title: Preclinical, pharmacologic, and phase I studies of gemcitabine.
abstract: Gemcitabine (2',2'-difluorodeoxycytidine) is a novel nucleoside analogue that exerts its antitumor activity via multiple mechanisms of action. These include (1) incorporation of gemcitabine into replicating DNA, which inhibits DNA replication and cell growth, (2) masked DNA chain termination, and (3) several self-potentiation mechanisms that serve to increase intracellular levels of the active compound. Preclinical experiments in various cell lines and animal models demonstrate a broad range of cytotoxic activity. Pharmacokinetic studies of gemcitabine delivered by its usual schedule (30-minute weekly infusion) reveal a short plasma half-life and a high clearance into central and peripheral compartments (two-compartment model). The drug is excreted almost completely in the urine as the parent compound and primary metabolite (difluorodeoxyuridine). Phase I trials demonstrate that pharmacokinetics are schedule dependent and that, in general, gemcitabine is well tolerated. Dose-limiting toxicities are primarily myelosuppression, with other toxicities being rash, flu-like symptoms, and transient elevations in liver function tests.
authors.affiliation: Department of Cancer Research and Clinical Investigations, Eli Lilly and Company, Indianapolis, IN 46285, USA.
authors.forename: A M
authors.initials: AM
authors.lastname: Storniolo
authors.forename: S R
authors.initials: SR
authors.lastname: Allerheiligen
authors.forename: H L
authors.initials: HL
authors.lastname: Pearce
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000378:metabolism; D017321:Clinical Trials, Phase I as Topic; D004261:DNA Replication / Q000187:drug effects; D004273:DNA, Neoplasm / Q000187:drug effects; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D004353:Drug Evaluation, Preclinical; D006207:Half-Life; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism; D012264:Ribonucleotide Reductases / Q000037:antagonists & inhibitors*; D012449:Safety; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D004273:DNA, Neoplasm; D003841:Deoxycytidine; D012264:Ribonucleotide Reductases; D000093542:Gemcitabine