Pyrrolidinedithiocarbamate increases the therapeutic index of 5-fluorouracil in a mouse model.
OBJECTIVE
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.
Bach
S P
SP
Cancer Research Campaign, Department of Epithelial Biology, The Paterson Institute, Manchester, England.
Chinery
R
R
O'Dwyer
S T
ST
Potten
C S
CS
Coffey
R J
RJ
Watson
A J
AJ
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000633:toxicity*; D000975:Antioxidants / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D003106:Colon / Q000166:cytology / Q000187:drug effects*; D004347:Drug Interactions; D005472:Fluorouracil / Q000008:administration & dosage / Q000633:toxicity*; D007421:Intestine, Small / Q000166:cytology / Q000187:drug effects*; D051379:Mice; D008815:Mice, Inbred Strains; D008938:Mitosis / Q000187:drug effects*; D011759:Pyrrolidines / Q000494:pharmacology*; D013859:Thiocarbamates / Q000494:pharmacology*
D000964:Antimetabolites, Antineoplastic; D000975:Antioxidants; D011759:Pyrrolidines; D013859:Thiocarbamates; C020972:pyrrolidine dithiocarbamic acid; D005472:Fluorouracil