Enhanced antitumor activity of 5-fluorouracil in combination with 2'-deoxyinosine in human colorectal cell lines and human colon tumor xenografts.

We investigated the effects of 2'-deoxyinosine (d-Ino), a modulator yielding thymidine phosphorylase activity, on cellular pharmacology of 5-fluorouracil (FUra) in various human colorectal cell lines and its antitumoral activity when combined with FUra in human xenografts. Associating d-Ino with FUra increased by 38 up to 700 times the sensitivity of HT29 and FUra-resistant SW620 lines, respectively, but not of CaCO2 cells, although high levels of intracellular FdUMP and subsequent higher thymidylate synthase inhibition were observed. Cell death studies confirmed the ability of d-Ino to enhance both early and late apoptosis induced by FUra in HT29 and SW620 but not in CaCo2. Similarly, we showed that associating d-Ino increased by 68 up to 101% the Fas overexpression induced by FUra in HT29 and SW620 but not in CaCo2 cells. Anti-Fas and anti-FasL antibodies both partly reversed this increase of cell sensitivity, thus confirming the role Fas plays in the modulation of FUra toxicity by d-Ino. This Fas component could explain the discrepancy between the lines because CaCO2 has been described as insensitive to Fas-mediated apoptosis. Antitumor activity of the combination was next investigated in nude mice transplanted with SW620. Results showed that although FUra alone has little effect on SW620 xenografts (P > 0.05), associating d-Ino significantly reduced the tumor growth by 57% (P < 0.05). This study suggests that it is possible to reduce both in vitro and in vivo resistance to FUra by modulating the way the drug is converted after cellular uptake.
AuthorsJ Ciccolini, L Peillard, A Evrard, P Cuq, C Aubert, A Pelegrin, P Formento, G Milano, J Catalin
JournalClinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 6 Issue 4 Pg. 1529-35 (Apr 2000) ISSN: 1078-0432 [Print] UNITED STATES
PMID10778986 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Antigens, CD95
  • Thymine Nucleotides
  • Tritium
  • Inosine
  • Thymidylate Synthase
  • deoxyinosine
  • thymidine 5'-triphosphate
  • Fluorouracil
  • Analysis of Variance
  • Animals
  • Antigens, CD95 (drug effects, metabolism)
  • Antineoplastic Combined Chemotherapy Protocols (pharmacology, therapeutic use)
  • Apoptosis (drug effects)
  • Cell Division (drug effects)
  • Colonic Neoplasms (drug therapy, pathology)
  • Colorectal Neoplasms (drug therapy, pathology)
  • Drug Synergism
  • Fluorouracil (administration & dosage, metabolism)
  • Humans
  • Inhibitory Concentration 50
  • Inosine (administration & dosage, analogs & derivatives)
  • Mice
  • Mice, Nude
  • Neoplasm Transplantation
  • Thymidylate Synthase (antagonists & inhibitors, metabolism)
  • Thymine Nucleotides (metabolism)
  • Transplantation, Heterologous
  • Tritium
  • Tumor Cells, Cultured

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