The importance of p53-independent apoptosis in the intestinal toxicity induced by raltitrexed (ZD1694, Tomudex): genetic differences between BALB/c and DBA/2 mice.

2.50
Hdl Handle:
http://hdl.handle.net/10541/86183
Title:
The importance of p53-independent apoptosis in the intestinal toxicity induced by raltitrexed (ZD1694, Tomudex): genetic differences between BALB/c and DBA/2 mice.
Authors:
Pritchard, D Mark; Bower, Lawrence; Potten, Christopher S; Jackman, Ann L; Hickman, John A
Abstract:
The thymidylate synthase inhibitor raltitrexed (ZD1694, Tomudex) induces greater intestinal toxicity, manifested as diarrhea and weight loss, in BALB/c than in DBA/2 mice. No convincing pharmacokinetic or pharmacodynamic reason for this strain difference has been established. We have investigated whether this strain difference in response to raltitrexed is related to differential susceptibilities of intestinal mucosae to undergo apoptosis and also whether p53 expression, a critical factor in 5-fluorouracil-induced intestinal apoptosis and toxicity, modulates this response. Ten mg/kg or 100 mg/kg raltitrexed were administered as single or double i.p. injections 24 h apart to BALB/c, DBA/2, and p53-/- mice. Apoptosis, mitosis, and tissue damage were assessed in intestinal epithelium, and animal weight was recorded. BALB/c mice developed diarrhea and weight loss following 100 mg/kg x2 raltitrexed, whereas DBA/2 mice did not. BALB/c mice were more sensitive than DBA/2 to induction of small-intestinal and colonic apoptosis 24 h following 100 mg/kg raltitrexed. Inhibition of mitosis was equivalent in both strains. Both strains showed histopathological damage to the small intestine after 100 mg/kg x2 raltitrexed, but only BALB/c mice demonstrated colonic damage. p53-null mice showed the same level of small intestinal apoptosis as their wild-type counterparts 24 h after 100 mg/kg x1 raltitrexed and also the same levels of intestinal toxicity 3, 5, and 7 days after 100 mg/kg x2 raltitrexed. Thus, BALB/c mice were more susceptible to induction of intestinal apoptosis by raltitrexed than DBA/2 mice and also demonstrated more histopathological damage in the colon correlating with the induction of diarrhea and weight loss. In contrast to 5-fluorouracil, the intestinal apoptosis and toxicity induced by raltitrexed were p53-independent.
Affiliation:
Cancer Research Campaign Department of Epithelial Biology, Paterson Institute, Christie Hospital National Health Service Trust, Manchester, United Kingdom. dmpritch@liverpool.ac.uk
Citation:
The importance of p53-independent apoptosis in the intestinal toxicity induced by raltitrexed (ZD1694, Tomudex): genetic differences between BALB/c and DBA/2 mice. 2000, 6 (11):4389-95 Clin. Cancer Res.
Journal:
Clinical Cancer Research
Issue Date:
Nov-2000
URI:
http://hdl.handle.net/10541/86183
PubMed ID:
11106258
Type:
Article
Language:
en
ISSN:
1078-0432
Appears in Collections:
All Paterson Institute for Cancer Research

Full metadata record

DC FieldValue Language
dc.contributor.authorPritchard, D Marken
dc.contributor.authorBower, Lawrenceen
dc.contributor.authorPotten, Christopher Sen
dc.contributor.authorJackman, Ann Len
dc.contributor.authorHickman, John Aen
dc.date.accessioned2009-11-13T14:55:37Z-
dc.date.available2009-11-13T14:55:37Z-
dc.date.issued2000-11-
dc.identifier.citationThe importance of p53-independent apoptosis in the intestinal toxicity induced by raltitrexed (ZD1694, Tomudex): genetic differences between BALB/c and DBA/2 mice. 2000, 6 (11):4389-95 Clin. Cancer Res.en
dc.identifier.issn1078-0432-
dc.identifier.pmid11106258-
dc.identifier.urihttp://hdl.handle.net/10541/86183-
dc.description.abstractThe thymidylate synthase inhibitor raltitrexed (ZD1694, Tomudex) induces greater intestinal toxicity, manifested as diarrhea and weight loss, in BALB/c than in DBA/2 mice. No convincing pharmacokinetic or pharmacodynamic reason for this strain difference has been established. We have investigated whether this strain difference in response to raltitrexed is related to differential susceptibilities of intestinal mucosae to undergo apoptosis and also whether p53 expression, a critical factor in 5-fluorouracil-induced intestinal apoptosis and toxicity, modulates this response. Ten mg/kg or 100 mg/kg raltitrexed were administered as single or double i.p. injections 24 h apart to BALB/c, DBA/2, and p53-/- mice. Apoptosis, mitosis, and tissue damage were assessed in intestinal epithelium, and animal weight was recorded. BALB/c mice developed diarrhea and weight loss following 100 mg/kg x2 raltitrexed, whereas DBA/2 mice did not. BALB/c mice were more sensitive than DBA/2 to induction of small-intestinal and colonic apoptosis 24 h following 100 mg/kg raltitrexed. Inhibition of mitosis was equivalent in both strains. Both strains showed histopathological damage to the small intestine after 100 mg/kg x2 raltitrexed, but only BALB/c mice demonstrated colonic damage. p53-null mice showed the same level of small intestinal apoptosis as their wild-type counterparts 24 h after 100 mg/kg x1 raltitrexed and also the same levels of intestinal toxicity 3, 5, and 7 days after 100 mg/kg x2 raltitrexed. Thus, BALB/c mice were more susceptible to induction of intestinal apoptosis by raltitrexed than DBA/2 mice and also demonstrated more histopathological damage in the colon correlating with the induction of diarrhea and weight loss. In contrast to 5-fluorouracil, the intestinal apoptosis and toxicity induced by raltitrexed were p53-independent.en
dc.language.isoenen
dc.subjectTumour Suppressor Protein p53en
dc.subject.meshAnimals-
dc.subject.meshAntimetabolites, Antineoplastic-
dc.subject.meshApoptosis-
dc.subject.meshFluorouracil-
dc.subject.meshIntestines-
dc.subject.meshMale-
dc.subject.meshMice-
dc.subject.meshMice, Inbred BALB C-
dc.subject.meshMice, Inbred DBA-
dc.subject.meshMitosis-
dc.subject.meshQuinazolines-
dc.subject.meshSpecies Specificity-
dc.subject.meshThiophenes-
dc.subject.meshTumor Suppressor Protein p53-
dc.titleThe importance of p53-independent apoptosis in the intestinal toxicity induced by raltitrexed (ZD1694, Tomudex): genetic differences between BALB/c and DBA/2 mice.en
dc.typeArticleen
dc.contributor.departmentCancer Research Campaign Department of Epithelial Biology, Paterson Institute, Christie Hospital National Health Service Trust, Manchester, United Kingdom. dmpritch@liverpool.ac.uken
dc.identifier.journalClinical Cancer Researchen

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