Abstract |
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.
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Authors | J Ciccolini, L Peillard, A Evrard, P Cuq, C Aubert, A Pelegrin, P Formento, G Milano, J Catalin |
Journal | Clinical 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 |
PMID | 10778986
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Thymine Nucleotides
- fas Receptor
- Tritium
- Inosine
- Thymidylate Synthase
- deoxyinosine
- thymidine 5'-triphosphate
- Fluorouracil
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Topics |
- Analysis of Variance
- Animals
- 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
- fas Receptor
(drug effects, metabolism)
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