Abstract
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.
Highlights
Malignant brain tumors in combination with other tumors of central nervous system (CNS) represent less than 2% of cancers in adults [1] and affect approximately 0.3% of world population [2]
Exposure to TMZ caused a significant increase in frequency of cancer-related mutations in U87MG glioblastoma cells as measured by quantifying known nucleotide polymorphisms using Exon-Seq analysis
While the TMZinduced mutagenesis has been extensively explored in recent research, the inhibitory action of DFMO leading to decrease in mutation frequency has not been reported before
Summary
Malignant brain tumors in combination with other tumors of central nervous system (CNS) represent less than 2% of cancers in adults [1] and affect approximately 0.3% of world population [2]. Brain cancers have a devastating impact on patients and society due to poor prognosis and limited treatment options. The five-year survival rate after diagnosis varies widely between approximately 5 and 80% with differences largely attributable to type and histology of tumors, patient age and genetic molecular markers. The post-surgery treatment of malignant infiltrative gliomas, such as anaplastic astrocytoma and glioblastoma, usually involves a combination of radiotherapy and chemotherapy. Typical chemotherapy agents used are alkylating agents. Longest in use have been the nitrosoureas, such as carmustine (BCNU), lomustine (CCNU), and fotemustine, bifunctional alkylating agents that cross-link DNA, and more recently, the monofunctional alkylating agent temozolomide (TMZ)
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