A novel antimetabolite, TAS-102 retains its effect on FU-related resistant cancer cells.
, Murakami Y
, Nakagawa F
, Fukushima M
, Kitazato K
Cancer Research Laboratory, Hanno Research Center, Taiho Pharmaceutical Co., Ltd. 1-27, Misugidai, Hanno-city, Saitama 357-8527, Japan. email@example.com
TAS-102 is a new oral anti-tumor drug preparation, composed of a 1:0.5 mixture (on a molar basis) of alpha,alpha,alpha-tri-fluorothymidine (FTD) and thymidine phosphorylase inhibitor (TPI). TAS-102 is currently undergoing clinical trials, and has been demonstrated to have at least 2 mechanisms; inhibition of thymidylate synthase (TS) and incorporation into DNA. 5-FU is widely used in the treatment of solid tumor, but the inherent or acquired resistance of certain tumors to 5-FU therapy is a major clinical problem. In the present study, we investigated FTD in vitro and in vivo comparing with 5-FU and using FU-resistant cells. There was no relationship between FTD and 5-FU growth inhibition effect in vitro. A different sensitivity pattern was observed by the log-mean graph. We next investigated the anti-tumor activity of TAS-102 in a FU-resistant xenograft model. Comparative efficacy was observed between FU-resistant cell and its parent cell. We also studied the influence of TAS-102 on liver metastasis in a mouse model of human colorectal cancer, because liver metastasis of colorectal cancer is associated with patient survival. Human cancer DNA was detected by PCR, and TAS-102 markedly inhibited the number of liver metastasis. A novel angiogenic factor, platelet-derived endothelial cell growth factor (PD-ECGF), was shown to be identical to a previously characterized intracellular enzyme, thymidine phosphorylase, TAS-102 can be expected to have not only anti-tumor cytocidal effects but also antiangiogenesis activity and may inhibit liver metastasis. Our findings suggested that TAS-102 is a promising candidate for clinical use and can be expected to decrease minimal residual disease.
PMID: 15010854 [PubMed - indexed for MEDLINE]