Rational Design of an Orally Active Anticancer Fluoropyrimidine, Pencitabine, a Hybrid of Capecitabine and Gemcitabine.

The structure of the anticancer drug capecitabine was redesigned to prevent metabolic conversion to 5-fluorouracil and its associated potentially fatal toxicities. The resulting cytidine analogue, pencitabine, is a hybrid of capecitabine and gemcitabine, another anticancer drug in clinical use. Preliminary biological evaluation revealed that pencitabine is cytotoxic in cell culture and orally active in a human xenograft test system. Pencitabine may mimic the known therapeutically advantageous combination of its parent drugs. Pencitabine is postulated to interfere with DNA synthesis and function by inhibiting multiple nucleotide-metabolizing enzymes and by misincorporation into DNA. Based on detailed mechanistic analyses and literature precedents, the hypothesis is put forward that the significant DNA damage caused by pencitabine may be accounted for by two additional effects not shown by the parent drugs: inhibition of DNA glycosylases involved in base excision repair and of DNA (cytosine-5)-methyltransferase involved in epigenetic regulation of cellular metabolism.