2020-2021 Grant in Aid of Research
Novel Hybrid Temozolomides-Aspirin Compounds as Potential Antiglioblastoma Agents
Joshua Kiprono Rotich
Cancer is the second leading cause of death in the United States. Last year, there were more than 600,000 mortalities and more than 1.7 million new cases. Brain tumor cases account for a small percentage of all cancers but have a very high mortality rate. Only 10 % of patients live more than 5 years after diagnosis. The most common brain cancer is glioblastoma multiforme (GBM). Treatment of GBM often involves surgical removal of the tumor followed by temozolomide (TMZ) chemotherapy and radiotherapy. TMZ is a prodrug of an alkylating agent 5-(3 methyltriazen1-yl) imidazole-4-carboximide (MTIC). TMZ readily penetrates the blood brain barrier and upon hydrolysis to MTIC, it methylates either N7 or O6 positions of DNA guanine residues. This eventually leads to DNA disintegration within the tumor cells as well as cell death by apoptosis and cytotoxicity. Unfortunately, GBM develops resistance to TMZ over time. Research has shown that daily use of aspirin has anticancer effects. A combination of TMZ, which becomes less effective over time due to GBM resistance, and aspirin which is effective over a long time may be a promising strategy against GBM. However, there are no published studies involving use of a hybrid tomozolomide-aspirin compound as therapeutic agents against glioblastoma multiforme. In my proposed study, I will synthesize novel hybrid drugs with TMZ and aspirin then will, for each novel hybrid drug, determine lethal concentration 50% (LC 50) and assess the impact on mitosis of cancer cells. Finally, I will determine morphological changes of glioblastoma cells treated with novel hybrid TMZ compounds.