Treatment of infiltrative
glioma presents a number of unique challenges due to poor penetration of typical chemotherapeutic agents into the infiltrating edge of
tumors. The current
chemotherapy options include nitrosoureas (e.g.,
lomustine) and the imidazotetrazine-class monofunctional
DNA alkylating agent,
temozolomide (TMZ). Both classes of drugs alkylate
DNA and have relatively unrestricted passage from blood into brain where infiltrative
tumor cells reside. Recent research indicates that secondary mutations detected in the RB and AKT-mTOR signaling pathways are linked to characteristics of recurrent
tumors specific to TMZ-treated patients. It has been hypothesized that a decrease in rate of secondary mutations may result in delay of
tumor recurrence. To that end, this study was designed to test viability of decreasing secondary mutations by disrupting the cell division cycle using
eflornithine, a specific inhibitor of
ornithine decarboxylase. U87MG
glioblastoma cell line characterized by
chromosomal abnormalities commonly attributed to primary
cancers was used as a model for this study. The cells were subjected to TMZ treatment for 3 days followed by
eflornithine (DFMO) treatment for 4 or 11 days. It was shown that TMZ significantly increased the frequency of mutations in U87MG
glioblastoma cells while DFMO-treated cells showed mutation frequency statistically similar to that of the untreated cells on the respective treatment days. The findings of this study provide evidence to support the hypothesis that DFMO may inhibit progression of
DNA mutations caused by alkylating
chemotherapy agents, such as TMZ.