, on temozolomide-induced growth inhibition in human medulloblastoma models. Pharmacokinetic, pharmacodynamic and toxicity assays were performed in tumour-bearing mice.
resultsSensitivity to temozolomide in vitro was consistent with methylguanine methyltransferase (MGMT) and DNA mismatch repair (MMR) status; MGMT(+) MMR(+) D384Med cells (temozolomide GI(50)=220 μM), representative of most primary medulloblastomas, were sensitised fourfold by AG-014699; MGMT⁻ MMR(+) D425Med cells were hypersensitive (GI(50)=9 μM) and not sensitised by AG-014699, whereas MGMT(+) MMR⁻ temozolomide-resistant D283Med cells (GI₅₀=807 μM) were sensitised 20-fold. In xenograft models, co-administration of AG-014699 produced an increase in temozolomide-induced tumour growth delay in D384Med xenografts. Consistent with the in vitro data, temozolomide caused complete tumour regressions of D425Med xenografts, whereas D283Med xenografts were relatively resistant. AG-014699 was not toxic, accumulated and reduced PARP activity ≥75% in xenograft and brain tissues.
conclusionWe show for the first time central nervous system penetration and inhibition of brain PARP activity by AG-014699. Taken together with our in vitro chemosensitisation and toxicity data, these findings support further evaluation of the clinical potential of AG-014699-temozolomide combinations in intra-cranial malignancies.
Indexed as
Identifiers
What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.