Michael Tapner

Treatment of Fluorouracil-Refractory Patients With Liver Metastases From Colorectal Cancer by Using Yttrium-90 Resin Microspheres Plus Concomitant Systemic Irinotecan Chemotherapy

PURPOSE Liver metastases are the principal cause of death in patients with advanced colorectal cancer (CRC). Irinotecan is a chemotherapeutic agent used in the treatment of CRC and has demonstrated synergistic potential when used with radiation. Radioembolization with yttrium-90 microspheres has demonstrated increased response and survival rates when given with fluorouracil chemotherapy. This studys goal was to evaluate the maximum-tolerated dose of concomitant irinotecan and radioembolization in fluorouracil-refractory patients with CRC hepatic metastases. PATIENTS AND METHODS Twenty-five irinotecan-naive patients who had experienced relapse after previous chemotherapy were enrolled onto three dose-escalating groups. Irinotecan was administered at 50, 75, or 100 mg/m(2) on days 1 and 8 of a 3-week cycle for the first two cycles, and full irinotecan doses (ie, 100 mg/m(2)) were administered during cycles 3 to 9. Radioembolization was administered during the first chemotherapy cycle. RESULTS Most patients experienced acute, self-limiting abdominal pain and nausea. Mild lethargy and anorexia were common. Grades 3 to 4 events were seen in three of six patients at 50 mg/m(2) (obstructive jaundice, thrombocytopenia, diarrhea), in five of 13 patients at 75 mg/m(2) (neutropenia, leukopenia, thrombocytopenia, elevated alkaline phosphatase, abdominal pain, ascites, fatigue) and in four of six patients at 100 mg/m(2) (diarrhea, deep vein thrombosis, constipation, leukopenia). Eleven (48%) of 23 patients had a partial response, and nine patients (39%) had stable disease. The median progression-free survival was 6.0 months; the median survival was 12.2 months. CONCLUSION Concomitant use of radioembolization plus irinotecan did not reach a maximum-tolerated dose. The recommended dose of irinotecan in this setting is 100 mg/m(2) on days 1 and 8 of a 3-week cycle.

Halothane‐induced liver injury in guinea‐pigs: Importance of cytochrome P450 enzyme activity and hepatic blood flow

The basis for susceptibility to halothane‐induced liver necrosis in guinea‐pigs was examined. In hepatic microsomes, the following were similar in susceptible and resistant animals: total cytochrome (CYP) P450 (P450), phenobarbital‐inducible pathways of mixed function oxidation (androstenedione 6β‐ and 16β‐hydroxylase activities) and the CYP2E1‐catalysed pathway of N‐nitrosodimethylamine N‐demethylase activity. Similarly, immunohistochemical staining of CYP2E1 protein was equivalent in livers from susceptible and resistant guinea‐pigs. Prior treatment with the P450‐inhibitors, metyrapone and SKF‐525A ameliorated halothane‐induced liver damage in susceptible animals. Conversely, in resistant guinea‐pigs, stimulation of hepatic CYP2E1 activity by treatment with 4‐methylpyrazole produced severe hepatotoxicity after re‐exposure to halothane. These results confirm the conclusions of others, that P450‐mediated metabolism produces halothane‐induced liver necrosis in the guinea‐pig model but, as in other work, the data fail to explain why no difference in activity of these enzymes could be found between susceptible and resistant guinea‐pigs. To establish whether a differential effect on hepatic blood flow between susceptible and resistant guinea‐pigs could explain this paradox, studies were performed using a radiolabelled microsphere technique. The effect of halothane on lowering cardiac output was identical in both groups of animals and halothane significantly reduced hepatic arterial but not portal blood flow. The effect on arterial blood flow was more profound in susceptible guinea‐pigs (0.67 ± 0.17% of injected microspheres) than in resistant animals (0.99 ± 0.13%; P< 0.005). It is concluded that P450‐catalysed metabolism and reduced hepatic blood flow are both necessary to produce halothane‐induced liver injury in susceptible guinea‐pigs, but it is the effect of halothane on hepatic arterial blood flow that differs between susceptible and resistant animals.

Culture and transfection of mammalian primary hepatocytes and hepatocyte‐derived cell lines

Mammalian hepatocytes and hepatocyte-derived cell lines provide a convenient model for the study of hepatic parenchymal cell function while minimizing the multiplicity of variables inherent in the in vivo situation (Table 1). However, such models do have their limitations and require optimization for specific tasks. Our own interest in cytochrome P450 (P450) regulation provides an excellent paradigm for the use of cell culture models. This is because P450 expression represents a highly specialized function of the hepatocyte which, up until recently, has been difficult to achieve in vitro. The aim of this review is to provide practical advice regarding hepatocyte culture, rather than an exhaustive review of the subject.