2000 Abstract: 2457: The Antioxidant N-Acetylcysteine Modulates 5-Fluorouracil Activity Against Colorectal Cancer Xenografts in Nude Mice.
Abstracts
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Background: The antioxidant pyrrolidinedithiocarbamate (PDTC) promotes cytotoxicity of 5-FU against human colorectal cancer (CRC) xenografts1. This combined treatment is less toxic to normal mouse intestinal epithelium than 5-FU alone2. We investigated the effect of another antioxidant compound, N-acetylcysteine (NAC), upon human CRC xenograft growth in the nude mouse. NAC is of interest as it is licenced for clinical use in high doses to treat acetaminophen poisoning. Method: Athymic nude mice (n=28) were injected subcutaneously, in each flank, with the mutant p53 human CRC cell line HCT 15 (1×106 cells per site). Treatment was administered by intraperitoneal injection on day 7 when the tumours were visible. Groups included: (1) saline 0.2 ml, (2) 5- FU 120 mg/kg, (3) NAC 200mg/kg, (4) NAC and 5-FU. Serial measurements of tumour volume were made in a blinded fashion. Mice were culled when individual tumour volume exceeded 1000mm3. Results: Tumour volume is significantly reduced from day 13 in mice treated with NAC/5-FU compared to those treated with 5-FU alone (day 13, p=0.03; days 17 and 20, p<0.001, Mann-Whitney U test). NAC administered, as a single agent does not retard tumour growth (p=0.31, Mann-Whitney U test). Prior to treatment at day 7, no significant difference exists between groups (p=0.18, Kruskal-Wallis). Conclusion: Growth of established human CRC xenografts was retarded more effectively by combined therapy with NAC/5-FU than with 5-FU alone. Extensive clinical experience with NAC will facilitate development of clinical trials. 1 Chinnery R, Brockman JA, Peeler MO, Shyr Y, Coffey RJ. Nature Medicine 1997; 3(11): 1233-1241. 2 Bach SP, Chinnery R, O’Dwyer ST, Potten CS, Coffey RJ, Watson AJM. Gastroenterology (In press). |
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