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dc.contributor.authorBach, Simon P
dc.contributor.authorChinery, Rebecca
dc.contributor.authorO'Dwyer, Sarah T
dc.contributor.authorPotten, Christopher S
dc.contributor.authorCoffey, Robert J
dc.contributor.authorWatson, Alastair
dc.date.accessioned2009-11-23T12:12:48Zen
dc.date.available2009-11-23T12:12:48Zen
dc.date.issued2000-01en
dc.identifier.citationPyrrolidinedithiocarbamate increases the therapeutic index of 5-fluorouracil in a mouse model. 2000, 118 (1):81-9 Gastroenterologyen
dc.identifier.issn0016-5085en
dc.identifier.pmid10611156en
dc.identifier.doi10.1016/S0016-5085(00)70416-1en
dc.identifier.urihttp://hdl.handle.net/10541/86692en
dc.description.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.
dc.language.isoenen
dc.subject.meshAnimalsen
dc.subject.meshAntimetabolites, Antineoplasticen
dc.subject.meshAntioxidantsen
dc.subject.meshApoptosisen
dc.subject.meshColonen
dc.subject.meshDrug Interactionsen
dc.subject.meshFluorouracilen
dc.subject.meshIntestine, Smallen
dc.subject.meshMiceen
dc.subject.meshMice, Inbred Strainsen
dc.subject.meshMitosisen
dc.subject.meshPyrrolidinesen
dc.subject.meshThiocarbamatesen
dc.titlePyrrolidinedithiocarbamate increases the therapeutic index of 5-fluorouracil in a mouse model.en
dc.typeArticleen
dc.contributor.departmentCancer Research Campaign, Department of Epithelial Biology, The Paterson Institute, Manchester, England.en
dc.identifier.journalGastroenterologyen
html.description.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.


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