Induction of apoptosis in human tumour xenografts after oral administration of uracil and tegafur to nude mice bearing tumours.
Various types of anti-neoplastic agents induce apoptosis in vitro, but less is known of the role of this mode of cell death in tumours treated in vivo. We examined the induction of apoptosis by oral anti-neoplastic agents, tegafur and uracil (UFT, a combined preparation of 1 mol tegafur and 4 mol uracil), and the relationship of effects on tumour growth. Seven different human gastrointestinal tumour xenografts were transplanted into nude mice, including two colon adenocarcinomas (KM20C and Col-1), three gastric carcinomas (SC-6, St-40 and 4-1ST) and two pancreatic carcinomas (PAN-4 and PAN-12), followed by oral administration of UFT (24 mg kg(-1) day(-1)) for 9 days. The percentage of apoptotic cells in each tumour was scored in histological sections, chronologically, using a molecular biological-histochemical system and growth inhibition was examined in each tumour. A significant growth inhibition by UFT was observed for all tumours, except PAN-12. In KM20C and SC-6, growth inhibition rates were 61.7% and 60.6% respectively. Quantitative assay for apoptosis showed a remarkable induction of apoptosis in KM20C (4.2%) and SC-6 (3.5%), which were relatively sensitive to UFT. In addition, KM20C and SC-6 showed a higher incidence of spontaneous apoptosis. In five other tumours, which responded to a lesser extent than KM20C and SC-6, UFT altered little the changes in apoptosis (less than 2%) and spontaneous apoptosis was relatively low. Thus, tumours with a higher apoptosis induced by UFT had a higher response to UFT. Apoptosis observed in tumours might serve as a predictor of a preferable response to UFT.
Oki
E
E
Cancer Centre of Kyushu University Hospital, Fukuoka, Japan.
Sakaguchi
Y
Y
Toh
Y
Y
Oda
S
S
Maehara
Y
Y
Yamamoto
N
N
Sugimachi
K
K
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002277:Carcinoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002455:Cell Division; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000473:pathology; D005770:Gastrointestinal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000473:pathology; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000473:pathology; D005641:Tegafur / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D014498:Uracil / Q000494:pharmacology*
D000964:Antimetabolites, Antineoplastic; D019394:Ki-67 Antigen; D016159:Tumor Suppressor Protein p53; D005641:Tegafur; D014498:Uracil