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

Int J Mol Med. 2004 Apr;13(4):545-9.

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.

MeSH terms

  • 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
  • Trifluridine / pharmacology*
  • Uracil / analogs & derivatives
  • Uracil / chemistry
  • Uracil / pharmacology*

Substances

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