title: Cellular transport of CI-980.
abstract: CI-980, originally synthesized as a potential folate antagonist, is a tubulin-binding mitotic inhibitor currently in pediatric phase I and adult phase II clinical trials. Because of its extensive tissue distribution in animals and its favorable activity against multidrug resistant (MDR)-cells compared with other mitotic inhibitors, such as vincristine, we examined the membrane transport properties of CI-980. CI-980 accumulated rapidly in L1210 and CHO/K1 cells, reaching intracellular levels 40- and 8-fold higher, respectively, than those in the extracellular medium. Efflux was also quite rapid, but a small fraction of drug remained associated with the cells in drug-free medium. The uptake of CI-980 was not temperature or energy dependent, nor was it saturable up to an extracellular concentration of 100 microM. Inhibitors of nucleoside transport had no effect on CI-980 uptake. A cell line deficient in the transport of reduced folate was not resistant to CI-980, nor did it exhibit reduced CI-980 uptake. A 100-fold excess of the R-enantiomer inhibited CI-980 uptake by only 50%. These results are consistent with a model of CI-980 uptake involving passive diffusion followed by significant but largely reversible binding to intracellular or membrane components.
authors.affiliation: Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, Ann Arbor, Michigan 48105, USA.
authors.forename: K E
authors.initials: KE
authors.lastname: Hook
authors.forename: S A
authors.initials: SA
authors.lastname: Przybranowski
authors.forename: W R
authors.initials: WR
authors.lastname: Leopold
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D001692:Biological Transport; D016466:CHO Cells / Q000378:metabolism; D002219:Carbamates / Q000493:pharmacokinetics*; D002352:Carrier Proteins / Q000502:physiology; D002417:Cattle; D006224:Cricetinae; D004176:Dipyridamole / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D005493:Folic Acid Antagonists / Q000493:pharmacokinetics*; D006801:Humans; D007939:Leukemia L1210 / Q000378:metabolism; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D011719:Pyrazines / Q000493:pharmacokinetics*; D011725:Pyridines / Q000493:pharmacokinetics*; D013237:Stereoisomerism
chemical_list: D000970:Antineoplastic Agents; D002219:Carbamates; D002352:Carrier Proteins; D005493:Folic Acid Antagonists; D010975:Platelet Aggregation Inhibitors; D011719:Pyrazines; D011725:Pyridines; D004176:Dipyridamole; C072383:canertinib dihydrochloride