Pyrrolidinedithiocarbamate Increases the Therapeutic Index of 5-fluorouracil in a Mouse Model

Gastroenterology. 2000 Jan;118(1):81-9. doi: 10.1016/s0016-5085(00)70416-1.

Abstract

Background & 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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Antimetabolites, Antineoplastic / administration & dosage
  • Antimetabolites, Antineoplastic / toxicity*
  • Antioxidants / pharmacology*
  • Apoptosis / drug effects*
  • Colon / cytology
  • Colon / drug effects*
  • Drug Interactions
  • Fluorouracil / administration & dosage
  • Fluorouracil / toxicity*
  • Intestine, Small / cytology
  • Intestine, Small / drug effects*
  • Mice
  • Mice, Inbred Strains
  • Mitosis / drug effects*
  • Pyrrolidines / pharmacology*
  • Thiocarbamates / pharmacology*

Substances

  • Antimetabolites, Antineoplastic
  • Antioxidants
  • Pyrrolidines
  • Thiocarbamates
  • pyrrolidine dithiocarbamic acid
  • Fluorouracil