[Non-clinical studies of gemcitabine--the mode of action and antitumor activities]

Gemcitabine (2', 2'-difluorodeoxycytidine: dFdC) is a nucleoside analogue of deoxycytidine (dCyd). In the cells, dFdC is rapidly phosphorylated by dCyd kinase. dFdC inhibits ribonucleotide reductase and the subsequent decrease in cellular deoxynucleotides (particularly dCTP) is an important self-potentiating mechanism, resulting in decreased dFdC nucleotide incorporation into DNA. Other self-potentiating mechanisms of dFdC include increased formation of active dFdCDP and dFdC TP, and decreased elimination of dFdC nucleotides. After dFdC nucleotide is incorporated on the end of the DNA strand, one more deoxynucleotide is added and thereafter the DNA polymerases are unable to proceed (masked chain termination). dFdC is a better transport substrate compared with Ara-C, phosphorylated more efficiently and eliminated more slowly. These differences together with self-potentiation, masked chain termination and the inhibition of ribonucleotide reductase may explain why dFdC is active against human solid cancers compared with Ara-C. Schedule-dependent antitumor activities of dFdC were observed against various rodent tumors and human cancer xenograft systems.