Comparison of intraperitoneal continuous infusion of floxuridine and bolus administration in a peritoneal gastric cancer xenograft model

Kentaro Inoue, Hiraku Onishi, Yoshinori Kato, Taku Michiura, Koji Nakai, Mutsuya Sato, Keigo Yamamichi, Yoshiharu Machida, Yasushi Nakane

Research output: Contribution to journalArticle

Abstract

Purpose: 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.

Original languageEnglish (US)
Pages (from-to)415-422
Number of pages8
JournalCancer Chemotherapy and Pharmacology
Volume53
Issue number5
DOIs
StatePublished - May 2004
Externally publishedYes

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Parenteral Infusions
Floxuridine
Microspheres
Heterografts
Stomach Neoplasms
Maximum Tolerated Dose
Toxicity
Tumors
Neoplasm Micrometastasis
Injections
Intraperitoneal Injections
Neoplasms
Appointments and Schedules
Assays
Animals
Plasmas
Therapeutics
Growth
Pharmaceutical Preparations
Testing

Keywords

  • Adjuvant chemotherapy
  • Drug delivery system
  • FUDR
  • Microsphere
  • PLGA

ASJC Scopus subject areas

  • Cancer Research
  • Pharmacology
  • Oncology

Cite this

Comparison of intraperitoneal continuous infusion of floxuridine and bolus administration in a peritoneal gastric cancer xenograft model. / Inoue, Kentaro; Onishi, Hiraku; Kato, Yoshinori; Michiura, Taku; Nakai, Koji; Sato, Mutsuya; Yamamichi, Keigo; Machida, Yoshiharu; Nakane, Yasushi.

In: Cancer Chemotherapy and Pharmacology, Vol. 53, No. 5, 05.2004, p. 415-422.

Research output: Contribution to journalArticle

Inoue, Kentaro ; Onishi, Hiraku ; Kato, Yoshinori ; Michiura, Taku ; Nakai, Koji ; Sato, Mutsuya ; Yamamichi, Keigo ; Machida, Yoshiharu ; Nakane, Yasushi. / Comparison of intraperitoneal continuous infusion of floxuridine and bolus administration in a peritoneal gastric cancer xenograft model. In: Cancer Chemotherapy and Pharmacology. 2004 ; Vol. 53, No. 5. pp. 415-422.
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T1 - Comparison of intraperitoneal continuous infusion of floxuridine and bolus administration in a peritoneal gastric cancer xenograft model

AU - Inoue, Kentaro

AU - Onishi, Hiraku

AU - Kato, Yoshinori

AU - Michiura, Taku

AU - Nakai, Koji

AU - Sato, Mutsuya

AU - Yamamichi, Keigo

AU - Machida, Yoshiharu

AU - Nakane, Yasushi

PY - 2004/5

Y1 - 2004/5

N2 - Purpose: 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.

AB - Purpose: 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.

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KW - Microsphere

KW - PLGA

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