Chemopreventive effect of S-methylmethane thiosulfonate and sulindac administered together during the promotion/progression stages of colon carcinogenesis.
S-methylmethane thiosulfonate (S-MMTS), isolated from cauliflower and having antiproliferative activity, and the non-steroidal anti-inflammatory drug sulindac have been shown to inhibit chemically induced colon carcinogenesis when they are administered during the initiation and/ or post-initiation stages. The present study was designed to investigate the chemopreventive efficacy of 80 p.p.m. S-MMTS administered during the initiation and post-initiation stages and of S-MMTS and sulindac administered together at low doses (40 and 160 p.p.m., respectively) during the promotion/progression phases (late in the premalignant stage) of colon carcinogenesis. At 5 weeks of age, groups of male F344 rats were fed diets containing 0 (control diet) or 80 p.p.m. S-MMTS. At 7 and 8 weeks of age all rats except those in the vehicle-treated groups were given s.c. injections of 15 mg/kg body wt azoxymethane (AOM). Rats receiving the control diet and intended for the study of inhibition of colon carcinogenesis during the promotion/progression phases were continued on the control diet for 14 weeks after the second AOM treatment; they were then switched to experimental diets containing 80 p.p.m. S-MMTS, 160 p.p.m. sulindac or 40 p.p.m. S-MMTS plus 160 p. p.m. sulindac. The rats were maintained on their respective dietary regimens until 52 weeks after carcinogen treatment and were then killed. Colon tumors were evaluated histopathologically. Administration of 80 p.p.m. S-MMTS alone during the initiation and post-initiation stages and promotion/progression stages had no significant effect on colon tumor inhibition. In contrast, the administration of 160 p.p.m. sulindac during the promotion/progression stages did significantly inhibit total colon tumor multiplicity (P < 0.05). Moreover, co-administration of 40 p.p. m. S-MMTS with 160 p.p.m. sulindac during the promotion/progression stages suppressed the incidence and multiplicity of non-invasive adenocarcinomas (P < 0.05-0.01) and multiplicity of invasive and total adenocarcinomas of the colon to a significant degree (P < 0. 05-0.01). These findings have potential clinical implications.
Reddy
B S
BS
Division of Nutritional Carcinogenesis, American Health Foundation, Valhalla, NY 10595, USA. b_reddy@ix.netcom.com
Kawamori
T
T
Lubet
R
R
Steele
V
V
Kelloff
G
G
Rao
C V
CV
D000230:Adenocarcinoma / Q000139:chemically induced / Q000517:prevention & control; D000236:Adenoma / Q000139:chemically induced / Q000517:prevention & control; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use*; D001397:Azoxymethane; D002273:Carcinogens; D003110:Colonic Neoplasms / Q000139:chemically induced / Q000517:prevention & control*; D004354:Drug Screening Assays, Antitumor; D004359:Drug Therapy, Combination; D008297:Male; D008741:Methyl Methanesulfonate / Q000627:therapeutic use*; D051381:Rats; D011916:Rats, Inbred F344; D013467:Sulindac / Q000627:therapeutic use*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D018906:Antineoplastic Agents, Alkylating; D002273:Carcinogens; D013467:Sulindac; D008741:Methyl Methanesulfonate; D001397:Azoxymethane