PMID- 17179993
OWN - NLM
STAT- MEDLINE
DCOM- 20070222
LR  - 20201209
IS  - 0007-0920 (Print)
IS  - 1532-1827 (Electronic)
IS  - 0007-0920 (Linking)
VI  - 96
IP  - 1
DP  - 2007 Jan 15
TI  - The Hollow Fibre Assay as a model for in vivo pharmacodynamics of 
      fluoropyrimidines in colon cancer cells.
PG  - 61-6
AB  - The Hollow Fibre Assay (HFA) is usually applied as an early in vivo model for 
      anti-cancer drug screening, but is potentially an excellent model for short-term 
      in vivo pharmacodynamic studies. We used the model to study the in vivo role of 
      thymidine phosphorylase/platelet-derived endothelial cell growth factor 
      (TP/PD-ECGF) in the cytotoxicity and pharmacodynamics of TAS-102 in colon cancer 
      cells. TAS-102 is a new oral drug formulation, which is composed of 
      trifluorothymidine (TFT) and thymidine phosphorylase inhibitor (TPI), which 
      prevents TFT degradation. We compared the activity with Xeloda (capecitabine), 
      which is activated by TP into 5FU. Hollow fibres filled with human Colo320 or 
      Colo320TP1 colorectal cancer cells with deficient or high TP expression, 
      respectively, were implanted subcutaneously (s.c.) at both flanks of BALB/c mice. 
      The mice were treated orally over 5 days with TAS-102, TFT alone, 5'DFUR+/-TPI or 
      capecitabine at their maximum tolerated dose (MTD). The cells were retrieved from 
      the fibres and assayed for growth (MTT assay), cell cycle distribution (flow 
      cytometry) and apoptosis induction (FragEL method). TAS-102 induced considerable 
      growth inhibition (50%, P<0.01) to both cell lines, which was completely 
      abolished in the absence of TPI. Capecitabine and its metabolite 5'DFUR reduced 
      proliferation of Colo320TP1 cells in the fibres significantly (down to 25-40%), 
      but much less in Colo320 cells, whereas addition of TPI reduced the effect of 
      5'DFUR, although not completely. These differences in cytotoxic effects were 
      reflected in the pharmacodynamic evaluation. TAS-102 induced a G2M-phase arrest 
      (from 25 to 40%) and apoptosis (>8-fold), which was more pronounced in Colo320 
      than in Colo320TP1. Again, omission of TPI neutralised the effect of TAS-102. 
      Similarly, 5'DFUR and capecitabine induced a significant G2M-phase arrest (up to 
      45%) in the Colo320TP1 cell line, but less pronounced in the parental Colo320. 
      Addition of TPI to 5'DFUR reduced this effect to control levels. Also induction 
      of apoptosis was reduced in the presence of TPI. The data demonstrated that the 
      HFA is excellently suited for studying short-term pharmacodynamic effects of 
      fluoropyrimidines in vivo. TAS-102 is only effective in inducing cytotoxicity 
      when systemic TPI is present, but acts against both low and high TP expressing 
      colon cancer cells, while 5'DFUR needs cellular TP to exert significant activity.
FAU - Temmink, O H
AU  - Temmink OH
AD  - Department of Medical Oncology, VU University Medical Center, Amsterdam, The 
      Netherlands.
FAU - Prins, H-J
AU  - Prins HJ
FAU - van Gelderop, E
AU  - van Gelderop E
FAU - Peters, G J
AU  - Peters GJ
LA  - eng
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20061219
PL  - England
TA  - Br J Cancer
JT  - British journal of cancer
JID - 0370635
RN  - 0 (Drug Combinations)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Pyrrolidines)
RN  - 0 (trifluridine tipiracil drug combination)
RN  - 039LU44I5M (Floxuridine)
RN  - 0W860991D6 (Deoxycytidine)
RN  - 56HH86ZVCT (Uracil)
RN  - 6804DJ8Z9U (Capecitabine)
RN  - EC 2.4.2.4 (Thymidine Phosphorylase)
RN  - QR26YLT7LT (Thymine)
RN  - RMW9V5RW38 (Trifluridine)
RN  - U3P01618RT (Fluorouracil)
RN  - V1JK16Y2JP (doxifluridine)
SB  - IM
MH  - Administration, Oral
MH  - Animals
MH  - Apoptosis/drug effects
MH  - Capecitabine
MH  - Cell Cycle/drug effects
MH  - Cell Line, Tumor
MH  - Colonic Neoplasms/*drug therapy
MH  - Deoxycytidine/*analogs & derivatives/pharmacokinetics/therapeutic use
MH  - Drug Combinations
MH  - Drug Synergism
MH  - Enzyme Inhibitors/pharmacokinetics/therapeutic use
MH  - Flow Cytometry
MH  - Floxuridine/pharmacokinetics/*therapeutic use
MH  - Fluorouracil/*analogs & derivatives/pharmacokinetics/therapeutic use
MH  - Humans
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - Pyrrolidines
MH  - Sensitivity and Specificity
MH  - Thymidine Phosphorylase/antagonists & inhibitors
MH  - Thymine
MH  - Treatment Outcome
MH  - Trifluridine/pharmacokinetics/*therapeutic use
MH  - Tumor Cells, Cultured
MH  - Uracil/*analogs & derivatives/pharmacokinetics/therapeutic use
MH  - *Xenograft Model Antitumor Assays/methods
PMC - PMC2360204
EDAT- 2006/12/21 09:00
MHDA- 2007/02/23 09:00
PMCR- 2008/01/15
CRDT- 2006/12/21 09:00
PHST- 2006/12/21 09:00 [pubmed]
PHST- 2007/02/23 09:00 [medline]
PHST- 2006/12/21 09:00 [entrez]
PHST- 2008/01/15 00:00 [pmc-release]
AID - 6603507 [pii]
AID - 10.1038/sj.bjc.6603507 [doi]
PST - ppublish
SO  - Br J Cancer. 2007 Jan 15;96(1):61-6. doi: 10.1038/sj.bjc.6603507. Epub 2006 Dec 
      19.