Skip to main content
Top
Published in: Investigational New Drugs 3/2012

01-06-2012 | PRECLINICAL STUDIES

Hepatic arterial infusion (HAI) with PEGylated liposomes containing 5-FU improves tumor control of liver metastases in a rat model

Authors: Uwe Pohlen, Heinz J. Buhr, Gerd Berger, Jörg-Peter Ritz, Christoph Holmer

Published in: Investigational New Drugs | Issue 3/2012

Login to get access

Summary

Purpose To investigate the cytostatic effect of 5-fluorouracil (5-FU) encapsulated in polyethylene glycol (PEG) liposomes with or without degradable starch microspheres (DSM) in a long-term trial using a rat liver tumor model. Materials and Methods The cytostatics were applied once either as a hepatic arterial infusion (HAI) or were systemically infused via the tail vein. Seven groups were compared with respect to tumor growth and survival times: 5-FU HAI (group I), 5-FU + DSM HAI (group II), PEG-5-FU HAI (group III), PEG-5-FU + DSM HAI (group IV), NaCl HAI (group V), 5-FU i.v. (group VI), and PEG-5-FU i.v. (group VII). Results Seven and 14 days after treatment in groups III and IV, only group IV had significantly inhibited tumor growth on day 21 compared to the groups treated intravenously. On day 28, none of the animals from the intravenously treated groups were still alive compared to a significantly longer survival time of 6 and 8 weeks in groups III and IV. Conclusion Locoregional therapy with 5-fluorouracil encapsulated in PEGylated liposomes may further improve the treatment success with longer-lasting tumor regression and prolonged survival times.
Literature
1.
2.
go back to reference Hotta T, Takifuji K, Arii K, Yokoyama S, Matsuda K, Higashiguchi T, Tominaga T, Oku Y, Yamaue H (2006) Potential predictors of long-term survival after surgery for patients with stage IV colorectal cancer. Anticancer Res 26(2B):1377–1383PubMed Hotta T, Takifuji K, Arii K, Yokoyama S, Matsuda K, Higashiguchi T, Tominaga T, Oku Y, Yamaue H (2006) Potential predictors of long-term survival after surgery for patients with stage IV colorectal cancer. Anticancer Res 26(2B):1377–1383PubMed
3.
go back to reference Smith MD, McCall JL (2009) Systematic review of tumour number and outcome after radical treatment of colorectal liver metastases. Br J Surg 96(10):1101–1131PubMedCrossRef Smith MD, McCall JL (2009) Systematic review of tumour number and outcome after radical treatment of colorectal liver metastases. Br J Surg 96(10):1101–1131PubMedCrossRef
4.
go back to reference Mise Y, Imamura H, Hashimoto T, Seyama Y, Aoki T, Hasegawa K, Beck Y, Sugawara Y, Makuuchi M, Nakajima J, Kokudo N (2010) Cohort study of the survival benefit of resection for recurrent hepatic and/or pulmonary metastases after primary hepatectomy for colorectal metastases. Ann Surg 251(5):902–994PubMedCrossRef Mise Y, Imamura H, Hashimoto T, Seyama Y, Aoki T, Hasegawa K, Beck Y, Sugawara Y, Makuuchi M, Nakajima J, Kokudo N (2010) Cohort study of the survival benefit of resection for recurrent hepatic and/or pulmonary metastases after primary hepatectomy for colorectal metastases. Ann Surg 251(5):902–994PubMedCrossRef
5.
go back to reference Pwint TP, Midgley R, Kerr DJ (2010) Regional hepatic chemotherapies in the treatment of colorectal cancer metastases to the liver. Semin Oncol 37(2):149–159PubMedCrossRef Pwint TP, Midgley R, Kerr DJ (2010) Regional hepatic chemotherapies in the treatment of colorectal cancer metastases to the liver. Semin Oncol 37(2):149–159PubMedCrossRef
6.
go back to reference Pasetto LM, Merenda R, Pilati P, Sinigaglia G, Monfardini S (2006) Hepatic metastases of colorectal cancer: locoregional intra-arterial treatment. Anticancer Res 26(6C):4785–4792PubMed Pasetto LM, Merenda R, Pilati P, Sinigaglia G, Monfardini S (2006) Hepatic metastases of colorectal cancer: locoregional intra-arterial treatment. Anticancer Res 26(6C):4785–4792PubMed
7.
go back to reference Dizon DS, Schwartz J, Kemeny N (2008) Regional chemotherapy: a focus on hepatic artery infusion for colorectal cancer liver metastases. Surg Oncol Clin N Am 17(4):759–771PubMedCrossRef Dizon DS, Schwartz J, Kemeny N (2008) Regional chemotherapy: a focus on hepatic artery infusion for colorectal cancer liver metastases. Surg Oncol Clin N Am 17(4):759–771PubMedCrossRef
8.
go back to reference Pohlen U, Rieger H, Binnenhei M, Reszka RC, Buhr HJ, Berger G (2005) Improvement in 5-fluorouracil (5-FU) and 5-fluoro-2'-deoxyuridine (FdUrd) concentration by 5-fluorouracil-polyethylene-glycol-liposomes in abdominal stop-flow: treatment of VX2 liver-tumor-bearing rabbits. J Chemother 17(4):428–434PubMed Pohlen U, Rieger H, Binnenhei M, Reszka RC, Buhr HJ, Berger G (2005) Improvement in 5-fluorouracil (5-FU) and 5-fluoro-2'-deoxyuridine (FdUrd) concentration by 5-fluorouracil-polyethylene-glycol-liposomes in abdominal stop-flow: treatment of VX2 liver-tumor-bearing rabbits. J Chemother 17(4):428–434PubMed
9.
go back to reference Pohlen U, Rieger H, Mansmann U, Berger G, Buhr HJ (2006) Hepatic arterial infusion (HAI). Comparison of 5-fluorouracil, folinic acid, interferon alpha-2b and degradable starch microspheres versus 5-fluorouracil and folinic acid in patients with non-resectable colorectal liver metastases. Anticancer Res 26(5B):3957–3964PubMed Pohlen U, Rieger H, Mansmann U, Berger G, Buhr HJ (2006) Hepatic arterial infusion (HAI). Comparison of 5-fluorouracil, folinic acid, interferon alpha-2b and degradable starch microspheres versus 5-fluorouracil and folinic acid in patients with non-resectable colorectal liver metastases. Anticancer Res 26(5B):3957–3964PubMed
10.
go back to reference August DA (1996) Theoretic and experimental aspects of regional liver infusion. Surg Oncol Clin N Am 5(2):399–409PubMed August DA (1996) Theoretic and experimental aspects of regional liver infusion. Surg Oncol Clin N Am 5(2):399–409PubMed
11.
go back to reference Wasser K, Giebel F, Fischbach R, Tesch H, Landwehr P (2005) Transarterial chemoembolization of liver metastases of colorectal carcinoma using degradable starch microspheres (Spherex): personal investigations and review of the literature. Radiologe 45(7):633–643PubMedCrossRef Wasser K, Giebel F, Fischbach R, Tesch H, Landwehr P (2005) Transarterial chemoembolization of liver metastases of colorectal carcinoma using degradable starch microspheres (Spherex): personal investigations and review of the literature. Radiologe 45(7):633–643PubMedCrossRef
12.
go back to reference Paolino D, Cosco D, Racanicchi L, Trapasso E, Celia C, Iannone M, Puxeddu E, Costante G, Filetti S, Russo D, Fresta M (2010) Gemcitabine-loaded PEGylated unilamellar liposomes vs GEMZAR((R)): Biodistribution, pharmacokinetic features and in vivo antitumor activity. J Control Release 144(2):144–150PubMedCrossRef Paolino D, Cosco D, Racanicchi L, Trapasso E, Celia C, Iannone M, Puxeddu E, Costante G, Filetti S, Russo D, Fresta M (2010) Gemcitabine-loaded PEGylated unilamellar liposomes vs GEMZAR((R)): Biodistribution, pharmacokinetic features and in vivo antitumor activity. J Control Release 144(2):144–150PubMedCrossRef
13.
go back to reference Chow TH, Lin YY, Hwang JJ, Wang HE, Tseng YL, Wang SJ, Liu RS, Lin WJ, Yang CS, Ting G (2009) Improvement of biodistribution and therapeutic index via increase of polyethylene glycol on drug-carrying liposomes in an HT-29/luc xenografted mouse model. Anticancer Res 29(6):2111–2120PubMed Chow TH, Lin YY, Hwang JJ, Wang HE, Tseng YL, Wang SJ, Liu RS, Lin WJ, Yang CS, Ting G (2009) Improvement of biodistribution and therapeutic index via increase of polyethylene glycol on drug-carrying liposomes in an HT-29/luc xenografted mouse model. Anticancer Res 29(6):2111–2120PubMed
14.
go back to reference Mayer LD, Reamer J, Bally MB (1999) Intravenous pretreatment with empty pH gradient liposomes alters the pharmacokinetics and toxicity of doxorubicin through in vivo active drug encapsulation. J Pharm Sci 88(1):96–102PubMedCrossRef Mayer LD, Reamer J, Bally MB (1999) Intravenous pretreatment with empty pH gradient liposomes alters the pharmacokinetics and toxicity of doxorubicin through in vivo active drug encapsulation. J Pharm Sci 88(1):96–102PubMedCrossRef
15.
go back to reference Krishna R, St-Louis M, Mayer LD (2000) Increased intracellular drug accumulation and complete chemosensitization achieved in multidrug-resistant solid tumors by co-administering valspodar (PSC 833) with sterically stabilized liposomal doxorubicin. Int J Cancer 85(1):131–141PubMedCrossRef Krishna R, St-Louis M, Mayer LD (2000) Increased intracellular drug accumulation and complete chemosensitization achieved in multidrug-resistant solid tumors by co-administering valspodar (PSC 833) with sterically stabilized liposomal doxorubicin. Int J Cancer 85(1):131–141PubMedCrossRef
16.
go back to reference Wu J, Lu Y, Lee A, Pan X, Yang X, Zhao X, Lee RJ (2007) Reversal of multidrug resistance by transferrin-conjugated liposomes co-encapsulating doxorubicin and verapamil. J Pharm Pharm Sci 10(3):350–357PubMed Wu J, Lu Y, Lee A, Pan X, Yang X, Zhao X, Lee RJ (2007) Reversal of multidrug resistance by transferrin-conjugated liposomes co-encapsulating doxorubicin and verapamil. J Pharm Pharm Sci 10(3):350–357PubMed
17.
go back to reference Arima H, Hagiwara Y, Hirayama F, Uekama K (2006) Enhancement of antitumor effect of doxorubicin by its complexation with gamma-cyclodextrin in pegylated liposomes. J Drug Target 14(4):225–232PubMedCrossRef Arima H, Hagiwara Y, Hirayama F, Uekama K (2006) Enhancement of antitumor effect of doxorubicin by its complexation with gamma-cyclodextrin in pegylated liposomes. J Drug Target 14(4):225–232PubMedCrossRef
18.
go back to reference Mross K, Niemann B, Massing U, Drevs J, Unger C, Bhamra R, Swenson CE (2004) Pharmacokinetics of liposomal doxorubicin (TLC-D99; Myocet) in patients with solid tumors: an open-label, single-dose study. Cancer Chemother Pharmacol 54(6):514–524PubMedCrossRef Mross K, Niemann B, Massing U, Drevs J, Unger C, Bhamra R, Swenson CE (2004) Pharmacokinetics of liposomal doxorubicin (TLC-D99; Myocet) in patients with solid tumors: an open-label, single-dose study. Cancer Chemother Pharmacol 54(6):514–524PubMedCrossRef
19.
go back to reference Cui J, Li C, Guo W, Li Y, Wang C, Zhang L, Zhang L, Hao Y, Wang Y (2007) Direct comparison of two pegylated liposomal doxorubicin formulations: is AUC predictive for toxicity and efficacy? J Control Release 118(2):204–215PubMedCrossRef Cui J, Li C, Guo W, Li Y, Wang C, Zhang L, Zhang L, Hao Y, Wang Y (2007) Direct comparison of two pegylated liposomal doxorubicin formulations: is AUC predictive for toxicity and efficacy? J Control Release 118(2):204–215PubMedCrossRef
20.
go back to reference Päuser S, Reszka R, Wagner S, Wolf KJ, Buhr HJ, Berger G (1997) Liposome encapsulates superparamagnetic iron oxide particles as markers in an MRT-guides search for tumor-specific drug carriers. Anticancer Drug Des 12:125–135PubMed Päuser S, Reszka R, Wagner S, Wolf KJ, Buhr HJ, Berger G (1997) Liposome encapsulates superparamagnetic iron oxide particles as markers in an MRT-guides search for tumor-specific drug carriers. Anticancer Drug Des 12:125–135PubMed
21.
go back to reference Forssen EA, Tokes ZA (1983) Attentuation of dermal toxicity of doxorubicin by liposome encapsulation. Cancer Treat Rep 67:481–484PubMed Forssen EA, Tokes ZA (1983) Attentuation of dermal toxicity of doxorubicin by liposome encapsulation. Cancer Treat Rep 67:481–484PubMed
22.
go back to reference Dreher MR, Liu W, Michelich CR, Dewhirst MW, Yuan F, Chilkoti A (2006) Tumor vascular permeability, accumulation, and penetration of macromolecular drug carriers. J Natl Cancer Inst 98(5):335–344PubMedCrossRef Dreher MR, Liu W, Michelich CR, Dewhirst MW, Yuan F, Chilkoti A (2006) Tumor vascular permeability, accumulation, and penetration of macromolecular drug carriers. J Natl Cancer Inst 98(5):335–344PubMedCrossRef
23.
go back to reference Strieth S, Eichhorn ME, Werner A, Sauer B, Teifel M, Michaelis U, Berghaus A, Dellian M (2008) Paclitaxel encapsulated in cationic liposomes increases tumor microvessel leakiness and improves therapeutic efficacy in combination with Cisplatin. Clin Cancer Res 14(14):4603–4611PubMedCrossRef Strieth S, Eichhorn ME, Werner A, Sauer B, Teifel M, Michaelis U, Berghaus A, Dellian M (2008) Paclitaxel encapsulated in cationic liposomes increases tumor microvessel leakiness and improves therapeutic efficacy in combination with Cisplatin. Clin Cancer Res 14(14):4603–4611PubMedCrossRef
24.
go back to reference Krasnici S, Werner A, Eichhorn ME, Schmitt-Sody M, Pahernik SA, Sauer B, Schulze B, Teifel M, Michaelis U, Naujoks K, Dellian M (2003) Effect of the surface charge of liposomes on their uptake by angiogenic tumor vessels. Int J Cancer 105(4):561–567PubMedCrossRef Krasnici S, Werner A, Eichhorn ME, Schmitt-Sody M, Pahernik SA, Sauer B, Schulze B, Teifel M, Michaelis U, Naujoks K, Dellian M (2003) Effect of the surface charge of liposomes on their uptake by angiogenic tumor vessels. Int J Cancer 105(4):561–567PubMedCrossRef
25.
go back to reference Wu NZ, Da D, Rudoll TL, Needham D, Whorton AR, Dewhirst MW (1993) Increased microvascular permeability contributes to preferential accumulation of Stealth liposomes in tumor tissue. Cancer Res 53:3765–3770PubMed Wu NZ, Da D, Rudoll TL, Needham D, Whorton AR, Dewhirst MW (1993) Increased microvascular permeability contributes to preferential accumulation of Stealth liposomes in tumor tissue. Cancer Res 53:3765–3770PubMed
26.
go back to reference van der Veen AH, Eggermont AM, Seynhaeve AL (1998) van Tiel, ten Hagen TL: Biodistribution and tumor localization of stealth liposomal tumor necrosis factor-alpha in soft tissue sarcoma bearing rats. Int J Cancer 77:901–906PubMedCrossRef van der Veen AH, Eggermont AM, Seynhaeve AL (1998) van Tiel, ten Hagen TL: Biodistribution and tumor localization of stealth liposomal tumor necrosis factor-alpha in soft tissue sarcoma bearing rats. Int J Cancer 77:901–906PubMedCrossRef
27.
go back to reference Pohlen U, Binnenhei M, Reszka R, Buhr HJ, Berger G (2004) 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. Chemotherapy 50(2):67–75PubMedCrossRef Pohlen U, Binnenhei M, Reszka R, Buhr HJ, Berger G (2004) 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. Chemotherapy 50(2):67–75PubMedCrossRef
Metadata
Title
Hepatic arterial infusion (HAI) with PEGylated liposomes containing 5-FU improves tumor control of liver metastases in a rat model
Authors
Uwe Pohlen
Heinz J. Buhr
Gerd Berger
Jörg-Peter Ritz
Christoph Holmer
Publication date
01-06-2012
Publisher
Springer US
Published in
Investigational New Drugs / Issue 3/2012
Print ISSN: 0167-6997
Electronic ISSN: 1573-0646
DOI
https://doi.org/10.1007/s10637-011-9646-0

Other articles of this Issue 3/2012

Investigational New Drugs 3/2012 Go to the issue
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine