Enhancement of anticancer effects of radiation and conventional anticancer agents by a quinolinone derivative, vesnarinone: studies on human gastric cancer tissue xenografts in nude mice.
Vesnarinone (3,4-dihydro-6-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]-2(1H)- quinolinone), a quinolinone derivative, is an orally active inotropic agent used in Japan for the treatment of chronic heart failure. Recently, it has been reported that vesnarinone induces differentiation and apoptosis in certain types of leukaemia and solid tumour cells, and exhibits antitumour effect on several tumours xenografted in nude mice. In the present study, we examined the antitumour effect of vesnarinone in combination with radiation and conventional anticancer agents in nude mice xenografted with human gastric carcinoma, a poorly-differentiated adenocarcinoma, MKN-45 cell line which has a wild-type p53 gene. Vesnarinone treatment combined with radiation resulted in a higher antitumour activity compared with a single treatment with either vesnarinone or radiation alone. Further, vesnarinone treatment together with radiation and conventional anticancer agents including 5-FU and picibanil (an immunopotentiator) produced the highest antitumour effect compared with any other treatment. Additionally, the combination treatment induced marked differentiation and apoptosis of the tumour cells and an increase in the expression of p53 gene in the treated tumour cells. The results suggest that vesnarinone, in combination with radiation and the conventional antitumour agents, may be of clinical interest for treatment of certain types of gastric tumours.
Kawai
K
K
Cellular Technology Institute, Otsuka Pharmaceutical Company, Tokushima, Japan.
Konishi
Y
Y
Izumi
K
K
Sato
M
M
Adachi
M
M
Hozumi
M
M
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D002277:Carcinoma / Q000188:drug therapy* / Q000532:radiotherapy*; D002455:Cell Division / Q000187:drug effects; D003131:Combined Modality Therapy; D004357:Drug Synergism; D005472:Fluorouracil / Q000008:administration & dosage*; D016158:Genes, p53; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010844:Picibanil / Q000008:administration & dosage*; D011719:Pyrazines; D011804:Quinolines / Q000008:administration & dosage*; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000532:radiotherapy*; D014183:Transplantation, Heterologous; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D014965:X-Rays
D000970:Antineoplastic Agents; D011719:Pyrazines; D011804:Quinolines; D016159:Tumor Suppressor Protein p53; D010844:Picibanil; C041667:vesnarinone; D005472:Fluorouracil