Oncotarget

Research Papers:

Effect of eflornithine on mutation frequency in temozolomide-treated U87MG cells

Noymi Yam _, Jason Levin, Zhengzheng Bao, Wubin Qian and Victor A. Levin

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Oncotarget. 2020; 11:3933-3942. https://doi.org/10.18632/oncotarget.27782

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Abstract

Noymi Yam1, Jason Levin1, Zhengzheng Bao2, Wubin Qian2 and Victor A. Levin3

1 Orbus Therapeutics, Inc., Palo Alto, CA, USA

2 Crown Bioscience, Inc., Santa Clara, CA, USA

3 Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

Correspondence to:

Noymi Yam,email: noymi.yam@orbustherapeutics.com

Keywords: glioma; eflornithine; temozolomide; chemotherapy; secondary mutations

Received: June 17, 2020     Accepted: September 29, 2020     Published: November 03, 2020

Copyright: © 2020 Yam et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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.


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