Phospholipid/deoxycytidine analogue prodrugs for the treatment of cancer

We synthesized thioether phospholipid carrier molecules, conjugated each of them to 1-b-D-arabinofuranosylcytosine (ara-C), and synthesized amido containing phospholipid carriers conjugated to gemcitabine. Changing the alkyl chain at the C1- and C2-positions of the phospholipid increased the conjugates’ cytotoxicity over previous conjugates. Dipyridamole increased ara-C’s and gemcitabine’s IC50 value while the IC50 values for the phospholipid conjugates were relatively unchanged suggesting that phospholipid conjugates do not require a transporter for entry into the cell. The phospholipid conjugates were cytotoxic to MCF-7 cells and its multidrug resistance-1 (MDR-1) overexpressing cell line derivative (BC-19). Ara-C had no effect on either cell line. Therefore, these novel phospholipid/nucleoside analogue conjugates could be used for the treatment of tumor cells that express certain resistance phenotypes such as a loss of transporter activity and/or MDR-1 overexpression. In vivo the gemcitabine-phospholipid conjugate was well tolerated and prolonged the survival of tumor bearing mice compared to control mice.