The antioxidant n-acetylcysteine increases 5-fluorouracil activity against colorectal cancer xenografts in nude mice.
The antioxidant pyrrolidinedithiocarbamate improves the therapeutic efficacy of 5-fluorouracil (5-FU) against HCT-15 colorectal cancer cell line xenografts in nude mice without increasing toxicity to normal intestinal or hematopoietic tissues. In the current study we have shown that a similar clinically licensed antioxidant, N-acetylcysteine (200 mg/kg), can modulate the activity of 5-FU (120 mg/kg) against HCT-15 tumor xenografts in nude mice. We demonstrate that this effect is accompanied by a sustained elevation in p53-independent apoptosis without accompanying alterations in cell cycle kinetics. Extensive tumor necrosis is also a prominent feature of treatment; however, no significant impairment of neovascularization as assessed by intratumor microvessel density occurred. We believe that the clinical efficacy of N-acetylcysteine as an adjunct to 5-FU in advanced colorectal cancer should be investigated further.
Bach
S P
SP
Cancer Research Campaign, Department of Epithelial Biology, The Paterson Institute, Christie Hospital, Withington, Manchester M20 4BX, UK. Sbach@picr.man.ac.uk
Williamson
S E
SE
Marshman
E
E
Kumar
S
S
O'Dwyer
S T
ST
Potten
C S
CS
Watson
A J
AJ
D000111:Acetylcysteine / Q000494:pharmacology / Q000627:therapeutic use*; D000230:Adenocarcinoma / Q000188:drug therapy*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy*; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D004357:Drug Synergism; D005434:Flow Cytometry; D005472:Fluorouracil / Q000494:pharmacology / Q000627:therapeutic use*; D016166:Free Radical Scavengers / Q000494:pharmacology / Q000627:therapeutic use*; D016158:Genes, p53 / Q000187:drug effects; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D000975:Antioxidants; D016166:Free Radical Scavengers; D005472:Fluorouracil; D000111:Acetylcysteine