A novel antimetabolite, TAS-102 retains its effect on FU-related resistant cancer cells.
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.
Emura
Tomohiro
T
Cancer Research Laboratory, Hanno Research Center, Taiho Pharmaceutical Co., Ltd. 1-27, Misugidai, Hanno-city, Saitama 357-8527, Japan. t-emura@taiho.co.jp
Murakami
Yuko
Y
Nakagawa
Fumio
F
Fukushima
Masakazu
M
Kitazato
Kenji
K
D000818:Animals; D000963:Antimetabolites / Q000494:pharmacology*; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000473:pathology; D004396:Coloring Agents / Q000494:pharmacology; D004338:Drug Combinations; D019008:Drug Resistance, Neoplasm; D005472:Fluorouracil / Q000494:pharmacology*; D005914:Globins / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000473:pathology; D008113:Liver Neoplasms / Q000556:secondary; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008956:Models, Chemical; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D016133:Polymerase Chain Reaction; D011759:Pyrrolidines; D012680:Sensitivity and Specificity; D013778:Tetrazolium Salts / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D013939:Thymidine Phosphorylase / Q000737:chemistry; D013941:Thymine; D014271:Trifluridine / Q000737:chemistry / Q000494:pharmacology*; D014498:Uracil / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology*
D000963:Antimetabolites; D000964:Antimetabolites, Antineoplastic; D004396:Coloring Agents; D004338:Drug Combinations; D011759:Pyrrolidines; D013778:Tetrazolium Salts; D013844:Thiazoles; C000613803:trifluridine tipiracil drug combination; D014498:Uracil; D005914:Globins; D013939:Thymidine Phosphorylase; C022616:thiazolyl blue; D013941:Thymine; D014271:Trifluridine; D005472:Fluorouracil