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Pyrrolidinedithiocarbamate increases the therapeutic index of 5-fluorouracil in a mouse model.

AbstractBACKGROUND & AIMS:
The thiol-containing antioxidant pyrrolidinedithiocarbamate (PDTC) enhances the cytotoxic efficacy of 5-fluorouracil (5-FU) against human colorectal cancer cell lines in vitro and in vivo. This process appears to be mediated by a sustained increase in p21 expression, independent of p53 function, resulting in growth arrest and apoptosis. We determined whether PDTC augmented 5-FU intestinal toxicity in non-tumor-bearing mice.
METHODS:
Apoptotic and mitotic indices were measured in the small and large intestine on a cell positional basis at intervals throughout the 72-hour period after administration of 5-FU (40 mg/kg) and PDTC (250 mg/kg). The proportion of crypts regenerating after 5-FU (600-1200 mg/kg) and PDTC (500 mg/kg) was also measured.
RESULTS:
5-FU therapy induces substantial apoptotic cell death with simultaneous inhibition of mitotic activity within the small and large intestinal epithelium. PDTC reduces 5-FU-induced apoptotic events in the colon by 49%, predominantly among clonogenic stem and transit cells while promoting the early recovery of mitotic activity. As a consequence, PDTC increased the proportion of regenerating colonic crypts after 5-FU therapy. PDTC did not, however, significantly modulate 5-FU toxicity in the small intestine.
CONCLUSIONS:
PDTC does not augment the intestinal toxicity of 5-FU and actually protects the colonic mucosa. These results support further investigation of PDTC and related compounds as treatments for colorectal cancer.
AuthorsS P Bach, R Chinery, S T O'Dwyer, C S Potten, R J Coffey, A J Watson
JournalGastroenterology (Gastroenterology) Vol. 118 Issue 1 Pg. 81-9 (Jan 2000) ISSN: 0016-5085 [Print] United States
PMID10611156 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • Antimetabolites, Antineoplastic
  • Antioxidants
  • Pyrrolidines
  • Thiocarbamates
  • pyrrolidine dithiocarbamic acid
  • Fluorouracil
Topics
  • Animals
  • Antimetabolites, Antineoplastic (administration & dosage, toxicity)
  • Antioxidants (pharmacology)
  • Apoptosis (drug effects)
  • Colon (cytology, drug effects)
  • Drug Interactions
  • Fluorouracil (administration & dosage, toxicity)
  • Intestine, Small (cytology, drug effects)
  • Mice
  • Mice, Inbred Strains
  • Mitosis (drug effects)
  • Pyrrolidines (pharmacology)
  • Thiocarbamates (pharmacology)

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