ReviewDeterminants of resistance to 2′,2′-difluorodeoxycytidine (gemcitabine)
Introduction
Gemcitabine (2′,2′-difluorodeoxycytidine, dFdC, Gemzar®) is a deoxycytidine analog with activity against human leukemia and murine solid tumors, which was first described in 1986 (Grindey et al., 1986, Hertel et al., 1988, Hertel et al., 1990). Although the functionally and structurally related deoxycytidine analog 1-β-d-arabinofuranosylcytosine (ara-C) is only active against leukemias, gemcitabine has been found to be active against several experimental solid tumors such as non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), ovarian and pancreatic cancers (Hertel et al., 1990, Braakhuis et al., 1995, Boven et al., 1993, Merriman et al., 1996, Jansen et al., 1995), and in the clinic (Abratt et al., 1994, Heinemann, 2001, Kaye, 1994). Combinations are active against many other solid tumors such as bladder cancer, gastric cancer, esophageal cancer and ovarian cancer (Van Moorsel et al., 1997). Although the activation steps of ara-C and gemcitabine are basically the same, gemcitabine has a more complicated mechanism of action with more cellular targets (Fig. 1). An alteration in these cellular targets may result in a decreased sensitivity to gemcitabine. Moreover, resistance can be multifactorial. Since gemcitabine is now extensively used in the treatment of patients with various tumor types, it is very likely that tumors will develop an acquired resistance to gemcitabine. Acquired resistance after prolonged and repeated exposure to gemcitabine is only one mechanism of resistance. Some tumors seem to be inherently resistant, which was shown by low response rates in clinical trials of patients with advanced colon cancer (Carmichael, 1998). To overcome low response rates, gemcitabine is combined with cytostatic agents with different mechanisms of action, e.g. gemcitabine and cisplatin for the treatment of NSCLC (Abratt et al., 1998). The mechanisms of resistance to gemcitabine and the possibilities to overcome them are described in this review.
Section snippets
Transport across the cell membrane
Like other nucleoside analogs gemcitabine is hydrophilic and cannot traverse cell membranes by passive diffusion (Cass, 1995). Specialized transport systems are required for the passage of nucleoside analogs in or out of cells. There are seven distinct carriers for the transport of nucleosides that are either of the sodium-dependent (concentrative) type (CNT) or of the sodium-independent (equilibrative) type (ENT) (Griffith and Jarvis, 1996). The latter type is classified into two major
Genomic alterations and resistance
Resistance to antimetabolite drugs such as gemcitabine can be achieved by various genomic alterations. Exposure to antimetabolite drugs results in genomic instability, which can eventually lead to gene deletions and gene mutations. In mortal and transformed fibroblasts, gemcitabine was found to induce DNA single-strand breaks, accumulation of cells in the S-phase of the cell cycle, chromatid exchange and micronuclei (Auer et al., 1997). In L1210 murine leukemia cells made resistant to ara-C by
Induction of apoptosis
Apoptosis is a distinct mode of cell death responsible for deletion of cells in normal and in pathological tissue (Arends and Wyllie, 1991). Morphologically, apoptosis involves rapid nuclear alterations characterized by chromatin condensation and nuclear fragmentation (Kerr et al., 1993). A characteristic biochemical feature of the process is double-strand cleavage of the nuclear DNA at the linkage regions between nucleosomes, leading to the production of oligonucleosomal fragments (McConkey et
Conclusions and perspectives
Gemcitabine has established its place in the treatment of several solid tumors. Despite its relative success, response rates are still low, especially in relapsed tumors after previous treatment. To increase the success of treatment with gemcitabine-based chemotherapy, research on the mechanisms of resistance to this drug is warranted. As described above, gemcitabine has a complicated mechanism of action. Many enzymes are involved in metabolism of the drug or are targets for the different
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