Abstract | PURPOSE: The aims of this study were to develop a stealth, pegylated liposomal formulation of 2'-deoxyinosine (d-Ino), a 5-fluorouracil (5-FU) modulator, to evaluate its efficacy in vitro and in tumor-bearing mice, and to study its pharmacokinetics in rats. METHOD: After designing a pegylated liposome encapsulating d-Ino (L-d-Ino), we evaluated its efficacy as 5-FU modulator in vitro. Antiproliferative assays, thymidylate synthase (TS) inhibition, and apoptosis studies were carried out to check whether an optimization of 5-FU action was achieved on the 5-FU-resistant SW620 cell line. Animal pharmacokinetic and ex vivo studies were next performed to confirm that L-d-Ino displayed a slower plasma elimination pattern than free d-Ino. Finally, effects on tumor growth of L-d-Ino + 5-FU combination was evaluated in xenografted mice. RESULTS: We developed a stable, sterile, and homogenous 100-nm population of pegylated liposomes encapsulating 30% of d-Ino. Liposomal d-Ino exhibited a strong potential as 5-FU modulator in vitro by enhancing TS inhibition and subsequent apoptosis induction, while displaying a better pharmacokinetic profile in animals, with a near seven times clearance reduction as compared with the free form. When used in tumor-bearing mice in combination with 5-FU, our results showed next that the association led to 70% of tumor reduction with a doubling median survival time as compared with untreated animals, whereas 5-FU alone was ineffective. CONCLUSION: Our data show that liposomal d-Ino, through an optimized pharmacokinetic profile, displays a potent effect as fluoropyrimidines modulator, both in vitro and in xenografted mice. Besides, we showed here that it is possible to reverse a resistant phenotype to 5-FU, a major drug extensively described in clinical oncology.
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Authors | Raphaelle Fanciullino, Sarah Giacometti, Claude Aubert, Frederic Fina, Pierre-Marie Martin, Philippe Piccerelle, Joseph Ciccolini |
Journal | Pharmaceutical research
(Pharm Res)
Vol. 22
Issue 12
Pg. 2051-7
(Dec 2005)
ISSN: 0724-8741 [Print] United States |
PMID | 16222443
(Publication Type: Journal Article)
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Chemical References |
- Antimetabolites, Antineoplastic
- Enzyme Inhibitors
- Liposomes
- Inosine
- Thymidylate Synthase
- deoxyinosine
- Fluorouracil
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Topics |
- Animals
- Antimetabolites, Antineoplastic
(pharmacology)
- Apoptosis
(drug effects)
- Cell Line, Tumor
- Cell Proliferation
(drug effects)
- Chemistry, Pharmaceutical
- Chromatography, High Pressure Liquid
- Drug Delivery Systems
- Drug Synergism
- Enzyme Inhibitors
(pharmacology)
- Fluorouracil
(pharmacology)
- Inosine
(administration & dosage, analogs & derivatives, pharmacology)
- Lasers
- Liposomes
- Male
- Mice
- Mice, Nude
- Neoplasm Transplantation
- Rats
- Rats, Wistar
- Scattering, Radiation
- Thymidylate Synthase
(antagonists & inhibitors)
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