Increased adriamycin levels in hepatic implants of rabbit Vx-2 carcinoma from regional infusion

Regional infusion chemotherapy for the treatment of primary or secondary hepatic cancer should allow delivery of a higher drug concentration to the tumor with decreased systemic exposure when compared with systemic therapy. Fifteen rabbits, each implanted with two hepatic Vx-2 tumors, were treated with infusion of Adriamycin (3 mg/kg and 7.5 muCi of [14C]Adriamycin) through the hepatic artery (n = 5), portal vein (n = 5), and a systemic vein (n = 5) at 20 mg/min. 99Tc-labeled macroaggregated albumin flow images documented specific hepatic perfusion in selected rabbits using this technique. Thirty min after infusion the animals were sacrificed, and multiple specimens of liver, tumor, and heart were taken for liquid scintillation counting and high-performance liquid chromatography. The 14C label remained associated with Adriamycin and metabolites. After systemic infusion 11.5 nmol/g of Adriamycin were found in tumor, and 32.4 nmol/g were found in liver. Infusion of Adriamycin through the hepatic artery produced drug levels of 34.3 nmol/g of tumor and 48.4 nmol/g of liver, while infusion through the portal vein produced drug levels of 6.5 nmol/g of tumor and 54.4 nmol/g of liver. The drug concentration in tumor was significantly higher after hepatic artery infusion compared with systemic (P less than 0.05) or portal vein (P less than 0.01) infusion. The tumor/liver ratio of [14C]Adriamycin tissue levels after hepatic artery infusion was greater than that measured after systemic vein treatment (no overlap of the 90% confidence intervals). Systemic infusion of Adriamycin produced a higher level of Adriamycin in the heart (13.6 nmol/g) than did hepatic artery (10.9 nmol/g) or portal vein (8.9 nmol/g) infusion. Hepatic artery infusion achieved the highest tumor Adriamycin level compared with systemic vein and portal vein infusion. The results suggest that these tumor implants are supplied primarily by the hepatic artery, that clearance of Adriamycin is efficient after regional infusion, and that systemic toxicity may be reduced using intraarterial infusion of Adriamycin for hepatic tumors.     

Tumor and liver drug uptake following hepatic artery and portal vein infusion

Anatomic dye injection studies of the blood supply of colorectal hepatic metastases suggest that tumors are supplied predominantly by the hepatic artery. Using 13N amino acids with dynamic gamma camera imaging in patients with colorectal hepatic metastases, it has been shown that hepatic artery infusion results in a significantly greater nutrient delivery to tumor compared with portal vein infusion. However, direct measurements of drug levels in tumor following hepatic artery and portal vein infusion in humans have not previously been reported. Patients with metastatic colorectal cancer confined to the liver received fluorodeoxyuridine (FUdR) through the hepatic artery or through the portal vein. All patients had previously failed systemic chemotherapy. Five patients with hepatic artery catheters were matched (by age, serum lactic dehydrogenase levels, percent hepatic replacement, and tumor size) with five patients with portal vein catheters. At operation, 3H-FUdR (1 microCi/kg) and 99mTc-macroaggregated albumin (MAA) (6 mCi) were injected into the hepatic artery or portal vein. Liver and tumor biopsies were obtained two and five minutes later. 3H and 99mTc were measured per gram tissue by scintillation and gamma counting. The mean liver levels following hepatic artery infusion (23.9 +/- 11.4 nmol/g) and portal vein infusion (18.4 +/- 14.5 nmol/g) did not differ. However, the mean tumor FUdR level following hepatic artery infusion was 12.4 +/- 12.2 nmol/g, compared with a mean tumor FUdR level following portal vein infusion of 0.8 +/- 0.7 nmol/g (P less than .01). This low level of tumor drug uptake after portal vein infusion of FUdR predicts minimal tumor response to treatment via this route. Thus, regional chemotherapy for established colorectal hepatic metastases should be administered through the hepatic artery.     

Regional administration of natural killer cells in a rat hepatic metastasis model results in better tumor infiltration and anti-tumor response than systemic administration

A syngeneic rat liver metastasis model, the CC531 colon carcinoma cell line in Wag rats, was used to study the homing properties and anti-tumor effects of adoptively transferred, interleukin-2 (IL-2)-activated, cultured natural killer (A-NK) cells. To identify the route of administration that gives the highest tumor infiltration, 1.5 × 10⁸ A-NK cells were dyed with fluorescent rhodamine and injected via 4 different routes into rats, bearing subcapsularly induced (day 10) liver metastases. The routes chosen were: jugular vein, portal vein, hepatic artery and directly into the peritoneal cavity (i.p). The rats were sacrificed 20 hr after administration of A-NK cells. The highest (p < 0.05) infiltration of tumors by A-NK cells was found both at the tumor border and in the tumor center after injection via the hepatic artery: 65 ± 7 A-NK cells/mm² at the tumor border and 26 ± 14 A-NK cells/mm² in the center of the tumor (jugular vein infusion: 32 ± 10 and 9 ± 5 A-NK cells/mm², respectively; portal vein infusion: 36 ± 13 and 7 ± 4 A-NK cells/mm², respectively). No A-NK cells were detected in the liver after i.p. injection. Rats bearing day 5 tumors were injected with 1.5 × 10⁸ A-NK cells via the hepatic artery or via the jugular vein (n = 5 and n = 6 respectively). Regional administration of A-NK cells via the hepatic artery resulted in a significant (p < 0.05) lower weight (35 ± 23 mg) of tumors than did systemic administration (70 ± 10 mg). Our results suggest that both the level of tumor infiltration by adoptively transferred A-NK cells and the therapeutic outcome depend on the route of administration. Int. J. Cancer 75:233–238, 1998. © 1998 Wiley-Liss, Inc.     

Augmentation of hepatic doxorubicin extraction with extracorporeal filtration avoids the dose-dependent, nonlinear increase in AUC observed with systemic administration

Purpose: Regional therapy of primary or metastatic liver cancer with low hepatic extraction ratio drugs such as doxorubicin is constrained by development of systemic toxicity. To examine the effect of augmentation of hepatic drug extraction, a swine model of hepatic artery infusion (HAI) with minimally invasive hepatic venous isolation and hepatic venous drug extraction (HVDE) was developed to study the comparative pharmacokinetic profiles of regional and systemically administered doxorubicin. Methods: Doxorubicin 0.5–9 mg/kg was administered to 31 pigs over 90 min either by HAI with simultaneous HVDE or by standard systemic vein infusion. Systemic artery and hepatic vein plasma samples were collected periodically (0 to 240 min) for determination of doxorubicin concentrations by high-performance liquid chromatography. Pharmacokinetic profiles were modeled with PCNONLIN 4.2. Results: Concentration-time data were best described in all pigs by a two-compartment open model of elimination. Independent of the route of administration, AUC and C_max values increased with dose. Mean systemic AUC and C_max values were consistently lower with regional administration, with statistically significant decreases at the 0.5 and 3 mg/kg doses, whereas there was no relationship between hepatic vein parameters and route of administration. There was a linear relationship between mean systemic AUC values and dose in pigs receiving doxorubicin via HAI with HVDE, whereas mean systemic AUC values increased exponentially at doses of 5 mg/kg or above with systemic vein administration. Conclusions: Administration of doxorubicin by HAI with simultaneous HVDE signifiantly decreases systemic exposure in comparison with standard systemic vein drug infusion, and may protect against nonlinear increases in exposure at higher doses. Received: 6 February 1997 / Accepted: 9 May 1997     

Pharmacokinetics of 5-fluorouracil following different routes of intrahepatic administration in the canine model

In an effort to achieve high concentrations of 5-fluorouracil (5-FUra) in the hepatic circulation while minimizing systemic exposure, several routes of intrahepatic administration were compared in the canine model. To ascertain these data, 5-FUra (30 mg/kg) was given as a bolus into either a systemic vein (femoral vein), hepatic artery, hepatic artery distal to its ligation after hepatic dearterialization, or through the portal vein. Three dogs were studied for each route with concomitant blood samples taken from the inferior vena cava and hepatic vein at 1, 2, 3, 5, 10, 15, 30, and 60 min after injection. 5-FUra levels were determined in plasma by high-pressure liquid chromatography. Blood flow in the portal vein and hepatic artery was measured by an electromagnetic flowmeter. The data were best described by a multicompartmental model including the measured flows. Hepatic components of the model were separate arterial and portal compartments, with elimination from each described by linear kinetics. Analysis of the results indicated that the highest hepatic levels with the least systemic exposure, as indicated by drug levels in hepatic and peripheral vein, were realized following hepatic artery administration distal to its ligation after hepatic dearterialization.     

Influence of the routes of continuous intrahepatic infusion of 5-fluorouracil on its pharmacokinetics

Continuous infusion chemotherapy via hepatic artery using newly available mechanical devices is frequently used to treat hepatic metastases to achieve a high concentration of 5-fluorouracil (5-FUra) in the hepatic circulation while minimizing systemic exposure. We compared four routes of intrahepatic administration to find out the best one in the canine model. To ascertain this data, 5-FUra (30 mg/kg) was given as a continuous infusion over a 3 hr period into either a systemic vein (femoral), portal vein, hepatic artery, or hepatic artery distal to its ligation after hepatic dearterialization. A total of eight dogs were studied. During 5-FUra infusion, concomitant blood samples were taken from the inferior vena cava and hepatic vein at 1, 2, 3, 5, 10, 15, 30, 60, 120, and 180 min. 5-FUra levels were determined in plasma by high-performance liquid chromatography. Blood flow in the portal vein and hepatic artery was measured by an electromagnetic flowmeter. The data described by a multicompartmental model, including the measured flows, had separate hepatic arterial and portal compartments with elimination from each described by linear kinetics. Mean area under the curve values in microgram/ml X min and the ratios of the systemic/hepatic vein areas following 5-FUra infusion via systemic, portal vein, hepatic artery, or hepatic artery after dearterialization routes were: 975/539 (R = 1.80), 939/748 (R = 1.35), 211/454 (R = 0.46), and 562/1,424 (R = 0.39). The results indicated that the administration of 5-FUra via the hepatic arterial route distal to its ligation results in the highest hepatic vein drug levels with the smallest systemic/hepatic vein exposure ratio, followed by intra-arterial route, while systemic and portal vein routes were not nearly as advantageous as the intra-arterial routes.     

Potentiation of the cytostatic effect of melphalan on colorectal cancer hepatic metastases by infusion of buthionine sulfoximine (BSO) in the rat Enhanced tumor glutathione depletion by infusion of BSO in the hepatic artery

Purpose: Glutathione (GSH) plays an important role in the resistance of tumors to cytostatics. Therefore, depletion of GSH by the GSH synthesis inhibitor buthionine sulfoximine (BSO) has been proposed to enhance the efficacy of certain anticancer agents. We studied the effect of BSO in rats bearing intrahepatically implanted tumors of the CC531 colorectal cancer cell line on the antitumor activity of melphalan (L-PAM). Since these liver tumors tend to derive most of their blood supply from the hepatic artery, we evaluated whether delivery of BSO into the hepatic artery would more selectively decrease GSH levels in the implanted tumor tissue as compared with normal liver and extrahepatic tissues. Methods: Tumor-bearing rats were treated with a 24-h continuous infusion of 0.375 mmol/kg BSO via the jugular vein, immediately followed by a bolus L-PAM (15 μmol/kg; 4.5 mg/kg) infusion via the hepatic artery. Laparotomy was performed on day 14 and 28 after treatment for measurement of the liver tumors. For the evaluation of locoregional administration of BSO, a 24-h continuous infusion of 0.375 mmol/kg BSO was delivered into either the hepatic artery, the portal vein, or the jugular vein in freely moving rats and GSH levels in the tumor, liver, kidney, lung, heart, bone marrow, and blood were measured. Results: BSO infusion via the jugular vein increased the antitumor efficacy of L-PAM injected into the hepatic artery 2-fold as determined at 14 days after treatment. Although infusion of BSO via the hepatic artery depleted GSH more severely in the tumor as compared with jugular vein or portal vein administration, the additional effect was only slight (10%). No difference was observed in any other tissue. Conclusion: GSH depletion increased the cytostatic efficacy of L-PAM 2-fold in vivo as determined at 14 days after treatment. Hepatic artery infusion of BSO translated into a statistically significant, but probably not therapeutically relevant, increase in tumor GSH depletion as compared with the other routes of BSO administration. Received: 21 September 1998 / Accepted: 4 January 1999     

Superiority of hepatic arterial infusion in preventing catabolism of 5-FU compared with portal vein infusion revealed by an in vivo 19F NMR study

Purpose: The aim of this study was to identify the route of administration of 5-FU with the greatest pharmacological advantage in a rat model using noninvasive in vivo ¹⁹F nuclear magnetic resonance (NMR) spectroscopy. Methods: 5-FU (50 mg/kg) was administered to anesthetized Wistar rats cannulated into the hepatic artery, portal vein or tail vein and 11 NMR spectra were acquired from the liver region to 60.5 min every 5.5 min. Results: With systemic i.v. (tail vein) infusion, the ¹⁹F-NMR signal for 5-FU from the liver region peaked in the first spectrum (0–5.5 min), and then gradually decreased. The signal for the 5-FU catabolite α-fluoro-β-alanine (FBAL) gradually increased to the sixth spectrum (0–33.0 min) and then plateaued. Following portal vein infusion the intensity of the first 5-FU spectrum was twice as high as that following i.v. infusion, but the intensity decreased and the FBAL signal increased gradually in the sixth spectrum as systemic i.v. infusion. In contrast, the intensity of the 5-FU signal following hepatic artery infusion was the same as that following portal vein infusion in the first spectrum, and maintained a strong intensity to the final spectrum (60.5 min). The FBAL signal was detected from the second spectrum following hepatic artery infusion, but its intensity was significantly weaker than that following i.v. or portal vein infusion. Conclusions: Hepatic arterial infusion resulted in the active form of 5-FU being present for a longer time and its degradation in the liver being suppressed compared with the results following portal vein infusion. This catabolic advantage of hepatic areterial infusion could lead to a more potent anti-tumor activity against liver metastases, but could also lead to significant host toxicity including biliary toxicity. We recommend that the dose/schedule of 5-FU administered via the hepatic artery should be adjusted carefully. Received: 4 August 1997 / Accepted: 16 January 1998     

Comparative study on the comparative efficacy of hepatic arterial or portal venous infusion of adriamycin to control hepatic carcinoma growth

To compare the efficacy of intrahepatic arterial and intraportal venous infusions of anticancer drugs, the following two experiments were performed. 1. Adriamycin (3 mg kg) aqueous solution (ADR) was administered into hepatic artery (HA group) and portal vein (PV group) of a rabbit with 2 cm diameter VX2 liver tumor. The ADR levels of the tumor tended to be about 3-fold higher in HA than in PV group (p less than 0.1) one hour after ADR infusion. No significant difference was seen in the ADR levels of liver, heart, kidney, and bone marrow between the two groups. The ADR concentration ratio of tumor to liver was significantly higher in HA group than in PV group. 2. VX2 tumor cells (1 x 10(7) cells) were transplanted through the portal vein of the rabbit. ADR aqueous solution (1 mg/kg, 5 ml) was infused into the rabbit liver via HA and PV, at 3, 5, and 7 days after tumor inoculation. The rabbits were killed and the livers were excised 21 days after tumor implantation. The number of VX2 tumor nodules on the liver surface was less in HA group than in PV group. These results suggest that hepatic arterial infusion of anticancer drug is more useful to inhibit the growth of liver tumor than portal venous infusion.     

Hepatic artery infusion of high-dose melphalan at reduced flow during isolated hepatic perfusion for the treatment of colorectal metastases confined to the liver: A clinical and pharmacologic evaluation

Isolated hepatic perfusion (IHP) offers the advantage of high local drug exposure with limited systemic toxicity. To increase local drug exposure, we administered melphalan at a reduced flow in the hepatic artery during IHP (hepatic artery infusion, hepatic artery–portal vein perfusion, HI–HPP).     

Regional administration of lymphokine-activated killer cells can be superior to intravenous application.

A patient with liver metastases of human lymphocyte antigen (HLA) class II-negative malignant melanoma was treated with several cycles of adoptive immunotherapy with interleukin-2 and lymphokine-activated killer (LAK) cells. The authors evaluated the efficacy of regional transfer of LAK cells versus systemic intravenous administration. Initially, the patient was treated according to a regional treatment protocol, consisting of perfusion of the spleen with interleukin-2 and transfer of LAK cells into the portal vein; a partial remission was observed. Because of technical problems, interleukin-2 and LAK cells were administered intravenously in a second treatment cycle. This systemic treatment course resulted only in a minor mixed response of the hepatic metastases. A third treatment course was administered with the use of intravenous interleukin-2 infusion and arterial perfusion of the liver with LAK cells. The patient had separate hepatic arteries to both lobes of the liver as an anatomic variation. Because most of the tumor mass was present in the right lobe of the liver, a third of the LAK cells were injected into the right hepatic artery and the remaining cells were administered intravenously. The lesions in the right lobe of the liver regressed, but disease progression occurred in the left lobe. A fourth treatment cycle, consisting of intravenous infusion of interleukin-2 and arterial perfusion of both lobes of the liver with LAK cells, resulted in a complete response of all hepatic lesions, which has lasted 18 months to date. Because, in this patient, tumor regression was observed only in anatomic areas of the liver, which were perfused with LAK cells, it is suggested that the regional administration of LAK cells was essential for successful treatment.     

Lattice intrahepatic doxorubicin with and without in-flow occlusion: a pharmacokinetic study of direct liver injection.

AIM: To assess possible improvements in drug delivery to unresectable liver tumours we investigated the pharmacokinetics of intrahepatic doxorubicin in the dog liver with and without inflow occlusion. METHODS: Using a lattice template, doxorubicin was injected into 16 sites (over a 9 cm2 area) in each of three lobes of the liver for a total of 48 sites. The total doses of doxorubicin used were 4.8 mg and 96 mg (0.1 and 2 mg/site). Dogs with intravenous and intra-arterial delivery of the same total doses of doxorubicin were used as controls. Experiments using intrahepatic injection were performed with and without a 30 min occlusion of the hepatic artery, common bile duct and portal vein (inflow occlusion). The studies with vascular stasis were performed to determine if drug clearance from the injection sites and their plasma levels were reduced. Also, it was observed that blood and drug loss along the needle tract was reduced when inflow occlusion was used. Plasma and liver samples were harvested over a 90-min period and analysed by high pressure liquid chromatography (HPLC). RESULTS: In plasma mean peak levels and mean area under the curve (AUC) were significantly lower with intrahepatic doxorubicin (P<0.05) than with intravenous or intra-atrial delivery. In the liver AUCintrahepatic/AUCintravenous ratios were 3.45 and 3.6 with 4.8 mg and 96 mg of doxorubicin respectively. The AUCintrahepatic/AUCintraarterial ratios were 1.97 and 1.65 respectively. The liver extraction ratio (AUCliver/AUCplasma) after intravenous administration with 4.8 mg and 96 mg of doxorubicin was 31.9 with both doses of doxorubicin. The corresponding extraction ratios were 107.6 and 51 for intra-arterial administration and 425.2 and 237.7 for intrahepatic administration for the two doses of doxorubicin. Intrahepatic injection with inflow occlusion minimized the leakage back along the needle-tracts. The liver visibly retained the injected drug more completely. However, there was a decrease in systemic clearance resulting in a reduction of the pharmacological advantage. CONCLUSION: These results indicate that lattice-intrahepatic administration of doxorubicin into the liver using a lattice template was associated with a significant increase in local and decrease in systemic exposure as compared to intravenous or intra-arterial administration of the same doses. Simultaneous occlusion of arterial and portal venous inflow was not shown to improve regional drug delivery. These pharmacokinetic studies may constitute a basis for palliative treatment of liver tumours by lattice intralesional injection when these cancers are found to be unresectable at the time of exploratory surgery.     

Perfusion of colorectal hepatic metastases. Relative distribution of flow from the hepatic artery and portal vein

The importance of portal circulation in the delivery of drugs and nutrients to colorectal hepatic metastases is controversial. Using 13N (nitrogen 13) amino acids and ammonia with dynamic gamma camera imaging, we demonstrate, for the first time in human beings, a quantitative advantage of hepatic artery compared with portal vein infusion. Eleven patients were studied by hepatic artery injection, five patients were studied by portal vein injection, and two patients had injections through both routes. Data collected from the liver for 10 minutes after rapid bolus injection of 13N L-glutamate, L-glutamine, or ammonia were compared with 99mTc (technetium) macroaggregated albumin (MAA) images produced after injection through the hepatic artery or portal vein at the same session. Tumor regions defined from 99mTc sulfur colloid scans were compared with nearby liver areas of similar thickness. For the 13N compounds, the area-normalized count rate at first pass maximum (Qmax) and the tissue extraction efficiency were computed. The tumor/liver Qmax ratios for MAA and 13N compounds were highly correlated. Both tumor and liver extracted more than 70% of the nitrogenous compounds. The tumor/liver Qmax ratios reflect the relative delivery of injected tracer per unit volume of tissue. After hepatic artery injection the Qmax ratio was 1.03 +/- 0.33 (mean +/- SD), significantly exceeding the Qmax ratio of 0.50 +/- 0.34 after portal vein injection (P less than 0.003). Therefore, more than twice as much of a nutrient substrate is delivered per volume of tumor relative to liver by the hepatic artery as by the portal vein; the high extraction efficiency demonstrates that the hepatic artery flow is nutritive; and the delivery of substance in solution (such as nutrients or drugs) to tumor and liver tissue correlates with the distribution of colloids such as macroaggregated albumin after hepatic arterial and portal venous injection.     

The regional treatment of liver metastases from breast cancer

To determine the effect of aggressive regional therapy for liver metastasis from breast cancer, we retrospectively reviewed data on 74 patients identified with liver metastases. Forty had only liver metastases. In this group of 40 patients, 18 were treated with regional therapy only, i.e., surgical resection and/or regional chemotherapy via hepatic artery or portal vein catheters whereas 22 patients had systemic chemotherapy. The two groups were comparable. The regional chemotherapy regimen was 5-FU, Adriamycin, methotrexate, and cytoxan. Median survival (27 months) for those patients treated with regional therapy (N = 18) was significantly longer than for those (N = 22) treated with systemic therapy (5 months) (P = 0.001). Only 45% of the regional treatment group failed in the liver. Our data, although retrospective and selective, suggest that certain subgroups of breast cancer patients with metastatic liver disease may benefit from aggressive regional therapy. © Wiley-Liss, Inc.     

Pharmacokinetics and pharmacodynamics of locoregional 5 fluorouracil (5FU) in advanced colorectal liver metastases

By measuring peripheral drug levels in plasma, the effect of combining albumin microspheres with angiotensin II on systemic exposure to 5FU when administered by bolus injection into the hepatic artery in patients with advanced colorectal liver metastases has been assessed. The results suggest that despite hepatic arterial administration of 5FU, there was no reduction in systemic exposure when compared with that associated with intravenous injection of the same dose. Neither albumin microspheres nor angiotensin II appeared to improve the regional advantage. There have been a number of reports relating the plasma levels of cytotoxic agents with pharmacodynamic parameters. We have shown significant direct correlations between 5FU clearance and 1 week post treatment platelet and white cell counts, and an inverse relationship between the area under the 5FU plasma concentration-time curve (AUC) and 1 week post treatment platelet count and white cell count respectively.     

Extracorporeal hemofiltration: a model for decreasing systemic drug exposure with intra-arterial chemotherapy

Summary Cisplatin (3 mg/kg) was infused through the hepatic artery in nine mongrel dogs. Four of these dogs underwent simultaneous extracorporeal hemofiltration (ECH) of the hepatic venous effluent using a high-flow, dual-lumen catheter placed in the vena cava at the level of the hepatic veins. Platinum levels were measured in the plasma, urine, and ultrafiltrate and in kidney and liver tissue. ECH significantly reduced systemic drug exposure as measured by the AUC for free and total platinum, by urinary excretion, and by 24-h kidney levels. Regional liver levels were minimally affected. Recovery of platinum in the ultrafiltrate was 40% ± 14%. ECH resulted in efficient extraction of platinum and reduced systemic drug exposure with relative preservation of regional hepatic drug exposure. These studies were supported by the Ben Marcus Bequest and The University of Texas M. D. Anderson Cancer Center New Program Development Fund     

Intra-arterial administration of the angiogenesis inhibitor TNP-470 blocks liver metastasis in a rabbit model.

We evaluated the best route of administration of TNP-470, an angiogenesis inhibitor, by comparing the anti-tumour effects and toxicity following injection via the hepatic artery, the portal vein, or the jugular vein in a rabbit model of liver metastases. Following the injections of 1 x 10(6) VX2 carcinoma cells into the portal vein of rabbits, 50 mg of TNP-470 was injected continuously into the hepatic artery, portal vein, or jugular vein for 7 days. The number of tumours on the surface of the liver was counted 14 days following the start of the infusion, and the serum glutamic-oxaloacetic transamine (GOT), glutamic-pyruvic transaminase (GPT) and total bilirubin concentrations were examined. In addition, a coloured silicon rubber was injected into the vessels of the liver to visualise the capillary networks around the tumours and assess the degree of suppression of angiogenesis by TNP-470. The mean number of tumours following intra-arterial injection (17.5 +/- 2.9) was significantly less than the control (237.0 +/- 34.0) (P < 0.05). The mean numbers of the tumours following intraportal (89.1 +/- 16.0) and intravenous (140.6 +/- 31.2) injection were both less than the controls (215.3 +/- 45.5, 284.8 +/- 55.4 respectively), but the differences were not significant. We conclude that intra-arterial injection of TNP-470 is the most effective method for preventing liver metastases in this model.     

High mitomycin C concentration in tumour tissue can be achieved by isolated liver perfusion in rats

Summary To enable the treatment of hepatic metastasis with higher, theoretically more effective, doses of systemically toxic anticancer drugs, an isolated liver perfusion (ILP) technique was developed in WAG/Ola rats. First, in a toxicity study the maximally tolerated dose (MTD) of mitomycin C (MMC) was determined for a 25-min ILP and for hepatic artery infusion (HAI) after the administration of a bolus dose. The MTD in the ILP setting (4.8 mg/kg) was 4 times that using HAI (1.2 mg/kg). Subsequently, in a rat colorectal hepatic-metastasis model, concentrations of MMC in tumour, liver, plasma and perfusate were measured during a 25-min ILP to investigate the expected pharmacokinetic advantage of ILP. The mean plasma level determined after ILP (1.2 as well as 4.8 mg/kg MMC) was significantly lower (P<0.001) than that obtained following HAI. This may explain both the absence of severe systemic toxicity and the higher MTD in ILP-treated groups. No significant difference in mean tumour and liver tissue concentrations of MMC were found when the groups treated with 1.2 mg/kg drug via HAI vs ILP were compared. The mean MMC concentration in tumour tissue was significantly higher (almost 5 times;P<0.05) in rats treated by ILP with the MTD (4.8 mg/kg) than in those treated via HAI with the MTD (1.2 mg/kg). ILP of MMC can be safely performed using a dose 4 times higher than the MTD in the HAI setting, leading to an almost 5-fold concentration of MMC in hepatic metastasis. ILP of MMC may therefore represent a promising therapy for metastasis confined to the liver.Abbreviations HAI hepatic artery infusion - HPLC high-performance liquid chromatography - ILP isolated liver perfusion - MMC mitomycin C - MTD maximally tolerated dose Supported by grant IKW 88-07 from the Dutch Cancer Foundation     

Unchanged pharmacokinetics of etoposide given by intra-arterial hepatic infusion as compared with i.v. infusion

 We investigated the pharmacokinetics of etoposide given to a patient suffering from multifocal liver metastases from an unknown primary tumor. The drug was given either by i.v. infusion or by hepatic arterial infusion (HAI). The calculated pharmacokinetic parameters (mean values ± SD) were similar after i.v. infusion and HAI, viz., 6.4±0.7 versus 6.5±0.2 h for the terminal elimination half-life (t _1/2β), 98.5±1.3 versus 101.3±5.9 mg l^-1 h for the area under the plasma concentration-time curve (AUC), 21.2±0.3 versus 20.6±1.2 ml min^-1 m^-2 for clearance (Cl), 17.7±1.9 versus 18.1±2.6 mg/l for the peak concentration, and 11.7±1.3 versus 11.6±1.0 l/m² for the volume of distribution (V _d ), respectively. We therefore conclude that administration of etoposide by HAI does not result in a significantly higher liver extraction. Hepatic extraction of etoposide is determined by the fraction of non-protein-bound (free) drug present. The lack of a difference between the two administration routes suggests that under in vivo conditions the equilibrium between free and bound drug is established before the drug reaches the hepatic arterioles. Consequently, administration by HAI does not lead to an increased exposure of the tumor in the liver to free (active) etoposide. Furthermore, the overall exposure of the liver to total (bound + free) etoposide is increased only from about 100 to 120 mg l^-1 h. These results do not favor the use of this more complex route of drug administration in the treatment of (metastatic) cancer located in the liver. Received: 5 November 1995/Accepted: 17 January 1996     

Concentration of biologically active 5-fluorouracil in general circulation during continuous portal infusion in man: a preliminary report.

5-Fluorouracil (5-FU) was administered to 8 patients with malignant liver tumours either by regional portal or general intravenous infusion. During continuous portal infusion of 15 mg 5-FU/kg/24 h, systemic serum-concentrations were generally below 100 ng/ml and no side-effects were seen. Intravenous infusion of the same dose was accompanied by serum-concentrations above 100 ng/ml and bone-marrow depression. This preliminary study indicates that there are better prerequisites for high anti-toumour effect and low frequency of side-effects during portal infusion of 5-FU than during general intravenous administration to patients with liver tumours.