Gemcitabine monotherapy in recurrent ovarian cancer: from the bench to the clinic.
Gemcitabine (2'2'-difluorodeoxycytidine [dFdC]) is a synthetic analog of deoxycytidine with two fluorine atoms at the 2' position of the carbohydrate. As a hydrophobic molecule, dFdC competes for intracellular access via membrane-associated nucleoside transporter proteins. Following intracellular transport, dFdC is phosphorylated sequentially by deoxycytidine kinase to gemcitabine triphosphate, which inhibits ribonucleotide metabolism, hinders DNA processing, and increases accumulation of intrastrand adducts and interstrand cross-links, thereby leading to a G1 block in the cell cycle. dFdC monotherapy has been extensively evaluated at doses of 800-1250 mg/m2. dFdC is generally well tolerated, with the most frequently occurring dose-limiting toxicities being hematologic, noncumulative, and easily managed by dose alteration. Several studies involving treatment of recurrent ovarian cancer patients with dFdC monotherapy, most of whom had platinum-resistant disease and/or prior exposure to paclitaxel, led to overall response rates of 14-22% and a median duration of response of 4.0-10.6 months. An additional one third of the participants experienced stable disease for an overall clinical benefit in approximately one half of the treated patients. Tumor cells with a multidrug resistance phenotype have increased sensitivity to dFdC (collateral sensitivity). As dFdC is unaffected by platinum resistance, and not susceptible to classic multidrug resistance, it could be particularly beneficial to administer following treatment with agents that induce multidrug resistance. Integration of dFdC with platinum and/or radiation should also be investigated.
Bookman
M A
MA
Division of Medical Science, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA. ma_bookman@fccc.edu
D000964:Antimetabolites, Antineoplastic / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*; D004273:DNA, Neoplasm / Q000378:metabolism; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*; D018432:Drug Resistance, Multiple; D005260:Female; D006801:Humans; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics; D010641:Phenotype; D010766:Phosphorylation; D000093542:Gemcitabine
D000964:Antimetabolites, Antineoplastic; D004273:DNA, Neoplasm; D003841:Deoxycytidine; D000093542:Gemcitabine