Intra-aortal therapy with 5-fluorouracil- polyethylene glycol stealth liposomes: does the metabolism of 5-fluorouracil into 5-fluoro-2'-deoxyuridine depend on ph value?. An animal study in VX-2 liver tumor-bearing rabbits.
BACKGROUND
The application of liposome-encapsulated cytostatics results in higher concentrations in tumor tissue. This effect can be further increased by blood flow retardation with longer retention time in the tumor and by arterial administration realized in abdominal stop-flow therapy, a separate partial circulation with a defined flow under hypoxic conditions. The pH changes under stop-flow therapy may affect the further metabolism of 5-fluorouracil (5-FU), used here.


METHODS
The in vitro 5-fluoro-2'-deoxyuridine (5-FUrd) concentrations at increasing pH values were measured using liposomal encapsulated and free 5-FU. Subsequently, 20 chinchilla rabbits were treated intra-aortally with 5-FU or 5-FU-polyethylene glycol (PEG) liposomes. The pH value was maintained in the physiological range by continuous NaHCO3 application. After 20 min, concentrations of 5-FU and its metabolite 5-FUrd were determined in different organs, the perfusate, serum and the VX-2 tumor by HPLC.


RESULTS
The in vitro 5-FUrd concentrations, which occur only in the physiological pH range, were doubled by the use of 5-FU-PEG liposomes. In the animal trial, NaHCO(3) titration doubled the 5-FUrd concentrations found in our preliminary studies. Compared to free 5-FU, 5-FU-PEG liposomes significantly increased the concentrations in the VX-2 liver tumor by 6.6-fold and in the para-aortal lymph nodes by 8.76-fold.


CONCLUSIONS
The metabolism of 5-FU into its active metabolite 5-FUrd depends on the pH value and can be modulated. 5-FUrd concentrations can be approximately doubled with the intra-aortal application of 5-FU-PEG liposomes compared to free 5-FU.
Pohlen
U
U
Department of Surgery, University Hospital Benjamin Franklin, Free University of Berlin, Berlin, Germany. SU1110@aol.com
Binnenhei
M
M
Reszka
R
R
Buhr
H J
HJ
Berger
G
G
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000737:chemistry / Q000493:pharmacokinetics*; D001012:Aorta, Abdominal; D045744:Cell Line, Tumor; D002851:Chromatography, High Pressure Liquid; D005467:Floxuridine / Q000378:metabolism*; D005472:Fluorouracil / Q000737:chemistry / Q000493:pharmacokinetics*; D006863:Hydrogen-Ion Concentration; D066298:In Vitro Techniques; D008081:Liposomes; D008099:Liver / Q000378:metabolism; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy / Q000378:metabolism; D008297:Male; D011092:Polyethylene Glycols / Q000737:chemistry*; D011817:Rabbits; D014018:Tissue Distribution
D000964:Antimetabolites, Antineoplastic; D008081:Liposomes; D005467:Floxuridine; D011092:Polyethylene Glycols; D005472:Fluorouracil