Response of intestinal cells of differing topographical and hierarchical status to ten cytotoxic drugs and five sources of radiation

Ijiri, Kenichi; Potten, Christopher S

doi:10.1038/bjc.1983.25

Cited by 209 publications

(116 citation statements)

References 15 publications

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“…Indeed, irradiation of p53 null (Ϫ͞Ϫ) mice showed that the wave of irradiation-induced apoptosis observed at 4.5 hr was entirely p53-dependent (6). Cytotoxic drugs and chemicals also initiate apoptosis in intestinal epithelia after administration in vivo (7,8). The positional pattern of cell death induced after a single bolus injection of the pyrimidine antimetabolite 5-fluorouracil (5-FU) differed from that observed after radiation.…”

mentioning

confidence: 89%

“…Transverse sections of small intestine and the middle third of the colon (midcolon) were prepared and stained by hematoxylin and eosin (5,14). Fifty half-crypts were scored for apoptosis on a cell-positional basis per mouse as described in detail (7,8,(14)(15)(16). Briefly, cells were numbered from the base of the crypt, designated cell position 1, and scored as normal, apoptotic (containing one or more apoptotic fragments) or mitotic, up to the crypt-villus junction.…”

Section: Methodsmentioning

confidence: 99%

“…The positional pattern of cell death induced after a single bolus injection of the pyrimidine antimetabolite 5-fluorouracil (5-FU) differed from that observed after radiation. Stem cells in the small intestine were largely spared, and rapidly dividing early transit cells underwent the most frequent apoptosis (7,8).…”

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confidence: 99%

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Inhibition by uridine but not thymidine of p53-dependent intestinal apoptosis initiated by 5-fluorouracil: Evidence for the involvement of RNA perturbation

Pritchard

Watson

Potten

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

175

133

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The epithelia from the crypts of the intestine are exquisitely sensitive to metabolic perturbation and undergo cell death with the classical morphology of apoptosis. Administration of 40 mg͞kg 5-f luorouracil (5-FU) to BDF-1 p53؉͞؉ mice resulted in an increase in p53 protein at cell positions in the crypts that were also those subjected to an apoptotic cell death. In p53؊͞؊ mice apoptosis was almost completely absent, even after 24 hr. 5-FU is a pyrimidine antimetabolite cytotoxin with multiple mechanisms of action, including inhibition of thymidylate synthase (TS), which gives rise to DNA damage, and incorporation into RNA. The inhibition of TS can be increased by coadministration of folinic acid and can be abrogated by administration of thymidine. The incorporation of 5-FU into RNA is inhibited by administration of uridine. p53-Dependent cell death induced by 5-FU was only inhibited by administration of uridine. Uridine had no effect on the apoptosis initiated by 1 Gy of ␥-radiation. Although thymidine abrogated apoptosis induced by the pure TS inhibitor Tomudex, it had no effect on 5-FU-induced apoptosis, and coadministration of folinic acid did not increase apoptosis. The data show that 5-FU-induced cell death of intestinal epithelial cells is p53-dependent and suggests that changes in RNA metabolism initiate events culminating in the expression of p53.

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confidence: 89%

Section: Methodsmentioning

confidence: 99%

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Inhibition by uridine but not thymidine of p53-dependent intestinal apoptosis initiated by 5-fluorouracil: Evidence for the involvement of RNA perturbation

Pritchard

Watson

Potten

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

175

133

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“…A drug often used in the adjuvant and palliative treatment of colorectal tumours is 5-fluorouracil (Cunningham and Findlay, 1993;Moertel, 1994). This agent inhibits nucleic acid biosynthesis by a number of different mechanisms and induces apoptosis both in vitro and in vivo (Ijiri and Potten, 1983;Fisher et al, 1993). In vitro studies have demonstrated that bcl-2 can inhibit apoptosis induced by 5-fluorouracil (Fisher et al, 1993).…”

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confidence: 99%

Bcl-2 expression and response to chemotherapy in colorectal adenocarcinomas

Schneider

Sampson²,

Cunningham³

et al. 1997

Br J Cancer

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SummaryIn the last year, a number of studies have reported the expression of bcl-2 in colorectal adenocarcinomas. However, the influence of bcl-2 expression on response to chemotherapy and outcome in patients with advanced colorectal adenocarcinoma has not been reported. We analysed bcl-2 expression in 231 colorectal tumours from patients that were treated by surgery alone or with 5-fluorouracil-based chemotherapy. Of 231 tumours, 149 (64.5%) overexpressed bcl-2. Bcl-2 expression was associated with low plasma CEiA levels (P=0. 01 3) and inversely associated with poor differentiation (P=0.049). However, bcl-2 expression did not significantly influence failure-free or overall survival in surgically treated patients. In the group of patients receiving 5-fluorouracil-based chemotherapy bcl-2 expression did not influence response to chemotherapy; nor did it effect failure-free or overall survival.

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“…Each position was scored as containing a normal cell, an apoptotic cell (with one or more apoptotic bodies) or a mitotic figure. Data were recorded using a PC microcomputer and software developed at the Paterson Institute (Ijiri and Potten, 1983). Group treatment was masked and a single observer (SPB) scored the slide sections.…”

Section: Animalsmentioning

confidence: 99%

Regional localisation of p53-independent apoptosis determines toxicity to 5-fluorouracil and pyrrolidinedithiocarbamate in the murine gut

et al. 2006

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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 ( þ / þ ) and p53 null (À/À) mice 6, 12, 24, 36, 48 and 72 h after the administration of high (200 mg kg À1 ) or low (40 mg kg À1 ) dose 5-FU7250 mg kg À1 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.

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Response of intestinal cells of differing topographical and hierarchical status to ten cytotoxic drugs and five sources of radiation

Cited by 209 publications

References 15 publications

Inhibition by uridine but not thymidine of p53-dependent intestinal apoptosis initiated by 5-fluorouracil: Evidence for the involvement of RNA perturbation

Inhibition by uridine but not thymidine of p53-dependent intestinal apoptosis initiated by 5-fluorouracil: Evidence for the involvement of RNA perturbation

Bcl-2 expression and response to chemotherapy in colorectal adenocarcinomas

Regional localisation of p53-independent apoptosis determines toxicity to 5-fluorouracil and pyrrolidinedithiocarbamate in the murine gut

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