Apoptosis in normal tissues induced by anti-cancer drugs.
To investigate the damage mediated by anti-cancer drugs in normal cells, we examined the effect of such drugs on apoptosis of normal cells of the small intestinal epithelium and the bone marrow by in situ DNA end-labelling and transmission electron microscopy. Mice received a single dose of 5-fluorouracil (5-FU) or cisplatin, or repeated daily doses of 5-FU for 7 days. In mice treated with a single dose of 5-FU 50 mg/kg or cisplatin 5 mg/kg, the number of apoptotic cells appearing in the small intestine 12 h after injection was relatively small, but increased steadily reaching a peak after 36 h and then decreasing to close to that in the control group by 48 h. In bone marrow cells, results were similar in mice treated with single doses of 5-FU 50 mg/kg but apoptosis increased much less in those treated with cisplatin 5 mg/kg. The proportion of apoptotic cells reached peak values earlier at higher concentrations of 5-FU or cisplatin both in small intestine and in bone marrow. In the mice treated repeatedly with 5-FU 50 mg/kg, the proportion of apoptotic small intestinal epithelial cells reached a succession of peaks at 48-h intervals. Mice treated repeatedly with 5-FU 50 mg/kg also showed a rapid increase in diarrhoea symptoms and a steady decrease in the height of villi. Our results suggest it may be possible to prevent the side-effects of anti-cancer drugs by inhibiting apoptosis in the gastrointestinal tract.
Tamaki
T
T
Department of Gastroenterological Surgery, Transplant and Surgical Oncology, Graduate School of Medicine and Dentistry, Okayama University, Okayama, Japan.
Naomoto
Y
Y
Kimura
S
S
Kawashima
R
R
Shirakawa
Y
Y
Shigemitsu
K
K
Yamatsuji
T
T
Haisa
M
M
Gunduz
M
M
Tanaka
N
N
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002945:Cisplatin / Q000494:pharmacology; D005260:Female; D005472:Fluorouracil / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D008854:Microscopy, Electron; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D002945:Cisplatin; D005472:Fluorouracil