Clinical and in vitro studies of the correlation between MGMT and the effect of streptozocin in pancreatic NET
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This study aimed to determine the correlation between DNA repair enzyme O6-methylguanine DNA methyltransferase (MGMT) status and the response to streptozocin in advanced well-differentiated pancreatic neuroendocrine tumors (WD panNETs).
To test the hypothesis that MGMT deficiency was required for an alkylating drug response, we retrospectively reviewed the response of 13 patients with WD panNETs to alkylating agents in relation to MGMT status. We also studied MGMT expression in streptozocin resistance using panNET cell lines.
The cohort included 54% of patients with and 46% without MGMT expression. Among these, 83.3% (5/6) of MGMT-negative cases showed a partial response to streptozocin. In contrast, only 14.2% (1/7) of MGMT-positive cases showed a partial response (P = 0.013). Induced expression of MGMT in BON1 cells (a panNET cell line with undetectable endogenous MGMT) produced streptozocin resistance. Knockdown of MGMT in QGP1 cells, which express MGMT endogenously, did not alter the response to streptozocin.
We observed a relationship between MGMT status and streptozocin response in both patients and cell culture. Despite limited cases examined, high concordance of negative expression of MGMT and response to streptozocin treatment suggest that MGMT expression can be a potential biomarker for this treatment.
KeywordsMGMT Streptozocin Pancreatic neuroendocrine tumors Methylation BON1
The authors extend our sincere appreciation to Dr. Hironori Koga (Kurume University, Kurume, Japan).
This study was funded by the Aichi Cancer Research Foundation, Japan (K.S.).
Compliance with ethical standards
Conflict of interest
Susumu Hijioka has received speaker honoraria from Novelphama, Novartis, and Teijin Pharma. Nobumasa Mizuno has received research funding from AstraZeneca, Zeria Pharmaceutical, Taiho Pharmaceutical, Merck Serono, Eisai, NanoCarrier, MSD, Dainippon Sumitomo Pharma, and Novartis. Keiichiro Sakuma, Masahiro Aoki, Takamichi Kuwahara, Nozomi Okuno, Kazuo Hara, and Yasushi Yatabe have no conflicts of interest.
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Informed consent was obtained from all individual participants included in the study.
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