Antiproliferative activity and mechanism of action of fatty acid derivatives of gemcitabine in leukemia and solid tumor cell lines and in human xenografts.
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.
Bergman
A M
AM
Department Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands.
Kuiper
C M
CM
Noordhuis
P
P
Smid
K
K
Voorn
D A
DA
Comijn
E M
EM
Myhren
F
F
Sandvold
M L
ML
Hendriks
H R
HR
Fodstad
O
O
Breistøl
K
K
Peters
G J
GJ
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
D000964:Antimetabolites, Antineoplastic; D005227:Fatty Acids; D003841:Deoxycytidine; D002244:Carbon; D004247:DNA; D009700:Nucleoside Deaminases; D003564:Cytidine Deaminase; C011530:deoxycytidine deaminase; D000093542:Gemcitabine