Abstract 5127: In vitro and in vivo evaluation of FF-10502-01, a new pyrimidine nucleoside analogue
Authors: Mima Shinji , Nishikawa Hiroki , Watanabe Shinichi , Higuchi Tamami , Suzuki Takeaki , Iwamura Hiroyuki , Kakinuma Chihaya , Nakamura Takaaki , Shimada Yasuhiro 
Published: July 2017

Abstract
Introduction:FF-10502-01 is a synthetic pyrimidine nucleoside analogue structurally similar to gemcitabine (gem) with a substitution of sulfur for oxygen in the pentose ring. The anti-tumor effects of FF-10502-01 were studied in solid tumor cell lines and human tumor xenograft models.
Methods:10 human solid tumor cell lines were studied and included the following: 4 pancreatic (PANC) (BxPC-3, SUIT-2, Capan-1 and MIA PaCa-2), colon (HCT116), lung (NCI-H460), ovary (SK-OV-3), prostate (LNCap.FGC), breast (MDA-MB231) and mantle cell lymphoma (MCL) (Jeko-1). The effect of FF-10502-01 on DNA synthesis versus gem was evaluated in a PANC cell line (Capan-1). Tumor growth suppression was evaluated in human PANC xenograft models, SUIT-2 and Capan-1. FF-10502-01 or gem was administered at 240 or 480 mg/kg once a week starting 7d after orthotopic transplantation for 18 weeks, n=20/grp. Animals were followed for 128d after transplantation. Capan-1 was transplanted SC into nude mice (n=8/grp). FF-10502-01 or gem was administered at 120, 240, 360 or 480 mg/kg once weekly x 4 weeks 7d after transplantation. Tumor growth inhibitory effects were evaluated for 27d after starting treatment. FF-10502-01 single-dose pharmacokinetics (PK) were investigated in the mouse, rat and dog.
Results:FF-10502-01 demonstrated in vitro activity against the PANC, colon, lung, ovarian, prostate and MCL cell lines, with IC50s of 30 – 330 nM. The activity was 1.5 – 15-fold lower than gem, however, FF-10502-01 demonstrated a 23-fold higher inhibition of DNA α-polymerase-mediated synthesis over gem. In the SUIT-2 orthotropic implant model, both gem and FF-10502-01 improved survival over vehicle controls. Med survival was not reached for the 480 mg/kg gem grp or either the 240 or 480 mg/kg FF-10502-01 grps. The survival rate was 5%, 25%, 75% for the vehicle, 240 and 480 mg/kg gem grps (p&lt;0.0001 versus vehicle), and 100% for the 240 and 480 mg/kg FF-10502-01 grps (p&lt;0.0001 versus gem grps), respectively. In the Capan-1 xenograft model, both FF-10502-01 and gem demonstrated statistically significant tumor growth suppression versus vehicle control; FF-10502-01 demonstrated equivalent tumor growth suppression with less effect on body weight than gem at clinically achievable doses.
PK following single bolus IV doses indicated a similar PK profile to other pyrimidine nucleoside analogues, including gem.
Conclusions:FF-10502-01 is a new pyrimidine nucleoside analogue with demonstrated preclinical efficacy against solid tumors and a potentially more tolerable safety profile than gem.
Citation Format: Shinji Mima, Hiroki Nishikawa, Shinichi Watanabe, Tamami Higuchi, Takeaki Suzuki, Hiroyuki Iwamura, Chihaya Kakinuma, Takaaki Nakamura, Yasuhiro Shimada. In vitro and in vivo evaluation of FF-10502-01, a new pyrimidine nucleoside analogue [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5127. doi:10.1158/1538-7445.AM2017-5127