Date of Completion

Spring 5-14-2020

Thesis Advisor(s)

Dr. Charles Giardina

Honors Major

Molecular and Cell Biology

Disciplines

Cancer Biology | Cell Biology | Medical Cell Biology

Abstract

Cancer cells proliferate at rapid rates due to the aberrant activity of proteins involved in regulating the cell cycle. This characteristic allows mutated cancer cells to spread and metastasize, causing lesions to form throughout the body. Two treatment conditions, one classical antifolate methotrexate (MTX) and non-classical, novel antifolate UCP1162, were tested on a panel of acute myeloid leukemia (AML) cell lines to determine if UCP1162 has higher anti-proliferative activity. High dose MTX is used as a first line chemotherapy in common childhood malignancies such as acute lymphoid leukemia (ALL). Methotrexate is excluded from acute myeloid leukemia (AML) treatments based on clinical trials that suggest AML cells are intrinsically resistant. UCP1162, like MTX, targets dihydrofolate reductase (DHFR). UCP1162 does not appear to be limited by mutations of the reduced folate carrier (RFC) protein or folate polyglutamate synthase (FPGS) since it is not expected to use these mechanisms. UCP1162 is expected to accumulate better intracellularly and therefore, should provide more potent and longer-lasting anti-proliferative effects. Another main focus is how the anti-proliferative activity relates to the inhibition of nucleotide synthesis and DNA methylation. The comparison between these two treatments can be assessed by assays that provide information on the resulting cytotoxic effects. UCP1162 works with a lower EC50 than MTX, which may reduce cytotoxicity and side effects, allowing this treatment to be more tolerable. If UCP1162 is proven to have higher anti-proliferative effects than MTX, then it could play a key role in the arresting of cancer cells and improving patient care.

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