The influence of p53 status on the cytotoxicity of fluorinated pyrimidine L-nucleosides

• The cellular toxicity of novel L-nucleoside analogues of FdUrd was examined.
• The toxicity was examined in wild type and p53 null primary mouse fibroblasts.
• p53 null cells were over 7500 times more sensitive to the novel L-nucleosides.
• The L-nucleosides had a similar cellular toxicity to that of FdUrd.

Fluorinated nucleoside analogues are a major class of cancer chemotherapy agents, and include the drugs 5-fluorouracil (5FU) and 5-fluoro-2′-deoxyuridine (FdUrd). The aim of this study was to examine the cellular toxicity of two novel fluorinated pyrimidine L-nucleosides that are enantiomers of D-nucleosides and may be able to increase selectivity for cancer cells as a result of their unnatural L-configuration. Two fluorinated pyrimidine L-nucleosides were examined in this study, L110 ([β-L, β-D]-5-fluoro-2′-deoxyuridine) and L117 (β-l-deoxyuridine:β-D-5′-fluoro-2′-deoxyuridine). The cytotoxicity of these L-nucleoside was determined in primary mouse fibroblasts and was compared with 5FU and FdUrd. In addition, the influence of p53 status on cytotoxicity was investigated. These cytotoxicity assays were performed on a matched set of primary mouse fibroblasts that were either wild type or null for the p53 tumour suppressor gene. It was found that cells lacking functional p53 were over 7500 times more sensitive to the drugs L110, L117 and FdUrd than cells containing wild type p53.

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