An evaluation of thymidine phosphorylase as a means of preventing thymidine rescue from the thymidylate synthase inhibitor raltitrexed

Cancer Chemother Pharmacol. 2007 Feb;59(2):197-206. doi: 10.1007/s00280-006-0258-x. Epub 2006 May 24.

Abstract

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.

MeSH terms

  • Animals
  • Antibodies, Monoclonal / immunology
  • Antibodies, Monoclonal / metabolism
  • Antimetabolites, Antineoplastic / pharmacology
  • Antimetabolites, Antineoplastic / therapeutic use
  • Carcinoembryonic Antigen / immunology
  • Carcinoembryonic Antigen / metabolism
  • Cell Line, Tumor
  • Colorectal Neoplasms / drug therapy
  • Colorectal Neoplasms / metabolism
  • Colorectal Neoplasms / pathology
  • Dose-Response Relationship, Drug
  • Drug Evaluation, Preclinical / methods
  • Female
  • HT29 Cells
  • Humans
  • Immunoglobulin Fab Fragments / immunology
  • Immunoglobulin Fab Fragments / metabolism
  • Injections, Intravenous
  • Mice
  • Mice, Nude
  • Quinazolines / pharmacology
  • Quinazolines / therapeutic use*
  • Reproducibility of Results
  • Thiophenes / pharmacology
  • Thiophenes / therapeutic use*
  • Thymidine / metabolism*
  • Thymidine Phosphorylase / administration & dosage
  • Thymidine Phosphorylase / immunology
  • Thymidine Phosphorylase / metabolism*
  • Thymidylate Synthase / antagonists & inhibitors*
  • Thymidylate Synthase / metabolism
  • Xenograft Model Antitumor Assays / methods*

Substances

  • Antibodies, Monoclonal
  • Antimetabolites, Antineoplastic
  • Carcinoembryonic Antigen
  • Immunoglobulin Fab Fragments
  • Quinazolines
  • Thiophenes
  • Thymidylate Synthase
  • Thymidine Phosphorylase
  • raltitrexed
  • Thymidine