In vivo studies of the PARP inhibitor, AZD-2281, in combination with fractionated radiotherapy: An exploration of the therapeutic ratio

Gani, Cihan; Coackley, Carla; Kumareswaran, Ramanan; Schütze, Christina; Krause, Mechthild; Zafarana, Gaetano; Bristow, Robert G.

doi:10.1016/j.radonc.2015.08.003

Cited by 54 publications

(42 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This increase in DNA damage repair may be attributed to the dysregulation of NHEJ and activation of DNAPK, resulting in low levels of persistent DSBs and rapid dephosphorylation of DNAPK that was not observed in the HR proficient xenograft model. In contrast to results shown in prostate cancer [18], no radiosensitization was observed in the BRCA2 germline mutant tumor in response to treatment with AZD-2281. This is consistent with previous observations made by Karnak et al, where treatment with olaparib sensitized pancreatic cancer cells lines to IR in vitro but failed to reduce tumor growth in vivo [26].…”

Section: Discussioncontrasting

confidence: 99%

“…While PARP inhibition is functionally silent in HR proficient cells, PARP inhibition leads to the accumulation of SSBs and the development of DSBs in cells deficient in HR [19, 20]. A number of preclinical studies in a variety of cancer types, such as breast, ovarian and prostate cancer, have shown that PARP inhibition can enhance the effects of various chemotherapies and IR [12–15, 18, 20, 23, 24, 25]. In pancreatic cancer, however, responses to treatment with PARP inhibitors have been less impressive [26].…”

Section: Discussionmentioning

confidence: 99%

“…In addition to its function in BER, PARP has also been shown to be involved in the regulation of DSB repair pathways [17, 18, 27]. PARP has been shown to regulate repair through the error-prone NHEJ pathway by inhibiting DNAPK activation [27].…”

Section: Discussionmentioning

confidence: 99%

“…Animals (n = 10 per treatment group) were treated for 7 days with 150mg/kg olaparib by oral gavage (po), a single dose of 12Gy or both according to the schedule shown in Fig 1A. Animals were irradiated using an X-RAD 225Cx small animal X-Ray irradiator at 225 kVp, 13 mA setting (dose rate of 3.37 Gy/min) with a 1 cm or 1.5 cm collimator and 0.3 mm Cu filter [18]. Four animals per group were sacrificed at 24 hours following radiation treatment.…”

Section: Methodsmentioning

confidence: 99%

See 3 more Smart Citations

Effects of Combined Treatment with Ionizing Radiation and the PARP Inhibitor Olaparib in BRCA Mutant and Wild Type Patient-Derived Pancreatic Cancer Xenografts

et al. 2016

Self Cite

View full text Add to dashboard Cite

BackgroundThe BRCA2 gene product plays an important role in DNA double strand break repair. Therefore, we asked whether radiation sensitivity of pancreatic cancers developing in individuals with germline BRCA2 mutations can be enhanced by agents that inhibit poly (ADP-ribose) polymerase (PARP).MethodsWe compared the sensitivity of two patient-derived pancreatic cancer xenografts, expressing a truncated or wild type BRCA 2, to ionizing radiation alone or in combination with olaparib (AZD-2281). Animals were treated with either a single dose of 12Gy, 7 days of olaparib or 7 days of olaparib followed by a single dose of 12Gy. Response was assessed by tumour growth delay and the activation of damage response pathways.ResultsThe BRCA2 mutated and wild type tumours showed similar radiation sensitivity, and treatment with olaparib did not further sensitize either model when compared to IR alone.ConclusionsWhile PARP inhibition has been shown to be effective in BRCA-mutated breast and ovarian cancers, it is less well established in pancreatic cancer patients. Our results show no radiosensitization in a germline BRCA 2 mutant and suggest that combining PARP inhibition and IR may not be beneficial in BRCA 2 related pancreatic tumors.

show abstract

Section: Discussioncontrasting

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

Effects of Combined Treatment with Ionizing Radiation and the PARP Inhibitor Olaparib in BRCA Mutant and Wild Type Patient-Derived Pancreatic Cancer Xenografts

et al. 2016

Self Cite

View full text Add to dashboard Cite

show abstract

“…More, due to their properties, these tumours do not respond to targeted hormonal therapies. Consequently, many targeted therapies using inhibitors of poly (ADP-ribose) polymerase (PARP) or anti-EGFR monoclonal antibodies or combined therapies like anti-EGFR monoclonal antibodies/EGFR tyrosine kinase inhibitors or chemotherapy/radiotherapy are currently in development [35] [36] [37] [38] [39]. However, the management of TNBL carcinomas is still not standardized.…”

Section: Introductionmentioning

confidence: 99%

Cytotoxicity Study of Gold Nanoparticles on the Basal-Like Triple-Negative HCC-1937 Breast Cancer Cell Line

Massard¹,

Dubois²,

Raspal³

et al. 2018

JBNB

View full text Add to dashboard Cite

The Triple Negative "Basal-like" breast cancer (TNBL) tumours have a high proliferative capacity and develop a resistance phenotype associated with metastases. However, the management of TNBL carcinomas is still not standardized. Among the promising trails, gold nanoparticles could be a relevant tool for the development of a targeted treatment for this breast cancer subtype in monotherapy, associated and/or conjugated with other drugs. In this work, we report the cytotoxicity impact of gold nanoparticles wrapped in Poly-Ethylene Glycol (PEG) on the TNBL HCC-1937 breast cancer cell line. PEG-coated gold nanoparticles (PEG-Au NPs) were synthesized by a two-step method using a reduction process followed by a post-functionalization called PEGylation. PEG-Au NPs were characterized using transmission electron microscopy and X-ray diffraction. The gold content of the samples was determined using atomic absorption spectrometer. The cytotoxicity tests were performed using Sulforhodamine B survival test and resazurin viability test. PEG-Au NPs impact analysis on HCC1937 TNBL cell line showed a clear toxic action of type dose dependent and at long term. These PEGylated gold nanoparticles present a promising tool for the development of tumor-specific radiosensitizing vectors, with or without the association of other treatment strategies.

show abstract

Nanomedicine for the Treatment of Advanced Prostate Cancer

Vicente‐Ruiz

Serrano‐Martí

Armiñán

et al. 2020

Advanced Therapeutics

View full text Add to dashboard Cite

Current prostate cancer (PCa) treatment options include hormonal therapy, chemotherapy, immunotherapy, and radiotherapy; however, a lack of targeting and overall efficiency has failed to improve survival rates or reduce unwanted side‐effects in advanced stage PCa patients. The modification of existing therapeutics, including their reformulation as nanomedicines, can increase stability in plasma, enhance tumor targeting, and improve pharmacokinetics to foster improvements in patient outcomes. This review now describes those nanomedicinal approaches to advanced PCa treatment under evaluation in both preclinical and clinical studies. Despite the current advantages provided by nanomedicine in PCa treatment, there exists the opportunity to improve the design of novel therapeutic approaches. Therefore, this review also highlights the importance of identifying novel functional biomarkers to stratify patients and guide nanomedicinal design. Finally, the authors describe strategies employed to enhance the passive accumulation of nanomedicines in tumors and discuss the enormous potential of combination therapies that target tumor cells and the all‐important tumor microenvironment to reduce tumor growth and overcome therapeutic resistance.

show abstract

In vivo studies of the PARP inhibitor, AZD-2281, in combination with fractionated radiotherapy: An exploration of the therapeutic ratio

Cited by 54 publications

References 37 publications

Effects of Combined Treatment with Ionizing Radiation and the PARP Inhibitor Olaparib in BRCA Mutant and Wild Type Patient-Derived Pancreatic Cancer Xenografts

Effects of Combined Treatment with Ionizing Radiation and the PARP Inhibitor Olaparib in BRCA Mutant and Wild Type Patient-Derived Pancreatic Cancer Xenografts

Cytotoxicity Study of Gold Nanoparticles on the Basal-Like Triple-Negative HCC-1937 Breast Cancer Cell Line

Nanomedicine for the Treatment of Advanced Prostate Cancer

Contact Info

Product

Resources

About