ENHANCEMENT OF EXPERIMENTAL COLON-CANCER BY GENISTEIN

Several phytochemicals and micronutrients that are present in fruits a nd vegetables are known to exert cancer chemopreventive effects in sev eral organs, including the colon. Among them, the soybean isoflavonoid genistein received much attention due to its potential anticarcinogen ic, antiproliferative effects and its potential role in several signal transduction pathways. The present study was designed to investigate the effect of genistein on azoxymethane (AOM)-induced colon carcinogen esis and to study its modulatory role on the levels of activity of 8-i soprostane, cyclooxygenase (COX), and 15-hydroxyprostaglandin F-2 alph a dehydrogenase (15-PGDH) in the colonic mucosa and colon tumors of ma le F344 rats. At 5 weeks of age, groups of male F344 rats were fed con trol (AIN-76A) diet or a diet containing 250 ppm genistein. Beginning 2 weeks later, all animals except those in the vehicle-treated groups were given weekly s.c. injections of AOM (15 mg/kg body weight) for 2 successive weeks. All rats were continued on their respective dietary regimen for 52 weeks after AOM treatment and were then sacrificed. Col on tumors mere evaluated histopathologically. Colonic mucosae and tumo rs were analyzed for COX, 15-PGDH, and 8-isoprostane levels. Administr ation of genistein significantly increased noninvasive and total adeno carcinoma multiplicity (P < 0.01) in the colon, compared to the contro l diet, but it had no effect on the colon adenocarcinoma incidence nor on the multiplicity of invasive adenocarcinoma (P > 0.05). Also, geni stein significantly inhibited the 15-PGDH activity (>35%) and levels o f 8-iosoprostane (50%) in colonic mucosa and in tumors. In contrast, g enistein had no significant effect on the COX synthetic activity, as m easured by the rate of formation of prostaglandins and thromboxane B-2 from [C-14]arachidonic acid. The results of this investigation emphas ize that the biological effects of genistein mag be organ specific, in hibiting cancer development in some sites get showing no effect or an enhancing effect on the tumorigenesis at other sites, such as the colo n. The inhibition of 8-isoprostane levels by genistein indicates its p ossible antioxidant potential, which is independent of the observed co lon tumor enhancement, Set this agent may also possess several biologi cal effects that overshadow its antioxidant potential. The exact mecha nism(s) of colon tumor enhancement by genistein remain to be elucidate d; it is likely that its colon tumor-enhancing effects map, at least i n part, be related to inhibition of prostaglandin catabolic enzyme act ivities.