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 yieldin g thymidine phosphorylase activity, on cellular pharmacology of 5-fluoroura cil (FUra) in various human colorectal cell lines and its antitumoral activ ity when combined with FUra in human xenografts. Associating d-Ino with FUr a increased by 38 up to 700 times the sensitivity of HT29 and FUra-resistan t SW620 lines, respectively, but not of CaCo2 cells, although high levels o f intracellular FdUMP and subsequent higher thymidylate synthase inhibition were observed. Cell death studies confirmed the ability of d-Ino to enhanc e both early and late apoptosis induced by FUra in HT29 and SW620 but not i n 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 Ca Co2 cells. Anti-Fas and anti-Fast antibodies both partly reversed this incr ease of cell sensitivity, thus confirming the role Fas plays in the modulat ion of FUra toxicity by d-Ino. This Fas component could explain the discrep ancy between the lines because CaCo2 has been described as insensitive to F as-mediated apoptosis, Antitumor activity of the combination was next inves tigated 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 su ggests that it is possible to reduce both in vitro mid in vivo resistance t o FUra by modulating the way the drug, is converted after cellular uptake.