Novel Oligomeric Fluoropyrimidines and Their Efficacy for the Treatment of Colorectal Carcinoma Independent of p53 Mutation

The treatment of advanced stage colorectal carcinoma (CRC) is rarely achieved with today’s standard of care, including 5-fluorouracil (5-FU). Resistance to 5-FU is unfortunately frequent in CRC partially due to the dependency 5-FU displays towards normal p53 function, a tumor suppressor protein that is commonly mutated in advanced CRC. In addition to the relatively low success rate of 5-FU in aggressive CRC, 5-FU treatment also causes systemic toxicity, particularly to the GI-tract. The presented studies aimed to demonstrate that our novel oligomeric fluoropyrimidines are able to overcome these limitations of 5-FU in vivo. The results indicate that F10 and other fluoropyrimidines showed little-to-no p53 dependency in in vivo xenografts. While F10 displayed the same p53 independency in vitro when assessing cell viability and caspase activation, 5-FU showed a dependency on normal p53 function in vitro while further studies are needed to conclude in vivo p53-dependency. The results also indicate that these fluoropyrimidines are viable treatments for CRC by showing tumor suppression in xenograft models and in a more realistic orthotopic model. Systemic toxicity was not seen during novel fluoropyrimidine treatment in terms of GI-tract villi or crypt shortening, whereas 5-FU caused major toxicity, both short-term and long-term. These findings indicate that the limitations of 5-FU are eliminated by our fluoropyrimidines in a mouse model and may possibly transition to the clinical setting.

Grantor dc:publisher

Wake Forest University

Year dc:date.issued

2017

Author dc:creator

• Dominijanni, Anthony

• colorectal carcinoma

Language dc:language.iso

en

Handle dc:identifier.uri

http://hdl.handle.net/10339/86346

OAI identifier oai:identifier

oai:wakespace.lib.wfu.edu:10339/86346