Gemcitabine

Gemcitabine (2',2' difluorodeoxycytidine; dFdC), a difluoro analog of deoxycytidine, is used for patients with metastatic pancreatic cancer, non-small cell lung cancer, ovarian, bladder, esophageal, and head and neck cancer. Gemcitabine enters cells via active nucleoside transporters. IntracelMarly, deoxycytidine kinase phosphorylates gemcitabine to produce difluorodeoxycytidine monophosphate (dFdCMP), from which point it is converted to difluorodeoxycytidine di- and triphosphate (dFdCDP and dFdCTP). While its anabolism and effects on DNA in general mimic those of cytarabine, there are differences in kinetics of inhibition, additional sites of action, effects of incorporation into DNA, and spectrum of clinical activity. Unlike cytarabine, the cytotoxicity of gemcitabine is not confined to the S phase of the cell cycle. The cytotoxic activity may reflect several actions on DNA synthesis: dFdCTP competes with dCTP as a weak inhibitor of DNA poly-merase; dFdCDP is a potent inhibitor of ribonucleotide reductase, resulting in depletion of deoxyribonucleotide pools necessary for DNA synthesis; and incorporation of dFdCTP into DNA leads to DNA strand termination that is apparently resistant to repair. The ability of cells to incorporate dFdCTP into DNA is critical for gemcitabine-induced apoptosis.

Gemcitabine is administered by intravenous infusion. The pharmacokinetics of the parent compound is largely determined by deamination, and the predominant urinary elimination product is the inactive metabolite difluorodeoxyuridine (dFdU). Gemcitabine has a short plasma t122 (~15 minutes), with women and elderly subjects having slower clearance. Clearance is dose-independent but varies widely among individuals. The standard dosing schedule for gemcitabine (gemzar) is a 30-minute intravenous infusion of 1—1.2 g/m2 on days 1, 8, and 15 of each 28-day cycle. Similar to that of cytarabine, conversion of gemcitabine to dFdCMP by deoxycytidine kinase is saturated at infusion rates of ~10 mg/m2/min. To increase dFdCTP formation, the duration of infusion at this maximum concentration has been extended to 150 minutes. In contrast to infusion duration of 30 minutes, the 150-minute infusion produces a higher level of dFdCTP within peripheral blood mononuclear cells, increases the degree of myelosuppression, but has uncertain effects on antitumor activity.

The activity of dFdCTP on DNA repair mechanisms may allow for increased cytotoxicity of other chemotherapeutic agents, particularly platinum compounds. Preclinical studies of tumor cell lines show that cisplatin-DNA adducts are enhanced in the presence of gemcitabine, presumably through suppression of nuclear excision repair.

The principal toxicity of gemcitabine is myelosuppression. In general, longer-duration infusions lead to greater myelosuppression. Nonhematologic toxicities including a flu-like syndrome, asthenia, and mild elevation in liver transaminases may occur in 40% or more of patients. Although severe nonhematological toxicities are rare, interstitial pneumonitis may occur and is responsive to glucocorticoids. Rarely, patients on gemcitabine treatment for many months may develop a slowly progressive hemolytic uremic syndrome, necessitating drug discontinuation. Gemcitabine is a very potent radiosensitizer and generally should not be used with radiotherapy.

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