Abstract |
Gemcitabine (GEM) is presently the standard option for the treatment of advanced pancreatic cancer (PC). We investigated the in vitro and in vivo antitumor potential of GEM-loaded PEGylated liposomes (L-GEM) as a novel agent for the treatment of PC. In vitro analysis of antitumor activity against human PC cell lines, BXPC-3 and PSN-1, showed a significant time- and dose-dependent reduction of cell viability following exposure to L-GEM as compared to free GEM [at 72 h, IC(50): 0.009 vs. 0.027 microM (P = 0.003) for BXPC-3 and 0.003 vs. 0.009 microM (P < 0.001) for PSN1, respectively]. Confocal laser scanning microscopy demonstrated an effective liposome/cell interaction and internalization process following 3-h cell exposure to L-GEM. The in vivo antitumor activity of L-GEM was investigated in a cohort of SCID mice bearing BxPC-3 or PSN-1 xenografts. Animals were i.p. treated with L-GEM (5 mg/kg), or a threefold increased dose of free GEM (15 mg/kg), or empty liposomes or vehicle, twice a week for 35 days. A significant higher inhibition of tumor growth in mice treated with L-GEM versus free GEM (P = 0.006 and P = 0.004 for BXPC-3 and PSN-1, respectively) or control groups (P = 0.0001), translated in a survival advantage of L-GEM treated animals versus other groups. Pharmacokinetic studies showed enhancement of systemic bioavailability of L-GEM (t (1/2) = 8 h) versus to GEM (t (1/2) = 1.5 h). Our findings demonstrate that L-GEM is an effective agent against PC and exerts higher antitumor activity as compared to free GEM with no appreciable increase in toxicity. These results provide the pre-clinical rational for L-GEM clinical development for the treatment of PC patients.
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Authors | Donato Cosco, Alessandra Bulotta, Monica Ventura, Christian Celia, Teresa Calimeri, Gino Perri, Donatella Paolino, Nicola Costa, Paola Neri, Pierosandro Tagliaferri, Pierfrancesco Tassone, Massimo Fresta |
Journal | Cancer chemotherapy and pharmacology
(Cancer Chemother Pharmacol)
Vol. 64
Issue 5
Pg. 1009-20
(Oct 2009)
ISSN: 1432-0843 [Electronic] Germany |
PMID | 19263052
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Antimetabolites, Antineoplastic
- Drug Carriers
- Liposomes
- Deoxycytidine
- Polyethylene Glycols
- Gemcitabine
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Topics |
- Animals
- Antimetabolites, Antineoplastic
(administration & dosage, pharmacokinetics, therapeutic use)
- Cell Line, Tumor
- Cell Proliferation
(drug effects)
- Deoxycytidine
(administration & dosage, analogs & derivatives, pharmacokinetics, therapeutic use)
- Drug Carriers
- Half-Life
- Humans
- Liposomes
- Mice
- Mice, SCID
- Microscopy, Confocal
- Pancreatic Neoplasms
(drug therapy)
- Polyethylene Glycols
(chemistry)
- Xenograft Model Antitumor Assays
- Gemcitabine
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