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The Design, Synthesis and Evaluation of Antitumor Agents, Targeting T-Cell Factor Driven Colorectal Cancer
Başlık:
The Design, Synthesis and Evaluation of Antitumor Agents, Targeting T-Cell Factor Driven Colorectal Cancer
Yazar:
Abraham, Adedoyin David, author.
ISBN:
9780438003156
Yazar Ek Girişi:
Fiziksel Tanımlama:
1 electronic resource (650 pages)
Genel Not:
Source: Dissertation Abstracts International, Volume: 79-10(E), Section: B.
Advisors: Daniel V. Labarbera Committee members: Rajesh Agarwal; Jared Brown; Peter Harrington; Daniel V. Labarbera; Mark J. Petrash.
Özet:
Colorectal cancer (CRC) is one of the most prevalent cancer types in the world. Recent statistics show that CRC is the third most common cancer among men and women in the United States, accounting for up to 50, 000 deaths, with approximately 136,000 new cases each year. Various treatment regimens have been reported for CRC. However, the overall 5-year survival rate remains poor, which can be attributed to low efficacy and safety of the standard treatments against stage IV metastatic CRC. Therefore, more effective therapies for the treatment of metastatic CRC are unmet clinical needs. Neoamphimedine (neo), a natural product of marine origin, characterized as an ATP competitive inhibitor of TopoIIalpha was evaluated by the LaBarbera lab and found to possess effective therapeutic actions against TopoIIalpha through its competitive inhibition of ATP. Its antitumor activity has been described to be as effective as that of the conventional TopoIIalpha poison, etoposide, without evidence of DNA damage or complex stabilization, as seen with the latter. Conducting further biological studies on neo requires a lot of material (neo), which is a challenge since neo has thus far been difficult to make. The aim of this dissertation was to improve the synthesis of neo and rationally design novel analogs that improve the in vivo biological antitumor activity compared to neo. We designed a new method to synthesize neo from the commercially available starting material, in 10 steps, with a 25% yield, which can afford ≥ gram quantity of material. Following the successful synthesis of neo, we further characterized the mode by which neo inhibits TopoIIalpha and found that neo binds TopoIIalpha at the N-terminal ATPase domain, which is a different binding site from that of the clinically used TopoIIalpha poisons (e.g. etoposide). Furthermore, using neo as a probe, we characterized TopoII? as a required component of TCF transcriptional activity, and determined that neo's ATP-competitive inhibition blocks TopoIIalpha-dependent TCF transcription thereby reversing EMT and the associated malignant phenotype. We conclude that neo analogs may be effective therapeutics for metastatic CRC.
Notlar:
School code: 1639
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Yer Numarası | Demirbaş Numarası | Shelf Location | Lokasyon / Statüsü / İade Tarihi |
---|---|---|---|
XX(681060.1) | 681060-1001 | Proquest E-Tez Koleksiyonu | Arıyor... |
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