FATTY-ACID CONJUGATES OF 2'-DEOXY-5-FLUOROURIDINE AS PRODRUGS FOR THE SELECTIVE DELIVERY OF 5-FLUOROURACIL TO TUMOR-CELLS

We have prepared a novel class of prodrugs by coupling 2'-deoxy-5-fluorouridine (5dFU) to oleic (18:1) and docosahexaenoic (22:6).acids, respectively. The cytotoxic activity of the drug and its conjugates (5dFU-18:1 and 5dFU-22:6) has been assayed in vitro upon HT-29, a colon carcinoma cell line of human origin. After short term (2-hr) treatments with the drugs, both fatty acid conjugates of 5dFU showed cytotoxic activity in a dose-dependent way, while 5dFU alone was devoid of toxic effects within the whole range of concentrations (10-200-mu-M) tested. Following long term (24- or 48-hr) incubations only a fraction of the HT-29 cell population was sensitive to 5dFU, the rest of the population being resistant even at the highest concentration tested (200-mu-M). In contrast, 5dFU-oleic acid and, particularly, 5dFU-docosahexaenoic acids appeared toxic for the whole population of HT-29 cells under the same experimental conditions. The considerable gain in cell toxicity and, to a lesser extent, in selectivity resulted from the conjugation since the toxic effect of the drug alone was not modified when equimolar mixtures of 5dFU and fatty acids were assayed. These results confirm a previous study on the cytotoxicity of fatty acid derivatives of chlorambucil toward malignant lymphoblastoid cells and reinforce the potential use of fatty acid conjugates as efficient anti-tumor prodrugs.