PMID- 16721548
OWN - NLM
STAT- MEDLINE
DCOM- 20070423
LR  - 20141120
IS  - 0344-5704 (Print)
IS  - 0344-5704 (Linking)
VI  - 59
IP  - 2
DP  - 2007 Feb
TI  - An evaluation of thymidine phosphorylase as a means of preventing thymidine 
      rescue from the thymidylate synthase inhibitor raltitrexed.
PG  - 197-206
AB  - The antitumour effect of thymidylate synthase inhibitors such as raltitrexed 
      (RTX) may be reversed by salvage of thymidine (Thd). Since thymidine 
      phosphorylase (TP) depletes Thd, the potential for tumour-selective depletion of 
      Thd using antibody-mediated delivery of TP to tumours was investigated. In vitro 
      studies demonstrated that 25 x 10(-3) units/ml TP depleted extracellular Thd (3 
      microM) and restored sensitivity to the growth inhibitory effects of RTX in Lovo 
      and HT29 cell lines. Thymidine concentrations in xenograft tumours were inversely 
      proportional to the activity of TP in the tumour, and the presence of a 
      subcutaneous Lovo xenograft reduced plasma Thd concentrations from 0.92 +/- 0.07 
      to 0.37 +/- 0.04 microM. Intravenous administration of native TP enzyme depleted 
      plasma Thd to 5 nM, but following rapid elimination of TP, plasma Thd returned to 
      pretreatment values. There was no effect on tumour TP or Thd. Conjugation of TP 
      to the A5B7 F(ab)2 antibody fragment, which targets carcinoembryonic antigen 
      (CEA) expressed on colorectal cell-lines such as Lovo, did result in selective 
      accumulation of TP in the tumour. However, there was no tumour-selective 
      depletion of Thd and there did not appear to be any potential benefit of 
      combining antibody-targeted TP with RTX.
FAU - Graham-Cole, Claire L
AU  - Graham-Cole CL
AD  - Northern Institute for Cancer Research, Medical School, University of Newcastle, 
      Newcastle upon Tyne, NE2 4HH, UK.
FAU - Thomas, Huw D
AU  - Thomas HD
FAU - Taylor, Gordon A
AU  - Taylor GA
FAU - Newell, David R
AU  - Newell DR
FAU - Melton, Roger G
AU  - Melton RG
FAU - Hesp, Richard
AU  - Hesp R
FAU - Boddy, Alan V
AU  - Boddy AV
LA  - eng
PT  - Journal Article
DEP - 20060524
PL  - Germany
TA  - Cancer Chemother Pharmacol
JT  - Cancer chemotherapy and pharmacology
JID - 7806519
RN  - 0 (Antibodies, Monoclonal)
RN  - 0 (Antimetabolites, Antineoplastic)
RN  - 0 (Carcinoembryonic Antigen)
RN  - 0 (Immunoglobulin Fab Fragments)
RN  - 0 (Quinazolines)
RN  - 0 (Thiophenes)
RN  - EC 2.1.1.45 (Thymidylate Synthase)
RN  - EC 2.4.2.4 (Thymidine Phosphorylase)
RN  - FCB9EGG971 (raltitrexed)
RN  - VC2W18DGKR (Thymidine)
SB  - IM
MH  - Animals
MH  - Antibodies, Monoclonal/immunology/metabolism
MH  - Antimetabolites, Antineoplastic/pharmacology/therapeutic use
MH  - Carcinoembryonic Antigen/immunology/metabolism
MH  - Cell Line, Tumor
MH  - Colorectal Neoplasms/drug therapy/metabolism/pathology
MH  - Dose-Response Relationship, Drug
MH  - Drug Evaluation, Preclinical/methods
MH  - Female
MH  - HT29 Cells
MH  - Humans
MH  - Immunoglobulin Fab Fragments/immunology/metabolism
MH  - Injections, Intravenous
MH  - Mice
MH  - Mice, Nude
MH  - Quinazolines/pharmacology/*therapeutic use
MH  - Reproducibility of Results
MH  - Thiophenes/pharmacology/*therapeutic use
MH  - Thymidine/*metabolism
MH  - Thymidine Phosphorylase/administration & dosage/immunology/*metabolism
MH  - Thymidylate Synthase/*antagonists & inhibitors/metabolism
MH  - Xenograft Model Antitumor Assays/*methods
EDAT- 2006/05/25 09:00
MHDA- 2007/04/24 09:00
CRDT- 2006/05/25 09:00
PHST- 2006/01/26 00:00 [received]
PHST- 2006/04/23 00:00 [accepted]
PHST- 2006/05/25 09:00 [pubmed]
PHST- 2007/04/24 09:00 [medline]
PHST- 2006/05/25 09:00 [entrez]
AID - 10.1007/s00280-006-0258-x [doi]
PST - ppublish
SO  - Cancer Chemother Pharmacol. 2007 Feb;59(2):197-206. doi: 
      10.1007/s00280-006-0258-x. Epub 2006 May 24.