Antitumor activity and pharmacokinetics of liposomes containing lipophilic gemcitabine prodrugs.
BACKGROUND
Gemcitabine is a deoxycytidine analogue that exhibits antitumoral activity against adenocarcinomas of the colon, lung and pancreas. After intravenous injection, gemcitabine is rapidly converted to the inactive metabolite 2'-deoxy-2',2'-difluorouridine by cytidine deaminase.


METHODS
To improve the pharmacokinetic behavior and the antitumor activity of the drug, the gemcitabine prodrug, 4-(N)-stearoylgemcitabine (C18gem) was incorporated in liposomes and both the pharmacokinetic and the in vivo activity of this formulation intravenously or peritumorally administered in nude female CR1:Nu/Nu(CD-1)BR mice grafted with HT-29 and KB 396p cells were studied.


RESULTS
The C18gem-liposomes showed both higher plasma half life and tumor regression than control and gemcitabine.


CONCLUSIONS
The incorporation of C18gem-prodrug in liposomes increased the plasma half life of the drug resulting in increased accumulation in the tumor cells and a higher level of antitumoral efficacy. The results obtained with different tumors sensitive to gemcitabine support the efficacy of this proposed drug delivery system.
Brusa
Paola
P
Dipartimento di Scienza e Tecnologia del Farmaco, Università degli Studi di Torino, 10125 Torino, Italy.
Immordino
Maria Laura
ML
Rocco
Flavio
F
Cattel
Luigi
L
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage* / Q000493:pharmacokinetics; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000378:metabolism; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D005260:Female; D019073:HT29 Cells; D006801:Humans; D008081:Liposomes; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009303:Nasopharyngeal Neoplasms / Q000188:drug therapy / Q000378:metabolism; D011355:Prodrugs / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D013228:Stearates / Q000008:administration & dosage / Q000493:pharmacokinetics; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
D000964:Antimetabolites, Antineoplastic; D008081:Liposomes; D011355:Prodrugs; D013228:Stearates; D003841:Deoxycytidine; D000093542:Gemcitabine