Gemcitabine

Gemcitabine (difluorodeoxycitidine, dFdC) is an antimetabolite pyrimidine analog clinically used in the treatment of pancreas, lung, breast, and bladder cancers. The drug inhibits RR by the diphosphate metabolite dFdCDP and DNA synthesis by incorporation of the triphosphate metabolite (dFdCTP) during the S-phase of the cell cycle. Biochemical studies have demonstrated that the prodrug gemcitabine is converted into dFdCMP by deoxycytidine kinase (dCK), the rate-limiting enzyme of the salvage pathway of nucleotide synthesis, while cytidine deaminase (CdA) and 5'-nucleotidase (5'-NT) play an important role in drug catabolism (29,30). Preclinical studies have demonstrated that the sensitivity of tumor cells to dFdC depends, at least in part, on the expression of activating and inactivating enzymes, on the intracellular amount of dFdCTP, and also on the cellular target enzyme RR (29,31). These findings underscore the potential role of RR, an essential enzyme of DNA synthesis and repair, because it maintains a large deoxyribonucleotide pool by reduction of ribonucleotides (32). Indeed, chemosensitive tumors have low expression of RR, while dCK is upregulated; thus gemcitabine is converted into active metabolites, inhibits RR, lowers the deoxynucleotide pool, and thereby facilitates the incorporation of dFdCTP into the DNA (33) (Fig. 10). Conversely, in tumors resistant to gemcitabine, the expression of RR is high and dCK is low (34). Experimental studies have demonstrated that downregulation of the catalytic subunit of RR (RRM2) enhances chemosensitivity to gemcitabine (35) and clinical studies are underway to test the clinical advantage achieved by individually tailored chemotherapy on the basis of gene profiling of the tumor, which includes the regulatory subunit of RR (RRM1) (36). Finally, alternatively spliced dCK transcripts have been detected at high frequency in

Figure 10 Overview of molecular determinants of gemcitabine (dFdC) activity and opposite regulation of dCK and RR activity. A chemosensitive tumor (left) is characterized by elevated expression of dCK and low expression of RR; the opposite genetic signature is associated with the resistant tumor (right). Abbreviations: MP, DP, TP, mono-, di-, and tri-phosphate metabolites; dCK, deoxycytidine kinase; RR, ribonucleotide reductase; dCyd, deoxycytidine.

Figure 10 Overview of molecular determinants of gemcitabine (dFdC) activity and opposite regulation of dCK and RR activity. A chemosensitive tumor (left) is characterized by elevated expression of dCK and low expression of RR; the opposite genetic signature is associated with the resistant tumor (right). Abbreviations: MP, DP, TP, mono-, di-, and tri-phosphate metabolites; dCK, deoxycytidine kinase; RR, ribonucleotide reductase; dCyd, deoxycytidine.

cytarabine-resistant leukemic cell lines and preliminary data indicate that this also occurs in solid tumors; since this genetic abnormality does not have a dominant-negative inhibitory effect on normal dCK activity, cells must have lost wild-type dCK expression (37).

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