title: Antiproliferative activity and mechanism of action of fatty acid derivatives of gemcitabine in leukemia and solid tumor cell lines and in human xenografts.
abstract: Gemcitabine is a deoxycytidine analog, which can be inactivated by deamination catalyzed by deoxycytidine deaminase (dCDA). Altered transport over the cell membrane is a mechanism of resistance to gemcitabine. To facilitate accumulation, the fatty acid derivative CP-4125 was synthesized. Since, the fatty acid is acylated at the site of action of dCDA, a decreased deamination was expected. CP-4125 was equally active as gemcitabine in a panel of rodent and human cell lines and in human melanoma xenografts bearing mice. In contrast to gemcitabine, CP-4125 was not deaminated but inhibited deamination of deoxycytidine and gemcitabine. Pools of the active triphosphate of gemcitabine increased for over 20 hr after CP-4125 exposure, while these pools decreased directly after removal of gemcitabine.
  
  
  CONCLUSIONS
  CP-4125 is an interesting new gemcitabine derivative.
authors.affiliation: Department Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: A M
authors.initials: AM
authors.lastname: Bergman
authors.forename: C M
authors.initials: CM
authors.lastname: Kuiper
authors.forename: P
authors.initials: P
authors.lastname: Noordhuis
authors.forename: K
authors.initials: K
authors.lastname: Smid
authors.forename: D A
authors.initials: DA
authors.lastname: Voorn
authors.forename: E M
authors.initials: EM
authors.lastname: Comijn
authors.forename: F
authors.initials: F
authors.lastname: Myhren
authors.forename: M L
authors.initials: ML
authors.lastname: Sandvold
authors.forename: H R
authors.initials: HR
authors.lastname: Hendriks
authors.forename: O
authors.initials: O
authors.lastname: Fodstad
authors.forename: K
authors.initials: K
authors.lastname: Breistøl
authors.forename: G J
authors.initials: GJ
authors.lastname: Peters
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D002244:Carbon / Q000737:chemistry; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D049109:Cell Proliferation; D003564:Cytidine Deaminase; D004247:DNA / Q000737:chemistry; D004249:DNA Damage; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D005227:Fatty Acids / Q000378:metabolism*; D006801:Humans; D020128:Inhibitory Concentration 50; D007938:Leukemia / Q000188:drug therapy*; D008545:Melanoma / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D008956:Models, Chemical; D009368:Neoplasm Transplantation; D009700:Nucleoside Deaminases / Q000378:metabolism; D010766:Phosphorylation; D051381:Rats; D013997:Time Factors; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D005227:Fatty Acids; D003841:Deoxycytidine; D002244:Carbon; D004247:DNA; D009700:Nucleoside Deaminases; D003564:Cytidine Deaminase; C011530:deoxycytidine deaminase; D000093542:Gemcitabine