Date of Award
Honors Thesis (Open Access)
Colby College. Chemistry Dept.
Laromustine is an experimental chemotherapeutic sulfonyl hydrazine prodrug shown in clinical trials to be effective against acute myeloid leukemia. The mechanism of action of laromustine involves interstrand crosslinking, via chloroethylation, and enzyme inhibition, caused by carbamoylation. The work described herein aims to investigate whether inhibition of the replication-dependent interstrand crosslink repair Fanconi Anemia pathway further sensitizes cells to laromustine. By measuring metabolic activity immediately after drug exposure, we find laromustine to be equally as cytotoxic towards Fanconi Anemia deficient and wild type cells. However, through clonogenic assays we show Fanconi Anemia mutations sensitize cells to laromustine’s anti-proliferative effect. Furthermore, we show curcumin, which has previously been reported as a Fanconi Anemia pathway inhibitor, is able to induce a similar sensitization to laromustine as observed in mutant cells. A similar effect is not observed for another reported inhibitor, pimozide. Further research expanding on these findings could inform combination therapies that could reduce therapeutic dose of laromustine.
Laromustine, Cancer, Oncology, Curcumin, Pimozide, Fanconi Anemia
Recommended CitationMarchant, Sam W., "Use of Small Molecule Fanconi Anemia Pathway Inhibitors as Sensitizing Agents to Laromustine." (2021). Honors Theses. Paper 1315.