Computational Approaches Toward Development of Topoisomerase I Inhibitor: A Clinically Validated Target

2021 ◽  
pp. 441-462
Author(s):  
Arindam Talukdar ◽  
Sourav Pal
Keyword(s):  
Topoisomerase I ◽  
Computational Approaches ◽  
Topoisomerase I Inhibitor

Pharmacokinetics, tissue distribution, and metabolism of novel DNA topoisomerase I inhibitor yuanhuacine in rabbit

Xenobiotica ◽  
2009 ◽  
Vol 39 (3) ◽  
pp. 273-281 ◽  
Author(s):  
S. X. Zhang ◽  
P. W. Yang ◽  
D. C. Zhang ◽  
W. Q. Dong ◽  
F. H. Zhang ◽  
...  
Keyword(s):  
Tissue Distribution ◽  
Topoisomerase I ◽  
Dna Topoisomerase I ◽  
Dna Topoisomerase ◽  
Topoisomerase I Inhibitor

Isodiospyrin as a novel human DNA topoisomerase I inhibitor

2003 ◽  
Vol 66 (10) ◽  
pp. 1981-1991 ◽  
Author(s):  
Chun-Yuan Ting ◽  
Chia-Tse Hsu ◽  
Hsiang-Ting Hsu ◽  
Jin-Shan Su ◽  
Tzong-Yueh Chen ◽  
...  
Keyword(s):  
Topoisomerase I ◽  
Dna Topoisomerase I ◽  
Dna Topoisomerase ◽  
Topoisomerase I Inhibitor ◽  
Human Dna ◽  
Human Dna Topoisomerase I

Wide application of a novel topoisomerase I inhibitor-based drug conjugation technology

2016 ◽  
Vol 26 (20) ◽  
pp. 5069-5072 ◽  
Author(s):  
Yusuke Ogitani ◽  
Yuki Abe ◽  
Takuma Iguchi ◽  
Junko Yamaguchi ◽  
Tomoko Terauchi ◽  
...  
Keyword(s):  
Topoisomerase I ◽  
Topoisomerase I Inhibitor ◽  
Drug Conjugation

Efficacy of DAN-222, a novel investigational polymeric nanoparticle with topoisomerase I inhibitor, as monotherapy in breast cancer models and when combined with PARP inhibitor.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 1081-1081
Author(s):  
Ashley P Wright ◽  
Jodi D Bradley ◽  
Timothy Hagerty ◽  
Emily A Wyatt
Keyword(s):  
Breast Cancer ◽  
Tumor Growth ◽  
Growth Inhibition ◽  
Tumor Cells ◽  
Topoisomerase I ◽  
Parp Inhibitor ◽  
Parp Inhibitors ◽  
Topoisomerase I Inhibitor ◽  
Polymeric Nanoparticle ◽  
Cancer Tumor

1081 Background: Patients with BRCA-positive HER2-negative breast cancer benefit from PARP inhibitor therapy, but additional benefit is still desired. PARP inhibition alone does not prevent all mechanisms for repairing damage to DNA such as homologous recombination repair. An attractive combination for treating such patients would be combining a topoisomerase I inhibitor with a PARP inhibitor given the dual mechanism this would provide for DNA damage and inhibited repair, leading to tumor cell death. This combination has been tried in multiple phase 1 studies, but myelotoxicity prevented the combination from being evaluated further. DAN-222 is a novel investigational polymeric nanoparticle conjugated with camptothecin, a topoisomerase I inhibitor, that provides significant accumulation of drug in tumor tissues via the enhanced permeability and retention (EPR) effect and significantly reduced bone marrow exposure compared to native chemotherapy. These observations underscore the potential advantages of DAN-222 alone as well as in combination with other agents such as PARP inhibitors in solid tumors. Here, we report the effects of DAN-222 monotherapy and in combination with a PARP inhibitor on the growth inhibition in an HRD+ TNBC breast cancer (MDA-MB-436) and an HRD- ovarian (OVCAR3) xenograft mouse model. Methods: HRD+ breast cancer tumor cells (MDA-MB-436) were implanted into female NCr nu/nu mice and HRD- ovarian cancer tumor cells (OVCAR3) were implanted into female CB.17 SCID mice. Mice were randomized to vehicle or treatment arms until tumors reached 2000 mm3 or day 45 (MDA-MB-436) or 1000mm3 or day 45 (OVCAR3). The groups evaluated include multiple dose levels of DAN-222 as monotherapy and those also combined with niraparib. Results: Results were consistent in both the HRD+ and HRD- tumor models with profound dose-response of DAN-222 monotherapy inhibiting tumor growth. Additionally, synergy was demonstrated when DAN-222 was combined with niraparib, clearly evident with low doses of both products when used in combination. The table below highlights the synergy of the combination of DAN-222 at 0.3 mg/kg and niraparib at 25 mg/kg above each agent alone on the tumor growth inhibition in the MDA-MB-436 xenograft. Conclusions: Combining a PARP inhibitor with a topoisomerase I inhibitor delivered via this polymeric nanoparticle delivery system (DAN-222) has synergistic efficacy in both HRD+ and HRD- xenograft tumor models. These data support continued development of DAN-222 to treat solid tumors and its combination use with PARP inhibitors.[Table: see text]

scholarly journals Paradoxical effects of ethoxidine, a topoisomerase I inhibitor, in the cellular processes leading to angiogenesis on endothelial cells

2010 ◽  
Vol 32 (3) ◽  
pp. 286-295 ◽  
Author(s):  
N. Clere ◽  
S. Faure ◽  
J.-J. Helesbeux ◽  
O. Duval ◽  
R. Andriantsitohaina
Keyword(s):  
Endothelial Cells ◽  
Topoisomerase I ◽  
Topoisomerase I Inhibitor ◽  
Cellular Processes ◽  
Paradoxical Effects
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