A novel antimetabolite, TAS-102 retains its effect on FU-related resistant cancer cells.

Abstract

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.

• Authors: Tomohiro Emura, Yuko Murakami, Fumio Nakagawa, Masakazu Fukushima, Kenji Kitazato
• Journal: International journal of molecular medicine (Int J Mol Med) Vol. 13 Issue 4 Pg. 545-9 (Apr 2004) ISSN: 1107-3756 [Print] Greece
• PMID: 15010854 (Publication Type: Journal Article)

Chemical References

• Antimetabolites
• Antimetabolites, Antineoplastic
• Coloring Agents
• Drug Combinations
• Pyrrolidines
• Tetrazolium Salts
• Thiazoles
• trifluridine tipiracil drug combination
• Uracil
• Globins
• Thymidine Phosphorylase
• thiazolyl blue
• Thymine
• Trifluridine
• Fluorouracil

Topics

• Animals
• Antimetabolites (pharmacology)
• Antimetabolites, Antineoplastic (pharmacology)
• Cell Line, Tumor
• Colorectal Neoplasms (pathology)
• Coloring Agents (pharmacology)
• Drug Combinations
• Drug Resistance, Neoplasm
• Fluorouracil (pharmacology)
• Globins (metabolism)
• Humans
• Liver (pathology)
• Liver Neoplasms (secondary)
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Models, Chemical
• Neoplasm Metastasis
• Neoplasm Transplantation
• Polymerase Chain Reaction
• Pyrrolidines
• Sensitivity and Specificity
• Tetrazolium Salts (pharmacology)
• Thiazoles (pharmacology)
• Thymidine Phosphorylase (chemistry)
• Thymine
• Trifluridine (chemistry, pharmacology)
• Uracil (analogs & derivatives, chemistry, pharmacology)