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      Gemcitabine: metabolism, mechanisms of action, and self-potentiation.

      Seminars in Oncology
      Animals, Antimetabolites, Antineoplastic, chemistry, metabolism, pharmacology, Cell Death, drug effects, Cytidine Deaminase, DNA, Neoplasm, Deoxycytidine, analogs & derivatives, Drug Synergism, Half-Life, Humans, Prodrugs, Ribonucleotide Reductases, antagonists & inhibitors, Substrate Specificity, Tumor Cells, Cultured, enzymology

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          Abstract

          Gemcitabine (dFdC) is a new anticancer nucleoside that is an analog of deoxycytidine. It is a pro-drug and, once transported into the cell, must be phosphorylated by deoxycytidine kinase to an active form. Both gemcitabine diphosphate (dFdCTP) and gemcitabine triphosphate (dFdCTP) inhibit processes required for DNA synthesis. Incorporation of dFdCTP into DNA is most likely the major mechanism by which gemcitabine causes cell death. After incorporation of gemcitabine nucleotide on the end of the elongating DNA strand, one more deoxynucleotide is added and thereafter, the DNA polymerases are unable to proceed. This action ("masked termination") apparently locks the drug into DNA as the proofreading enzymes are unable to remove gemcitabine from this position. Furthermore, the unique actions that gemcitabine metabolites exert on cellular regulatory processes serve to enhance the overall inhibitory activities on cell growth. This interaction is termed "self-potentiation" and is evidenced in very few other anticancer drugs.

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