Inhibitory Effects of the Natural Products Indole‐3‐carbinol and Sinigrin during Initiation and Promotion Phases of 4‐Nitroquinoline 1‐Oxide‐induced Rat Tongue Carcinogenesis

The modifying effects of indole‐3‐carbinol (I3C) and sinigrin (SIN) on the initiation and post‐initiation phases of tongue carcinogenesis induced by 4‐nitroquinoline 1‐oxide (4‐NQO) were investigated in male ACI/N rats. Rats were divided into eight groups: group 1 was given 4‐NQO (10 ppm) in the drinking watar for 12 weeks, starting at 7 weeks of age; groups 2 and 3 were given 4‐NQO and fed the diets containing I3C (1,000 ppm) and SIN (1,200 ppm) for 14 weeks, respectively, starting at 6 weeks of age; groups 4 and 5 were given 4‐NQO and then they were fed I3C and SIN containing diets for 23 weeks, respectively, starting one week after 4‐NQO exposure; groups 6 and 7 were given I3C and SIN alone, respectively, during the experiment; group 8 served as an untreated control. At the termination of the experiment (week 37), the incidence of tongue neoplasms (squamous cell papilloma and carcinoma) in group 2 (1/15,7%), group 3 (1/15, 7%), group 4 (3/15, 20%) or group 5 (2/15, 13%) was significantly smaller than that in group 1 (12/17,71%) (P= 0.0003, P=0.005 or P=0.002). No tongue carcinomas developed in rats of groups 2, 3, and 5. Similarly, the incidence of preneoplastic lesions (hyperplasia and dysplasia) of the tougue in group 2 (11/15, 73%), group 3 (10/15, 67%), group 4 (11/15, 73%) or group 5 (10/15, 67%) was significantly lower than that in group 1 (17/17, 100%) (P=0.04 or P=0.02). There were no tongue neoplasms in rats of groups 6, 7, and 8. Administration of I3C and SIN also caused significant decreases in the number and area of silver‐stained nucleolar organizer regions protein (AgNORs), a new cell proliferation index, of tongue squamous epithelium. Thus, I3C and SIN inhibited rat tongue carcinogenesis in both the initiation and post‐initiation phases, when administered in these respective phases together with, or following treatment with, 4‐NQO.