The modifying effect of dietary exposure of a newly synthesized retinoidal
butenolide,
5-hydroxy-4-(2-phenyl-(E)-ethenyl)-2(5H)-furanone (KYN-54) during the initiation and post-initiation phases of oral
carcinogenesis initiated with
4-nitroquinoline-1-oxide (4-NQO) was investigated in male F344 rats. At 6 weeks of age, rats were divided into experimental and control groups. At 7 weeks of age, all animals except those treated with
KYN-54 alone and those in a control group were given 4-NQO (20 p.p.m.) in the
drinking water for 8 weeks to induce
oral neoplasms. Seven days after stopping 4-NQO exposure, groups of animals fed the diets containing 100 and 200 p.p.m.
KYN-54 for 10 weeks starting 1 week before 4-NQO exposure were switched to the basal diet and kept on this diet until the end of the experiment. Starting 1 week after the cessation of 4-NQO administration, the groups given 4-NQO and the basal diet were switched to the diets containing 100 or 200 p.p.m.
KYN-54 and maintained on these diets for 22 weeks. The other group consisted of rats given 200 p.p.m.
KYN-54 alone or untreated rats. All animals were necropsied at the termination of the study (week 32). The incidences of
tongue neoplasms and preneoplastic lesions,
polyamine levels in the tongue tissue, and cell proliferation activity estimated by
bromodeoxyuridine (
BrdU)-labeling index and by morphometric analysis of
silver-stained nucleolar organizer regions
protein (
AgNORs) were compared among the groups. Feeding of
KYN-54 during either initiation or post-initiation phase caused a significant reduction in the frequency of tongue
carcinoma (48-71% reduction, P < 0.05) and such chemopreventive efficacy was dose-related. The incidences of preneoplastic lesion in rats fed the diets mixed with
KYN-54 at both doses were also decreased (P < 0.05). Dietary administration of
KYN-54 also significantly decreased the labeling index of BrdUrd and the number of
AgNORs per cell nucleus of the tongue squamous epithelium (P < 0.05). In addition,
polyamine levels in the oral mucosa were lowered in rats given 4-NQO and test compound when compared to those given 4-NQO alone, but no significant difference was obtained. These results indicate that the novel synthesized retinoidal
butenolide KYN-54 inhibits oral
carcinogenesis initiated with 4-NQO and such inhibition may be related to suppression of cell proliferation.