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Xenografts of Human Hepatocellular Carcinoma: A Useful Model for Testing Drugs

Authors' Affiliations: ¹ Laboratory of Molecular Endocrinology, Division of Cellular and Molecular Research, National Cancer Centre; Departments of ² General Surgery and ³ Experimental Surgery, Singapore General Hospital, Singapore; and ⁴ Lady Davis Institute for Medical Research, Jewish General Hospital, McGill University, Montreal, Quebec, Canada

Requests for reprints: Hung Huynh, Laboratory of Molecular Endocrinology, Division of Cellular and Molecular Research, National Cancer Centre of Singapore, Singapore 169610. Phone: 65-436-8347; Fax: 65-226-5694; E-mail: cmrhth{at}nccs.com.sg.

Purpose: Our aims were to establish and characterize primary human hepatocellular carcinoma xenografts. They were used to screen new drugs and improve our current treatment regimens used in hepatocellular carcinoma.

Experimental Design: Primary hepatocellular carcinomas were used to create the xenografts. Western blotting was used to determine the changes in proteins in these xenografts before and after therapies. Apoptotic and cell proliferation were analyzed by immunohistochemistry.

Results: Seven lines of xenografts were established from primary human hepatocellular carcinomas. Lines 4-1318, 2-1318, 2006, and 26-1004 grew rapidly in severe combined immunodeficient (SCID) mice and doubled its volume every 48 to 72 hours. Series 5-1318 (5-1318, 30-1004, and 29-1104) grew relatively slowly in SCID mice and required 6 to 10 days to double its tumor volume. Western blot analysis revealed that the growth rate of these xenografts was associated with abnormal expression of proteins associated with the cell cycle, signaling pathways, and tumor suppressor genes. Although hepatocellular carcinoma xenografts expressed the receptors for androgens, estrogens, and progesterone, their growth rate was not affected by either castration or sex steroid hormone supplementation. Cisplatin, oxaliplatin, vitamin D analogue EB1089, and Iressa had no effects on the growth rate in SCID mice. Although 5-fluorouracil exerted mild growth inhibition of these xenografts, i.p. delivery of 2-chloroethyl-3-sarcosinamide-1-nitrosourea (SarCNU) or doxorubicin resulted in a significant growth inhibition. Doxorubicin-induced growth suppression was associated with elevation of p53 and p21^Cip1/Waf1. In addition to up-regulation of p53 and p21^Cip1/Waf1, SarCNU also increased the levels of phosphorylated cdc-2 at Tyr¹⁵.

Conclusion: Hepatocellular carcinoma xenografts are powerful tools for screening drugs and SarCNU may be useful in the treatment of this fatal disease.

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