5-FU-induced apoptosis correlates with efficacy against human gastric and colon cancer xenografts in nude mice.
Apoptosis may be an important mechanism by which cancer cells are killed by certain agents. It is reported here that apoptosis is a key event in the killing of human tumor cells by 5-fluorouracil (5-FU) in vivo. Apoptosis induced by 5-FU was determined using two human gastrointestinal tumor xenografts serially transplanted into nude mice: a gastric carcinoma (SC-1-NU) highly sensitive to 5-FU and a colon carcinoma (Co-4) less sensitive to 5-FU. Apoptosis was assayed using the terminal deoxynucleotidyl transferase (TdT)-mediated deoxyuridine triphosphate (dUTP)-biotin nick end labeling method in paraffin-embedded tissue sections, and by flow-cytometric analysis. Apoptosis-positive cells increased gradually during treatment. 24 hours after the initiation of 5-FU treatment a maximum, of 15.4% of the Co-4 cells were apoptotic. 48 hours after the initiation of 5-FU treatment, apoptosis was found in 34% of the tumor cells in the SC-1-NU strain. Flow-cytometry demonstrated the increase of S-phase fractions in both strains after the administration of 5-FU, and this coincided with the appearance of apoptotic-positive cells. Although the intrinsic. TS activities of two strains differed, TS activities were markedly suppressed in both strains immediately after the administration of 5-FU. Concentration of 5-FU in RNA (F-RNA) increased gradually in both strains, reaching a maximum 24 hours after the administration of 5-FU. These results suggest that apoptosis and inhibition of DNA synthesis induced by 5-FU are closely associated with its antitumor effect.
Inada
T
T
Department of Surgery, Tochigi Cancer Center, Uitsunomiya, Japan.
Ichikawa
A
A
Kubota
T
T
Ogata
Y
Y
Moossa
A R
AR
Hoffman
R M
RM
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D005434:Flow Cytometry; D005472:Fluorouracil / Q000627:therapeutic use*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D012334:RNA, Neoplasm / Q000096:biosynthesis; D016196:S Phase; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000473:pathology; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors; D013997:Time Factors; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D012334:RNA, Neoplasm; D013940:Thymidylate Synthase; D005472:Fluorouracil