SarCNU

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 p21Cip1/Waf1. In addition to up-regulation of p53 and p21Cip1/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.

To evaluate the activity and toxicity of SarCNU, an oral chloroethylnitrosourea in patients with recurrent or metastatic colorectal cancer who have progressed after first-line chemotherapy.

Eighteen patients with recurrent or metastatic colorectal cancer following first-line chemotherapy were treated with SarCNU 860 mg/m2 orally day 1, 5 and 9 every 6 weeks. The patient's median age was 64 and the ECOG performance status was 0 in six, 1 in eleven and 2 in one patients. All patients were evaluable for toxicity and 16 were evaluable for response.

There were no objective responses (0%). One patient had stable disease and 15 had progressive disease at their first follow-up assessment. Median survival was 7.36 months (3.75-7.49 95% C.I.). Neutropenia and thrombocytopenia were the most severe toxicities (grade 3-4 in six and nine patients respectively). Pulmonary toxicity was also seen in five patients who had a drop of DLCO grade from baseline and two patients who had a fall in FVC from baseline.

SarCNU is inactive in recurrent or metastatic colorectal patients who have progressed after first-line chemotherapy.