FF-10502, an Antimetabolite with Novel Activity on Dormant Cells, Is Superior to Gemcitabine for Targeting Pancreatic Cancer Cells

In this paper, we report that 1-(2-deoxy-2-fluoro-4-thio- -d-arabinofuranosyl) cytosine (FF-10502), a pyrimidine nucleoside antimetabolite with a chemical structure similar to gemcitabine, shows beneficial anticancer activity via a novel mechanism of action on dormant cells. The growth inhibition of...

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Bibliographic Details
Published in:The Journal of pharmacology and experimental therapeutics 2018-07, Vol.366 (1), p.125-135
Main Authors: Mima, Shinji, Kakinuma, Chihaya, Higuchi, Tamami, Saeki, Kazunori, Yamada, Takayuki, Uematsu, Rena, Ishino, Miki, Kito, Nobuko, Nishikawa, Hiroki, Kuniyoshi, Hidenobu, Matsumoto, Takuya, Fujiwara, Hideyasu, Paradiso, Linda J, Shimada, Yasuhiro, Iwamura, Hiroyuki
Format: Article
Language:English
Subjects:
Antineoplastic Agents - pharmacology
Cell Line, Tumor
Cell Proliferation - drug effects
Cytarabine - analogs & derivatives
Cytarabine - pharmacology
Deoxycytidine - analogs & derivatives
Deoxycytidine - pharmacology
Humans
Molecular Targeted Therapy
Pancreatic Neoplasms - pathology
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Summary:In this paper, we report that 1-(2-deoxy-2-fluoro-4-thio- -d-arabinofuranosyl) cytosine (FF-10502), a pyrimidine nucleoside antimetabolite with a chemical structure similar to gemcitabine, shows beneficial anticancer activity via a novel mechanism of action on dormant cells. The growth inhibition of pancreatic cancer cell lines by FF-10502 (IC , 60-330 nM) was moderately weaker than that by gemcitabine in vitro. In contrast, an in vivo orthotopic implantation model in mice with established human pancreatic cancer cell line, SUIT-2, revealed no mortality with FF-10502 intravenous treatment, which was related to regression of implanted tumor and little metastasis, whereas 75% of the mice treated with gemcitabine died by day 128. Two in vivo patient-derived xenograft models with gemcitabine-resistant pancreatic cancer cells also demonstrated complete tumor growth suppression with FF-10502, but only partial inhibition with gemcitabine. We also investigated the mechanism of action of FF-10502 by using dormant cancer cells, which are reportedly involved in the development of resistance to chemotherapy. In vitro serum starvation-induced dormant SUIT-2 cells developed resistance to gemcitabine even in combination with DNA damage inducers (DDIs; H O , cisplatin, and temozolomide). Interestingly, FF-10502 in combination with DDIs significantly induced concentration-dependent cell death in accordance with enhanced DNA damage. FF-10502 was far more potent than gemcitabine in inhibiting DNA polymerase , which may explain the difference in dormant cell injury, although further investigations for direct evidences are necessary. In conclusion, our study demonstrated the beneficial antitumor effects of FF-10502 in clinically relevant in vivo models, and suggests the importance of preventing DNA repair unlike gemcitabine.
ISSN:0022-3565
1521-0103
DOI:10.1124/jpet.118.248740