Embolization of hepatocellular carcinoma with drug-eluting beads: Doxorubicin tissue concentration and distribution in patient liver explants

Namur, Julien; Citron, Steven J.; Sellers, Marty T.; Dupuis, Mark H.; Wassef, Michel; Manfait, Michel; Laurent, Alexandre

doi:10.1016/j.jhep.2011.03.024

Cited by 151 publications

(145 citation statements)

References 29 publications

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“…For this, two different human HCC cell lines were incubated with doxorubicin at a concentration that killed >80% of the tumor cells within 48 h. The applied concentration of doxorubicin was in the range of tissue drug concentrations found in experimental TACE models in vivo, as well as in HCC explants of patients after the administration of TACE (33,34). After 2 days, cell culture of surviving HCC cells was continued without doxorubicin exposure to mimic the situation of a single doxorubicin dose application during TACE.…”

Section: Discussionmentioning

confidence: 99%

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Hepatocellular carcinoma cells surviving doxorubicin treatment exhibit increased migratory potential and resistance to doxorubicin re-treatment inï¿½vitro

et al. 2018

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Abstract. Transarterial chemoembolization (TACE) is an established therapeutic approach for the treatment of hepatocellular carcinoma (HCC). Although patients who undergo TACE may have prolonged survival, there are indications that the malignancy of residual HCC tissue can increase subsequent to the procedure. Although hypoxia, which occurs during TACE due to ischemia, is known to contribute to angiogenesis, little is known with regard to the undesirable effects of chemotherapeutic agents on residual HCC cells. Doxorubicin is one of the most commonly used drugs in TACE. The aim of the present study was to analyze alterations in Hep3B and HepG2 human HCC cell lines surviving doxorubicin treatment in vitro. Initially, the toxic concentration range was determined, and doxorubicin was subsequently applied in concentrations that killed >80% of the HCC cells. During the first days subsequent to treatment, surviving cells had higher expression levels of the epithelial-mesenchymal transition marker SNAIL, and exhibited increased migratory activity compared with control cells. At 3 weeks after the first doxorubicin treatment, surviving HCC cells tolerated significantly higher doxorubicin concentrations compared with control cells. As a potential explanation for this doxorubicin resistance, significantly increased mRNA expression levels of ATP-binding cassette ABCB1 (multidrug resistance protein 1) and ABCC1 (multidrug resistance-associated protein 1) were observed by reverse transcription-quantitative polymerase chain reaction. In summary, these findings indicate that, following TACE treatment, hypoxia as well as doxorubicin may induce a more malignant phenotype in surviving HCC cells and decrease susceptibility to further chemotherapeutic treatment.

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Section: Discussionmentioning

confidence: 99%

“…1C). For the next in vitro model that was designed to mimic the circumstances of TACE, doxorubicin was used at a concentration of 1 µM, which was in the range of doxorubicin concentrations found in human HCC explants following the administration of TACE (33,34 Fig. 2A).…”

Section: Selection Of Hcc Cells Surviving Doxorubicin Treatmentmentioning

confidence: 99%

Hepatocellular carcinoma cells surviving doxorubicin treatment exhibit increased migratory potential and resistance to doxorubicin re-treatment inï¿½vitro

et al. 2018

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“…By eluting beads, the Dox concentration (C max ) was 78.97 ± 38.3 ng/mL compare to 2,341.5 ± 3,951.9 ng/mL in conventional transarterial chemoembolization (Varela et al 2007) in the serum. In recent research, Namur et al (2011) showed Dox concentration in tissue from 5 lM at 8 h to 0.65 lM at 1 month using drug eluting beads (Namur et al 2011). This Dox concentration was much lower than the concentration used in this study (5 vs. 862 lM (0.5 lg/mL of Dox)).…”

Section: Discussionmentioning

confidence: 99%

Doxorubicin and 5-fluorouracil resistant hepatic cancer cells demonstrate stem-like properties

Nguyen

Tran³

et al. 2012

Cytotechnology

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The efficacy of hepatocellular carcinoma (HCC) treatment is very low because of the high percentage of recurrence and resistance to anticancer agents. Hepatic cancer stem cells (HCSCs) are considered the origin of such recurrence and resistance. Our aim was to evaluate the stemness of doxorubicin and 5-fluorouracil resistant hepatic cancer cells and establish the new method to isolate the HCSCs from primary cultured HCC tumors. HCC biopsies were used to establish primary cultures. Then, primary cells were selected for HCSCs by culture in medium supplemented with doxorubicin (0, 0.1, 0.25, 0.5 or 1 lg/mL), 5-fluorouracil (0, 0.1, 0.25, 0.5 or 1 lg/mL) or their combination. Selection was confirmed by detection of HCSC markers such as CD133, CD13, CD90, and the side population was identified by rhodamine 123 efflux. The cell population with the strongest expression of these markers was used to evaluate the cell cycle, gene expression profile, tumor sphere formation, marker protein expression, and in vivo tumorigenesis. Selective culture of primary cells in medium supplemented with 0.5 lg/mL doxorubicin and 1 lg/mL 5-fluorouracil selected cancer cells with the highest stemness properties. Selected cells strongly expressed CD13, CD133, CD90, and CD326, efflux rhodamine 123 and formed tumor spheres in suspension. Moreover, selected cells were induced to differentiate into cells with high expression of CD19 and AFP (alpha-fetoprotein), and importantly, could form tumors in NOD/SCID mice upon injection of 1 9 10 5 cells/mouse. Selective culture with doxorubicin and 5-fluorouracil will enrich HCSCs, is an easy method to obtain HCSCs that can be used to develop better therapeutic strategies for patients with HCC, and particularly HCSC-targeting therapy.

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“…Comparison with tissue concentrations is more representative of local drug activity, although more complicated to realize. Namur et al (2011) found doxorubicin concentrations in liver explants of patients after 8 h of embolization with doxorubicin-eluting beads to be approximately twice as high as after 9-14 days, indicating a drug concentration peak in the tissue shortly after embolization. 315…”

Section: In Vitro-in Vivo Correlation (Ivivc)mentioning

confidence: 88%

Sunitinib-eluting beads for chemoembolization: Methods for in vitro evaluation of drug release

Fuchs

Bize

Denys

et al. 2015

International Journal of Pharmaceutics

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Drug-eluting microspheres are used for embolization of hypervascular tumors and allow for 15 local controlled drug release. Although the drug release from the microspheres relies on fast ion-exchange, so far only slow-releasing in vitro dissolution methods have been correlated to in vivo data. Three in vitro release methods are assessed in this study for their potential to predict slow in vivo release of sunitinib from chemoembolization spheres to the plasma, and fast local in vivo release obtained in an earlier study in rabbits. 20Release in an orbital shaker was slow (t 50% = 4.5 h, 84% release) compared to fast release in USP 4 flow-through implant cells (t 50% = 1 h, 100% release). Release of sunitinib from microspheres in saline in dialysis inserts was prolonged and incomplete (t 50% = 9 d, 68% release) due to low drug diffusion through the dialysis membrane. The slow-release profile fitted best to low sunitinib plasma AUC following injection of sunitinib-eluting spheres. Although limited by lack of 25 standardization, release in the orbital shaker fitted best to local in vivo sunitinib concentrations.Drug release in USP flow-through implant cells was too fast to correlate with local concentrations, although this method is preferred to discriminate between different sphere types. 3 Graphical Abstract KeywordsIn vitro drug release, sunitinib, drug-eluting beads, USP dissolution apparatus 4, 35 chemoembolization, in vitro-in vivo correlation

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Embolization of hepatocellular carcinoma with drug-eluting beads: Doxorubicin tissue concentration and distribution in patient liver explants

Cited by 151 publications

References 29 publications

Hepatocellular carcinoma cells surviving doxorubicin treatment exhibit increased migratory potential and resistance to doxorubicin re-treatment inï¿½vitro

Hepatocellular carcinoma cells surviving doxorubicin treatment exhibit increased migratory potential and resistance to doxorubicin re-treatment inï¿½vitro

Doxorubicin and 5-fluorouracil resistant hepatic cancer cells demonstrate stem-like properties

Sunitinib-eluting beads for chemoembolization: Methods for in vitro evaluation of drug release

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