Abstract B87: Preclinical investigation of the potentiation in antitumor effect of TAS-102, a novel oral anti-neoplastic nucleoside agent, in combination with irinotecan (CPT-11) in colorectal cancer.
Authors: Ishida Keiji , Tanaka Nozomu , Tsukioka Sayaka , Eshima Kokoro , Fujioka Akio , Yamamura Keisuke , Ito Satoko , Matsuo Kenichi , Utsugi Teruhiro 
Published: August 2014

Abstract
Background: Irinotecan (CPT-11) is a topoisomeraseI (TopoI) inhibitor, which is widely used for the treatment of metastatic colorectal cancer. CPT-11 inhibits DNA religation by TopoI, thus it stabilizes DNA-TopoI complexes and subsequently induces cytotoxicity. TAS-102, a novel oral antitumor agent, consisting of trifluorothymidine(FTD) and thymidine phosphorylase inhibitor, has reported promising clinical results in metastatic colorectal cancer. Several reports indicated that aberrant nucleoside incorporation into DNA, such as with cytarabine or gemcitabine, enhanced DNA-TopoI complexes. FTD, the effector of TAS-102, is a nucleoside which is efficiently incorporated and retained into DNA. Here, we evaluated the potency of TAS-102 in combination with CPT-11 in vitro and in vivo
Materials and Methods: The combinational effect of FTD and SN-38 which is the active metabolite of CPT-11 was evaluated with several treatment schedules. Various colorectal cancer cell lines (SW48, SW620, LS174T and HCT116) were used in this assay. In one set, cells were washed after a 24 hour pre-exposure to FTD followed by a 48 hour exposure to SN-38 (FTD pre-exposure schedule); in the other set, cells were washed after a 6 hour pre-exposure to SN-38 followed by a 66 hour exposure to FTD (SN-38 pre-exposure schedule). A combinational intensity was estimated by using a combination index (CI) which indicates synergism (CI&lt;0.8), additivity (0.8&lt;CI&lt;1.2), or antagonism (CI&gt;1.2). Additionally, the antitumor effect of TAS-102 in combination with CPT-11 was investigated in a human colorectal cancer xenograft model. TAS-102 was orally administered for 14 days consecutively and CPT-11 was intravenously administered once a week to mice.
Results: The combination of SN-38 and FTD showed a synergistic effect (SW48, SW620 and LS174T) or an additive effect (HCT116) in both the FTD pre-exposure schedule as well as the SN-38 pre-exposure schedule. Also, the enhancement of antitumor effect of TAS-102 in combination with CPT-11 was observed in vivo. Furthermore, these cell lines had various genotypes as regards KRAS, PI3CA and other DNA repair enzymes frequently detected in colorectal cancer, indicating that the combination's efficacy seemed to be independent of genetic status.
Conclusion: TAS-102/CPT-11 represents a novel combination strategy for the treatment of advanced colorectal cancer. A synergistic effect was observed in both schedules tested, suggesting that various underlying mechanisms may exist. One potential mechanism is that FTD uptake or incorporation into DNA is increased by TopoI inhibition, and that FTD incorporation then further stabilizes the CPT-11 induced cleavable complex. However, the precise mechanism needs to be elucidated in the future.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B87.
Citation Format: Keiji Ishida, Nozomu Tanaka, Sayaka Tsukioka, Kokoro Eshima, Akio Fujioka, Keisuke Yamamura, Satoko Ito, Kenichi Matsuo, Teruhiro Utsugi. Preclinical investigation of the potentiation in antitumor effect of TAS-102, a novel oral anti-neoplastic nucleoside agent, in combination with irinotecan (CPT-11) in colorectal cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B87.