Gene Therapy for Liver Tumours
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GENE THERAPY FOR LIVER TUMOURS Ragai R. Mitry, Marc R. Mansour, Roman Havlik, and Nagy A. Habib Liver Surgery Section Division of Surgery Anaesthetics and Intensive Care Imperial College School of Medicine Hammersmith Hospital Campus Du Cane Road, London W12 ONN United Kingdom
1. EPIDEMIOLOGY 1.1. Hepatocellular Carcinoma Hepatocellular carcinoma (HCC) is one of the most common tumours worldwide with an estimated 1 million new cases diagnosed per year (Carr et al., 1997). In the Western world HCC is relatively rare representing less than 2% of all cancers. It is the most frequent primary liver malignancy, the remainder being made up of cholangiocarcinoma and fibrolamellar variant. There is a male to female ratio of 4:1. It is estimated that 60–90% of HCC cases occur in cirrhotic livers, depending on whether the tumour occurs in a high- or low-incidence areas (Wands and Blum, 1991). Geographically HCC clusters in areas such as Africa, South East Asia and the Middle East where hepatitis infection is endemic. Chronic hepatitis B infection, hepatitis B carrier status (Caselmann, 1995) and to a lesser degree chronic hepatitis C infection (Gerber, 1995) all confer an increased risk to HCC, primarily as a result of integration of viral DNA into the genome (which can be isolated in tumour specimens) with consequent mutations of tumour suppressor genes such as p53 (Wang et al., 1995). Aflotoxin exposure also induces mutations in p53 gene, primarily through the formation of adducts (Gerbes and Caselmann, 1993; Kobertz et al., 1997). Cirrhosis as related to alcohol (reviewed in Seitz et al., 1998) and haemochromatosis (Fellows
et al., 1988; reviewed in Barisani et al., 1996) are also important factors, as is exposure to chemical hepatocarcinogens such as nitrosamine (Olajos, 1977), organic halides (Weisburger, 1977), and the contrast agent Thorotrast (Kato, 1987). Long-term use of the oral contraceptive pill (reviewed by Dourakis et al., 1998) and steroids (Eagon et al., 1996) are implicated in the development and progression of several liver diseases including HCC. Cancer Gene Therapy: Past Achievements and Future Challenges, edited by Habib Kluwer Academic/Plenum Publishers, New York, 2000.
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1.2. Colorectal Liver Metastases In the UK, tumour involvement of the liver is more often due to metastatic deposits, particularly from abdominal, pelvic, lung or breast malignancies, compared to primary liver tumours. Colorectal cancer is the most frequent primary source acounting for over 90% of liver secondaries, accountable partly by its high prevalence as it is one of the most common tumours and partly by the venous drainage via the portal vein. Synchronous liver metastases are found in 15–25% of all cases at initial presentation and 20–50% will develop metachronous liver recurrence (Sheiner et al., 1994). If untreated 5 year survival after diagnosis of metastatic liver lesions from primary Colorectal cancer is extremely rare
and median survival is 5–6 months (Blumgart and Fong, 1995).
2. CURRENT
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