TITLE:
The Role of Thymidylate Synthase in Pemetrexed-Resistant Malignant Pleural Mesothelioma Cells
AUTHORS:
Tohru Obata, Motohiro Tanaka, Yuka Suzuki, Takuma Sasaki
KEYWORDS:
Malignant Pleural Mesothelioma; Thymidylate Synthase; Pemetrexed; ECyd
JOURNAL NAME:
Journal of Cancer Therapy,
Vol.4 No.6,
July
17,
2013
ABSTRACT:
We established new
pemetrexed-resistant cells originating from malignant pleural mesothelioma
MSTO-211H cells to clarify the mechanism involved in pemetrexed resistance in
malignant pleural mesothelioma. In the pemetrexed-resistant cells, only
thymidylate synthase (TYMS) mRNA was
overexpressed among other well-known molecular targets and chemosensitivity
determinants of pemetrexed, and the role of the TYMS gene was ascertained by artificial regulation induced by
specific siRNA. Silencing the TYMS expression partially restored the cytotoxicity of pemetrexed. The resistant cells
did not display other gene alterations related to folate metabolism. We
conclude that the primary mechanism imparting resistance to these cells is
specific up-regulation of TYMS function. Further, the TYMS gene may
serve as a useful biomarker for the prediction of pemetrexed chemosensitivity
in patients with malignant pleural mesothelioma. We also investigated the
efficacy of 1-(3-C-ethynyl-β-D-ribo-pento furanosyl)cytosine (ECyd)
in overcoming pemetrexed resistance; this compound is presently undergoing
clinical trials in the USA
as TAS-106. ECyd had a similar antitumor effect on the resistant cells as
that on the parental cells. In the clinical treatment of malignant pleural mesothelioma,
ECyd promises to emerge as a novel drug.