Selective targeting of 2'-deoxy-5-fluorouridine to urokinase positive malignant cells in vitro.
A urokinase targeting conjugate of 2'-deoxy-5-fluorouridine (5-FUdr) was synthesized and tested for tumor-cell selective cytotoxicity in vitro. The 5-FUdr prodrug 2'-deoxy-5-fluoro-3'-O-(3-carboxypropanoyl)uridine (5-FUdrsuccOH) containing an ester-labile succinate linker was attached to the specific urokinase inhibitor plasminogen activator inhibitor type II (PAI-2) and was found to preferentially kill urokinase-over expressing cancer cells. Up to 7 molecules of 5-FUdr were incorporated per PAI-2 molecule without affecting protein activity. This is the first time a small organic cytotoxin has been conjugated to PAI-2.
Vine
Kara L
KL
School of Biological Sciences and Centre for Medical Bioscience, University of Wollongong, NSW 2522, Australia. v
Locke
Julie M
JM
Bremner
John B
JB
Pyne
Stephen G
SG
Ranson
Marie
M
D045744:Cell Line, Tumor; D006801:Humans; D009369:Neoplasms / Q000201:enzymology; D017396:Plasminogen Activator Inhibitor 2 / Q000737:chemistry / Q000378:metabolism; D014529:Uridine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000633:toxicity; D014568:Urokinase-Type Plasminogen Activator / Q000037:antagonists & inhibitors / Q000378:metabolism*
D017396:Plasminogen Activator Inhibitor 2; C001943:5-fluorouridine; D014568:Urokinase-Type Plasminogen Activator; D014529:Uridine