5-Fluorouracil-induced intestinal toxicity: what determines the severity of damage to murine intestinal crypt epithelia?

被引:34
作者
Inomata, A
Horii, I
Suzuki, K
机构
[1] Nippon Roche Res Ctr, Dept Preclin Sci, Kamakura, Kanagawa 2478530, Japan
[2] Nippon Vet & Anim Sci Univ, Dept Vet Physiol, Tokyo, Japan
关键词
5-fluorouracil; microautoradiography; apoptosis; cell cycle arrest; p21(WAF/Cip1); Bax;
D O I
10.1016/S0378-4274(02)00204-7
中图分类号
R99 [毒物学(毒理学)];
学科分类号
100405 ;
摘要
To elucidate the relationship between 5-fluorouracil (5-FU) distribution and 5-FU-induced apoptosis and/or cell cycle arrest, microautoradiography was applied to murine intestinal crypts exposed to [C-14] 5-FU by intravenous infusion. The histologic location of apoptotic cells in the crypt did not correlate to that of 5-FU. The temporal profiles of apoptotic and/or mitotic indexes corresponded to those of orally administered 5-FU in a previous study. Two cell cycle-related proteins, p21(WAF/Cip1) and bax, were also investigated in the present study. With time, p21(WAF/Cip1)-positive nuclei apparently migrated up the crypt. Bax-positive cytoplasm was observed throughout the crypt epithelial cells, accompanied by the occurrence of apoptosis, and remained until 48 h when the control level recovered. The findings demonstrate that 5-FU mainly exerts an apoptotic effect and/or cell cycle arrest by systemic exposure, and p21 and bax expression determine an individual cell's fate. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved.
引用
收藏
页码:231 / 240
页数:10
相关论文
共 38 条
[1]   The Bcl-2 protein family: Arbiters of cell survival [J].
Adams, JM ;
Cory, S .
SCIENCE, 1998, 281 (5381) :1322-1326
[2]   RADIATION-INDUCED CELL-CYCLE ARREST COMPROMISED BY P21 DEFICIENCY [J].
BRUGAROLAS, J ;
CHANDRASEKARAN, C ;
GORDON, JI ;
BEACH, D ;
JACKS, T ;
HANNON, GJ .
NATURE, 1995, 377 (6549) :552-557
[3]  
Burns TF, 1999, J CELL PHYSIOL, V181, P231, DOI 10.1002/(SICI)1097-4652(199911)181:2<231::AID-JCP5>3.0.CO
[4]  
2-L
[5]   THYMOCYTE APOPTOSIS INDUCED BY P53-DEPENDENT AND INDEPENDENT PATHWAYS [J].
CLARKE, AR ;
PURDIE, CA ;
HARRISON, DJ ;
MORRIS, RG ;
BIRD, CC ;
HOOPER, ML ;
WYLLIE, AH .
NATURE, 1993, 362 (6423) :849-852
[6]  
DelSal G, 1996, ONCOGENE, V12, P177
[7]   P53-DEPENDENT INHIBITION OF CYCLIN-DEPENDENT KINASE-ACTIVITIES IN HUMAN FIBROBLASTS DURING RADIATION-INDUCED G1 ARREST [J].
DULIC, V ;
KAUFMANN, WK ;
WILSON, SJ ;
TLSTY, TD ;
LEES, E ;
HARPER, JW ;
ELLEDGE, SJ ;
REED, SI .
CELL, 1994, 76 (06) :1013-1023
[8]   WAF1, A POTENTIAL MEDIATOR OF P53 TUMOR SUPPRESSION [J].
ELDEIRY, WS ;
TOKINO, T ;
VELCULESCU, VE ;
LEVY, DB ;
PARSONS, R ;
TRENT, JM ;
LIN, D ;
MERCER, WE ;
KINZLER, KW ;
VOGELSTEIN, B .
CELL, 1993, 75 (04) :817-825
[9]   IDENTIFICATION OF PROGRAMMED CELL-DEATH INSITU VIA SPECIFIC LABELING OF NUCLEAR-DNA FRAGMENTATION [J].
GAVRIELI, Y ;
SHERMAN, Y ;
BENSASSON, SA .
JOURNAL OF CELL BIOLOGY, 1992, 119 (03) :493-501
[10]   p53 in growth control and neoplasia [J].
Gottlieb, TM ;
Oren, M .
BIOCHIMICA ET BIOPHYSICA ACTA-REVIEWS ON CANCER, 1996, 1287 (2-3) :77-102