Investigating the mechanism of novel anticancer agent, AS1411 : does metabolism to guanine play a role?
Date on Senior Honors Thesis
Senior Honors Thesis
College of Arts and Sciences
AS1411; Methuosis; Guanine; HGPRT
AS1411 is an oligonucleotide that has shown promising results in lab experiments and clinical trials as an anti-cancer drug, Likewise, treatments with guanine based purine compounds (GBPCs) have demonstrated similar anti-proliferative effects in vitro. This activity is dependent on the HGPRT enzyme. Similarities in activity and physical structure has led us to believe that AS1411 and GBPCs operate by a similar mechanism. To test this, we compare the activity of both in the presence of HGPRT siRNAs and HGPRT deficient cells. While siRNA treatment was unable to alter the activity of GBPCs or AS1411 in our cell lines, HGPRT deficient cells did exhibit statistically significant differences in relative proliferation when treated with both AS1411 and GBPCs. While inconclusive, these results suggest that HGPRT is implicated in the activity of both compounds.
Howard, Parker T, "Investigating the mechanism of novel anticancer agent, AS1411 : does metabolism to guanine play a role?" (2017). College of Arts & Sciences Senior Honors Theses. Paper 147.
AS1411 is a cancer drug with demonstrated potential but no known mechanism. Due to a number of similarities to guanine based compounds, we sought to explore if both compounds operate by the same mechanism. To do this, we knocked down HGPRT, an enzyme necessary for guanine activity, and treated cells with the drug compounds. While this was unable to alter the drug activity, we also tested the drug in cells without functioning HGPRT. In these cells, drug activity was reduced, suggesting that HGPRT is important for the activity of both drugs.
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