Organotropic Chemopreventive Effects of n‐3 Unsaturated Fatty Acids in a Rat Multi‐organ Carcinogenesis Model

Abstract

Organotropic chemopreventive effects of n-3 unsaturated fatty acids were studied using a multiorgan carcinogenesis model in male rats. Rats were treated with diethylnitrosamine (DEN), Nmethyl-N-nitrosourea (MNU), N-butyl-N-4-hydroxybutylnitrosamine (BBN), 1,2-dimethylhydrazine (DMH) and dihydroxy-di-n-propylnitrosamine (DHPN) during the first 7 weeks, and then given unsaturated fatty acid (UFAs), docosahexaenoic acid (n-3, C 22:6 ) (DHA), eicosapentaenoic acid (n-3, C 20:5 ) (EPA), linoleic acid (n-6, C 18:2 ) (LA) or oleic acid (n-9, C 18:1 ) (OA) at a dose of 1.0 ml/rat, 3 times a week by gavage for the consecutive 30 weeks. All rats were fed a low LA basal diet throughout the experiment and a calorie-restricted basal diet during the period of UFAs feeding administration. DHA significantly reduced tumor size and numbers in the large intestine as compared to OA treatment. Furthermore, DHA showed a tendency to inhibit carcinogenesis in the small intestine and lung. EPA also showed a tendency to inhibit intestinal carcinogenesis. On the other hand, LA showed a tendency to inhibit lung carcinogenesis, but to promote large intestinal carcinogenesis. However these UFAs did not influence preneoplastic and neoplastic lesion development in the liver, kidney, and urinary bladder. Levels of the administered fatty acids were clearly increased in the serum and organs. In contrast, arachidonic acid (AA) levels in the large and small intestines and liver were markedly decreased by treatment with DHA and EPA. Decreased levels of AA in the large intestine correlated well with tumor incidence, although the number of glutathione S-transferase-positive (GST-P + ) foci showed an inverse correlation with AA levels. The data thus provide evidence that an organotropism exists with regard to the influence of UFAs on carcinogenesis, which correlates with reduction of tissue AA levels in the target organs.

Conjugated Docosahexaenoic Acid Is a Potent Inducer of Cell Cycle Arrest and Apoptosis and Inhibits Growth of Colo 201 Human Colon Cancer Cells

“…In chemically induced carcinogenesis models, compared with oleic acid-treated male rats, DHA treatment significantly decreased incidence and multiplicity of the colon tumors; EPA treatment tended to decrease incidence and multiplicity, but not significantly (19). In culture, DHA more effectively suppressed the growth of HT-29 human colon adenocarcinoma cells than EPA (20).…”

Lack of Chemoprevention or Promotion Effects of Docosahexaenoic Acid on Small Intestine, Colon, Liver, Lung, Thyroid, Esophagus, Kidney, and Forestomach Carcinogenesis in a Rat Medium-Term Multi-Organ Carcinogenesis Model

“…The reason for the discrepancy with the many previous studies which showed chemopreventive effects on colon carcinogenesis and ACF development [1][2][3][4]27,31,32 , may be due to the different number of treatment times per week. DHA was injected five times a 20,21,23,33 incidences of colon tumor development have been reported to range from 10 to 80%, therefore the figure of 10% achieved in the present study was relatively low. Thus, one reason for the lack of obvious influence of DHA could have been due to weak initiation.…”

“…R e c e n t l y , d i f f e r e n t r e s u l t s r e g a r d i n g t h e chemopreventive effect of DHA-E in diet using the same model were published by an other group 33 . They showed an inhibitory effect on carcinogenesis in the small intestine, large intestine and lung by DHA.…”

Nutraceuticals in Human Urinary Bladder Cancer Prevention and Treatment

“…Chyou et al (1993) reported that men consuming fish (rich in omega-3) 5 times per week or more were associated with a non-significant reduction of bladder cancer risk than those who eat 1 time per week or less (the RR, 0.67; 95% CI, 0.26-1.67). In a rat multi-organ carcinogenesis model, Toriyama-Baba et al (2001) reported that n-3 unsaturated fatty acids did not affect preneoplastic and neoplastic lesion development in the urinary bladder.…”