ENHANCEMENT OF EXPERIMENTAL COLON CARCINOGENESIS BY DIETARY 6-PHENYLHEXYL ISOTHIOCYANATE

Naturally occurring and related synthetic isothiocyanates are known to exert chemopreventive effects in several organs in rodent models. The present study was designed to investigate the efficacy of 6-phenylhex yl isothiocyanate (PHITC), a potent chemopreventive agent in the lung tumor model in strain A mice, on azoxymethane-induced colon tumorigene sis, Another aim was to study the modulating effect of PHITC on coloni c mucosal and tumor phospholipase A(2) (PLA(2)), phosphatidylinositol- specific phospholipase C (PI-PLC), lipoxygenase (LOX), and cyclooxygen ase (COX) activities. At 5 weeks of age, groups of male F344 rats were fed control diet or diets containing 320 or 640 ppm of PHITC represen ting 40 and 80% maximum tolerated dose levels, respectively. At 7 week s of age, all animals except those in the vehicle-treated groups were given two weekly s.c. injections of azoxymethane at a dose rate of 15 mg/kg body weight/week. All animals continued on their respective diet ary regimen for 52 weeks after the carcinogen treatment; then the stud y was terminated. Colonic mucosa and tumors were analyzed for PLA(2), PI-PLC, prostaglandin (PG) E(2), COX, and LOX activities. Intestinal t umors were evaluated histopathologically and classified as invasive or noninvasive adenocarcinomas. Intestinal tumor incidence (percentage o f animals with tumors) and tumor multiplicity (tumors/animal; tumors/t umor-bearing animal) were compared among the dietary groups. At the 64 0-ppm dose level, dietary PHITC significantly increased the incidence of intestinal (small intestine plus colon) adenocarcinomas (P < 0.05) as well as the multiplicities of invasive and noninvasive adenocarcino mas of the colon (P < 0.05 to 0.01). At the 320-ppm dose level, PHITC increased the multiplicity (tumors/animal) of noninvasive adenocarcino mas and total (invasive plus noninvasive) adenocarcinomas of the colon (P < 0.05). Dietary PHITC also increased the colon tumor volume (2- t o 4.3-fold) in a dose-dependent manner. Moreover, PHITC significantly enhanced the activities of PLA(2) (50-100%) and levels of PGE(2) (2-fo ld) in the colonic mucosa and in tumors, but it had no significant eff ect (P > 0.05) on PI-PLC activity. The formation of COX metabolites, p articularly PGE(2), PGF(2 alpha), PGD(2), 6-keto PGF(1 alpha), and thr omboxane B-2, as well as LOX metabolites such as 8(S)-, 12(S)- and 15 (S)-hydroxyeicosatetraenoic acids, were significantly increased in the colonic mucosa and tumors of animals that were fed 640 ppm of PHITC. Although the exact mechanism by which PHITC promotes colon tumorigenes is remains to be elucidated, it is likely that the tumor-promoting eff ects of PHITC may, at least in part, be related to increased eicosanoi d metabolism in the colon.