Regional localisation of p53-independent apoptosis determines toxicity to 5-fluorouracil and pyrrolidinedithiocarbamate in the murine gut.
Pyrrolidinedithiocarbamate (PDTC) enhanced the activity of 5-fluorouracil (5-FU) in a colorectal cancer xenograft model. Pyrrolidinedithiocarbamate also reduced gastrointestinal toxicity associated with 5-FU therapy in large but not small bowel. We sought to clarify the basis of this differential enteric toxicity. Apoptosis and mitosis were assessed on a cell positional basis in small and large intestinal crypts of p53 wild-type (+/+) and p53 null (-/-) mice 6, 12, 24, 36, 48 and 72 h after the administration of high (200 mg kg(-1)) or low (40 mg kg(-1)) dose 5-FU+/-250 mg kg(-1) PDTC. Regimens were chosen to model a single human dose and a weekly schedule. The effects of another antioxidant N-acetylcysteine (NAC) were also investigated. Large intestinal crypts affect apoptosis purely by p53-dependent mechanisms, whereas small intestinal crypts are able to initiate both p53-dependent and -independent pathways following treatment with 5-FU. Pyrrolidinedithiocarbamate and NAC antagonised p53-dependent but potentiated p53-independent apoptotic activity. Consequently, the proportion of surviving clonogens increased in the large but not in the small intestine. Regional availability of p53-dependent and -independent apoptotic pathways in small and large intestine together with separate modulation of these pathways by antioxidants explains the different regional enterotoxicity following 5-FU therapy.
Bach
S P
SP
Nuffield Department of Surgery, University of Oxford, Level 2, John Radcliffe Hospital, Oxford OX3 9DU, UK. simon.bach@nds.ox.ac.uk
Williamson
S E
SE
O'Dwyer
S T
ST
Potten
C S
CS
Watson
A J M
AJ
D000818:Animals; D000975:Antioxidants / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004336:Drug Antagonism; D004357:Drug Synergism; D005472:Fluorouracil / Q000633:toxicity*; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D007420:Intestine, Large / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007421:Intestine, Small / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D008938:Mitosis / Q000187:drug effects; D009928:Organ Specificity; D011759:Pyrrolidines / Q000633:toxicity*; D013859:Thiocarbamates / Q000633:toxicity*; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
D000975:Antioxidants; D011759:Pyrrolidines; D013859:Thiocarbamates; D016159:Tumor Suppressor Protein p53; C020972:pyrrolidine dithiocarbamic acid; D005472:Fluorouracil