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.
Ciccolini
J
J
Laboratoire de Toxicocinetique et Pharmacocinetique, Faculté de Pharmacie, Marseille, France. joseph.ciccolini@pharmacie.univ-mrs.fr
Peillard
L
L
Evrard
A
A
Cuq
P
P
Aubert
C
C
Pelegrin
A
A
Formento
P
P
Milano
G
G
Catalin
J
J
D000704:Analysis of Variance; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D004357:Drug Synergism; D005472:Fluorouracil / Q000008:administration & dosage / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D007288:Inosine / Q000008:administration & dosage / Q000031:analogs & derivatives; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D013942:Thymine Nucleotides / Q000378:metabolism; D014183:Transplantation, Heterologous; D014316:Tritium; D014407:Tumor Cells, Cultured; D019014:fas Receptor / Q000187:drug effects / Q000378:metabolism
D013942:Thymine Nucleotides; D019014:fas Receptor; D014316:Tritium; D007288:Inosine; D013940:Thymidylate Synthase; C012271:deoxyinosine; C024157:thymidine 5'-triphosphate; D005472:Fluorouracil