Increasing the effective concentration of melphalan in experimental rat liver tumours: comparison of isolated liver perfusion and hepatic artery infusion

Marinelli, A.; Dierendonck, Jan Hein van; Brakel, G. M. Van; Irth, H.; Kuppen, Peter J. K.; Tjaden, U. R.; Velde, Cornelis J.H. van de

doi:10.1038/bjc.1991.466

Cited by 27 publications

(9 citation statements)

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“…Several techniques have been developed for regional therapy of hepatic malignancies, of which hepatic artery infusion (HAI) has become most widely used (Sullivan, 1964;Pentecost, 1993;De Takats, 1994 (Kemeny, 1987;Pentecost, 1993;De Takats, 1994;Chang, 1987). Alternatively, isolated hepatic perfusion (IHP), including total vascular isolation of the liver, has been reported to significantly increase intrahepatic drug concentrations when compared with HAI, while maintaining sufficiently low systemic drug levels (Aigner, 1982;Skibba, 1983;De Brauw, 1988;Marinelli, 1991;Radnell, 1990). However, large animal studies have revealed systemic leakage of the perfused anti-tumour agent owing to incomplete vascular isolation in up to 20% of animals (Sindelar, 1985;Van de Velde, 1986).…”

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confidence: 99%

Isolated hepatic perfusion in the pig with TNF-alpha with and without melphalan

Rinkes

Vries²,

Jonker³

et al. 1997

Br J Cancer

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Summary Isolated limb perfusion with tumour necrosis factor alpha (TNF-a) and melphalan is well tolerated and highly effective in irresectable sarcoma and melanoma. No data are available on isolated hepatic perfusion (IHP) with these drugs for irresectable hepatic malignancies. This study was undertaken to assess the feasibility of such an approach by analysing hepatic and systemic toxicity of IHP with TNF-a with and without melphalan in pigs. Ten healthy pigs underwent IHP. After vascular isolation of the liver, inflow catheters were placed in the hepatic artery and portal vein, and an outflow catheter was placed in the inferior vena cava (IVC). An extracorporeal veno-venous bypass was used to shunt blood from the lower body and intestines to the heart. The liver was perfused for 60 min with (1) 50 ,ug kg-' TNF-ca (n = 5), (2) 50 9g kg-' TNF-a plus 1 mg kg-' melphalan (n = 3) or (3) no drugs (n = 2). The liver was washed with macrodex before restoring vascular continuity. All but one pigs tolerated the procedure well. Stable perfusion was achieved in all animals with median perfusate TNF-a levels of 5.1 ± 0.78 x 106 pg ml-(± s.e.m). Systemic leakage of TNF-a from the perfusate was consistently < 0.02%. Following IHP, a transient elevation of systemic TNF-a levels was observed in groups 1 and 2 with a median peak level of 23 ± 3 x 103 pg ml-' at 10 min after washout, which normalized within 6 h. No significant systemic toxicity was observed. Mild transient hepatotoxicity was seen to a similar extent in all animals, including controls. IHP with TNF-a with(out) melphalan in pigs is technically feasible, results in minimal systemic drug exposure and causes minor transient disturbances of liver biochemistry and histology.Keywords: isolation; liver; perfusion; metastases; tumour necrosis factor The liver is the commonest site of dissemination in patients with colorectal cancer (Bengmark, 1969;Wagner, 1984;Strangl, 1994). Five-year survival rates of up to 35% have been reported for patients amenable for partial hepatic resection (Hughes, 1986;Scheele, 1990; Van Ooyen, 1992;Sugihara, 1993;Que, 1994). Unfortunately, the vast majority of colorectal metastases confined to the liver are considered to be unresectable (Greenway, 1988;Cady, 1991;Genari, 1992). In addition, systemic chemotherapy has so far failed to provide satisfactory results in these cases (Kemeny, 1983(Kemeny, , 1987. Therefore, it is mandatory to develop novel strategies to obtain tumour control in the liver.The concept of locoregional administration of chemotherapy is aimed at achieving high local concentrations while minimizing systemic drug levels in an attempt to reduce dose-limiting sideeffects. This might enhance anti-tumour efficacy as steep dose-response curves have been described for most chemotherapeutic agents (Frei, 1980;Canellos, 1987). Several techniques have been developed for regional therapy of hepatic malignancies, of which hepatic artery infusion (HAI) has become most widely used (Sullivan, 1964;Pentecost, 1993;De Takats, 1994 (Kemeny, ...

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confidence: 99%

Isolated hepatic perfusion in the pig with TNF-alpha with and without melphalan

Rinkes

Vries²,

Jonker³

et al. 1997

Br J Cancer

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“…Melphalan is an alkylating agent with a steep dose -response curve that is effective against colorectal cancer after a relatively short exposure time and is therefore a very interesting drug for IHP [72,73]. Alexander and colleagues [61,68] have reported IHP studies with different treatment strategies, including IHP with high doses of melphalan alone and moderately high doses of melphalan combined with TNF-a or followed by monthly hepatic intra-arterial infusion of FUDR and leucovorin.…”

Section: Isolated Hepatic Perfusionmentioning

confidence: 99%

Treatment of liver metastases of colorectal cancer

Velde¹

2005

Annals of Oncology

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“…Isolated liver perfusion and hepatic artery infusion are used in surgical oncology trials for the administration of chemotherapeutics and cytokines in patients with liver tumours (Marinelli et al, 1990;Marinelli et al, 1991;Kemeny et al, 1994;Kuppen et al, 1997;Alexander et al, 1998;de Vries et al, 1998). High local drug concentrations can be achieved at the tumour site by means of isolated hepatic perfusion (IHP), a technique with minimal systemic exposure.…”

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Prerequisites for effective adenovirus mediated gene therapy of colorectal liver metastases in the rat using an intracellular neutralizing antibody fragment to p21-Ras

et al. 2002

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Ras mutations are present in 40 -50% of colorectal cancers. Inactivating this oncogene may therefore reduce proliferation capacity. In order to target ras we studied the transduction efficacy and anti tumour activity of an adenoviral vector expressing an intracellular, neutralizing single chain antibody to p21-ras (Y28). In in vitro studies transfection levels of the K-ras mutated rat colon carcinoma cell line CC531 were studied using the LacZ marker gene. In our in vivo liver metastases model different routes of administration were evaluated to determine which regimen resulted in the best transfection levels and tumour responses: intravenous injection, intratumoural injection, isolated liver perfusion, or hepatic artery infusion. CC531 cells are readily transfected in vitro, resulting in significant inhibition of tumour cell proliferation by the Y28 construct. Intravenous injection did not result in any measurable transfection. Intratumoural injection resulted only in the transfection of tumour cells along the needle track. IHP as well as single HAI achieved low transfection levels of tumour tissue. Expression of Y28 was demonstrated in tumours after IT injection, HAI and IHP. Whereas, repeated HAI's clearly achieved expression in and around tumour associated vessels. Only five times repeated HAI's with Y28 resulted in a tumour response: in all animals tumour growth was inhibited, and in three rats out of eight a complete regression of the liver tumours was observed.

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Increasing the effective concentration of melphalan in experimental rat liver tumours: comparison of isolated liver perfusion and hepatic artery infusion

Cited by 27 publications

References 33 publications

Isolated hepatic perfusion in the pig with TNF-alpha with and without melphalan

Isolated hepatic perfusion in the pig with TNF-alpha with and without melphalan

Treatment of liver metastases of colorectal cancer

Prerequisites for effective adenovirus mediated gene therapy of colorectal liver metastases in the rat using an intracellular neutralizing antibody fragment to p21-Ras

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