Human liver cancer cells and endothelial cells incorporate iodised oil

Abstract

Summary lodised oil (lipiodol) al., 1985). Lipiodol, an iodinated derivative of poppyseed oil, has been in use for over a decade as a vehicle for targeted cytotoxic or radiotherapeutic treatment of unresectable HCCs. When injected into the hepatic artery the oil is retained by HCCs for several weeks to over a year, but is cleared from normal liver parenchyma within 7 days (Nakakuma et al., 1979). Trials using lipiodol in conjunction with cytotoxic drugs such as doxorubicin, epidoxorubicin, aclarubicin, 5-fluorouracil, mitomycin, cisplatin and SMANCS (a polymer of neocarzinostatin with styrene and maleic acid), or radioisotopes such as 131I have yielded improved survival rates (Bhattacharya et al., 1994). Lipiodol ultra fluid (Laboratoire Guerbet, Roissy Charles de Gaulle, France) is manufactured by ethyl trans-esterification of poppyseed oil, and consists of mono-, di-and tri-iodinated ethyl esters of linoleic (73%), oleic (14%), palmitic (9%) and stearic (3%) acid (I Chastin Laboratoire Guerbet; personal communication) with an iodine content of 37-39% by weight.Hypotheses attempting to explain lipiodol retention in HCCs fall into two major categories. One suggests that lipiodol is retained within the tumour blood vessels, which may be due to an altered electrostatic charge on the endothelial cell surface causing lipid adsorption, or impaired exit of lipid droplets due to altered drainage channels, embolisation being determined by droplet size. The other proposes that lipiodol lodges in the extracellular space, as tumour vessels are more 'leaky' than usual, and because lymphatics are absent in HCCs. Uptake by the reticuloendothelial cells in the liver, spleen, marrow and lungs is the probable route by which lipiodol is cleared when administered systemically, and HCCs may be unable to clear lipiodol because they lack a reticuloendothelial Kupffer cell component. There have been relatively few investigations into the role of the tumour cells (Javitt, 1990). HUVECs were used instead of tumour endothelium. They share a common embryological origin with hepatic sinusoidal endothelium (Hamilton and Mossman, 1976) and also have several surface markers in common with the tumour endothelium in HCCs, namely Ulex Europeus Lectin, Factor VIII and QBendlO (Dhillon et al., 1992). Monolayers of Hep G2 and HUVECs grown on tissue culture chamber slides were exposed for 4, 8, 24 and 32 h to culture media containing 1%, 2% and 4% of lipiodol by volume [in human subjects, bolus injection of 10 ml lipiodol over a period of 1 min into the hepatic artery, which has an average flow of 500 ml min-' (Tygstrup et al., 1962) is likely to yield a lipiodol concentration of 2% in the hepatic arterial blood reaching the tumour]. The iodised oil which is heavier than water, initially remained suspended as fine droplets in the aqueous medium following vigorous agitation and then settled as droplets on the surface of the cell monolayer. Following exposure to lipiodol the monolayers were stained by a silver nitrate impregnation technique adap...

In vitro assessment of Lipiodol-targeted radiotherapy for liver and colorectal cancer cell lines

“…Using previously described method, Lipiodol uptake by all the cancer cell lines and by the endothelial cells was demonstrated on light and electron microscopy as early as 3 h (Al-Mufti et al, 1996). In this study, 131 I-Lipiodol was also demonstrated within the cancers cells and the benign endothelial cells as early as 6 h. Lipiodol alone as a control (without 131 I) had no effect on the cell growth or viability when compared to the controls, and was therefore not cytotoxic to any of the cell lines used in this study.…”

“…Although the mechanism of Lipiodol uptake is poorly understood, this study confirms our previous reports that Lipiodol is taken up and is retained in the form of cytoplasmic membrane-bound vesicles (Al-Mufti et al, 1995). Quantification methods using computer-assisted image analysis of the uptake of Lipiodol by the malignant and the non-malignant cell lines (Al-Mufti et al, 1996) have revealed that cancer cell lines, unlike non-malignant cells, are unable to expel Lipiodol. This may further enhance the cytotoxic effect of 131 I-Lipiodol in cancer cells.…”

Transarterial Injection of 131I-Lipiodol, Compared with Chemoembolization, in the Treatment of Unresectable Hepatocellular Cancer

“…Thus, for bilobar disease 2 separate treatment sessions are needed, whereas with 131 I-lipiodol a single infusion into the common hepatic artery beyond the gastroduodenal artery will result in tumor uptake in both lobes. In addition, the mechanism of action of 131 I-lipiodol, which involves direct uptake into tumor cells, results in a higher tumor radiation dose than do the methods requiring embolization of radioactive particles (9). In a prospective phase 2 study of 65 patients with biopsy-proven HCC, the administration of TheraSpheres However, there are 2 major caveats to the use of these techniques, as they are essentially embolic in nature: severe liver dysfunction and PVT represent theoretic contraindications, as in TACE.…”

“…The diagnosis of HCC was made according to the criteria of the 2000 Barcelona European Association for Study of the Liver consensus conference (9). At baseline (the day of the first session of intraarterial treatment), standard laboratory data and imaging characteristics of the HCC and liver from cross-sectional imaging (CT or MRI) were recorded.…”

Treatment of Intermediate Stage Hepatocellular Carcinoma: A Review of Intrahepatic Doxorubicin Drug-Delivery Systems

“…The fate of LIP in the hepatic vascular system LIP (also known as Ethiodol ® ) is an iodinated and ethylated poppy seed oil that consists of ethyl linoleate (70% w/w), ethyl oleate (15% w/w), ethyl palmitate (10% w/w), ethyl stearate (5% w/w), and contains 37-39% iodine (400 mg/ml) [44,45]. Following injection into the HA, LIP is accumulated in tumor tissue for at least 3 months, as lipid layers (nonglobular) extracellularly and as droplets (globular) intracellularly (Figure 3) [7,46].…”