Comparison of intraperitoneal continuous infusion of floxuridine and bolus administration in a peritoneal gastric cancer xenograft model.
OBJECTIVE
To identify the optimal schedule for intraperitoneal (i.p.) infusion of floxuridine (FUDR) against peritoneal micrometastases from gastric cancer.


METHODS
The efficacy of continuous i.p. infusion of FUDR was compared with that of bolus i.p. administration in peritoneal gastric cancer (MKN45) xenografts. The FUDR continuous delivery system in this study was in the form of injectable poly(lactic-coglycolic) acid (PLGA) microspheres intended for i.p. injection. Animals were treated by continuous i.p. infusion using FUDR-loaded microspheres or bolus i.p. administration of FUDR.


RESULTS
In vitro testing demonstrated that FUDR was released slowly from the microspheres at a rate of approximately 5% of the total encapsulated drug per day. In in vivo studies, the peritoneal level was found to persist and was approximately 5- to 50-fold higher than that of plasma for more than 2 weeks following a single injection of the microspheres. An in vitro MTT assay showed that exposure time clearly influenced the cytotoxic potency of FUDR. In vivo, continuous infusion was more effective against peritoneal tumor than bolus administration at equivalent doses. However, compared with bolus administration, toxicity was increased, resulting in a reduced maximum tolerated dose (MTD) with continuous infusion. When the treatment was carried out at each MTD (continuous 1 mg/kg, bolus 600 mg/kg), continuous infusion had no advantage in inhibiting tumor growth.


CONCLUSIONS
Owing to the higher toxicity and the equal efficacy of continuous infusion compared with bolus administration, continuous infusion is not recommended in i.p. FUDR treatment.
Inoue
Kentaro
K
Second Department of Surgery, Kansai Medical University, Osaka, Japan. inoueke@takii.kmu.ac.jp
Onishi
Hiraku
H
Kato
Yoshinori
Y
Michiura
Taku
T
Nakai
Koji
K
Sato
Mutsuya
M
Yamamichi
Keigo
K
Machida
Yoshiharu
Y
Nakane
Yasushi
Y
D000818:Animals; D005467:Floxuridine / Q000008:administration & dosage* / Q000493:pharmacokinetics; D006801:Humans; D007274:Injections, Intraperitoneal; D019344:Lactic Acid / Q000008:administration & dosage; D008297:Male; D020714:Maximum Tolerated Dose; D051379:Mice; D008807:Mice, Inbred BALB C; D008863:Microspheres; D009368:Neoplasm Transplantation; D011100:Polyglycolic Acid / Q000008:administration & dosage; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011108:Polymers / Q000008:administration & dosage; D051381:Rats; D011916:Rats, Inbred F344; D013274:Stomach Neoplasms / Q000188:drug therapy*; D014183:Transplantation, Heterologous
D011108:Polymers; D005467:Floxuridine; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid