**9.3.11 Dairy products**

Our study confirms that dairy products and yoghourt are protective factors for CRC and CRP, but low-fat dairy products must be available, in order to prevent cardiovascular diseases. Low-fat dairy products supply calcium and vitamin D, both of which has protective effect for CRC. The contradictory data about the protective role of dairy products is associated with the quantity of the contained fat (World Cancer Research Fund and American Institute for Cancer Research, Food, Nutrition and the Prevention of Cancer, 1997).

**In summary**, the intake of fats cause increased influx of bile in the small intestine, whereas part of the fat and bile reaches the large bowel, where bacteria metabolize fat and bile into bile acids and fat acids. These products impair the epithelium of large bowel and stimulate cell proliferation, which is a prerequisite for carcinogenesis of large bowel. The secondary products of bile metabolism and by-products of some foods, which are cooked in certain way, could act like carcinogens, especially in persons with genetic predisposition for development of CRC. The food exerts effect upon intraluminal content and wall of the large bowel, but also part of the digested substances are absorbed and release of the local

bioactive compounds present in traditional Bulgarian cuisine. Therefore, it is reasonable to keep the tradition of healthy Balkan (Bulgarian) diet from the first half of the 20-th century.

Consumption of rye and whole grain bread are protective factors for CRP according to our data. Low incidence of CRC and other cancers is observed in countries with high consumption of complex long-chained carbohydrates, which is found in cereals (Gerber, 2003). This fact is based on the presumption that complex long-chained carbohydrates successfully substitute fats as a source of energy. Recommended dose of cereals is 600-800

Regular consumption of fruit and vegetables is a protective factor for CRC and CRP according to our data. Fruit and vegetables contain vitamins, minerals, biologically active substances and some insoluble fibers. All of them are regarded as protective. The suggested daily dose of fruit and vegetables is 400-800g/day divided in at least 5 meals. The protective role of regular consumption of fruits and vegetables is proven: the replacement of high calorie food with low calorie fruits and vegetables (cabbage and broccoli) decreases overall energy intake and reduce the risk for CRC. Compounds with hypothetical antiproliferative and anticancer action, which inactivate free radicals, are antioxidant vitamins (A, C, E), folic acid, thioethers (garlic, onions, leeks), terpens (citrus fruits), plant phenols (grapes, strawberries), carotenoids (carrots, sweet potatos, water melons), selenium, flavonoids, calcium, etc (Levin et al., 2002). With high consummation of fibres (cereals, fruits, vegetables) the risk for CRC is reduced with 40% (Guidance on Cancer Services. Improving Outcomes in Colorectal Cancers – Manual Update. National Institute for Clinical Excellence 2004). Protective effect of fibers is augmented from the fluid intake, calcium, etc. (Levin et

Our study confirms that dairy products and yoghourt are protective factors for CRC and CRP, but low-fat dairy products must be available, in order to prevent cardiovascular diseases. Low-fat dairy products supply calcium and vitamin D, both of which has protective effect for CRC. The contradictory data about the protective role of dairy products is associated with the quantity of the contained fat (World Cancer Research Fund and American Institute for Cancer Research, Food, Nutrition and the Prevention of Cancer,

**In summary**, the intake of fats cause increased influx of bile in the small intestine, whereas part of the fat and bile reaches the large bowel, where bacteria metabolize fat and bile into bile acids and fat acids. These products impair the epithelium of large bowel and stimulate cell proliferation, which is a prerequisite for carcinogenesis of large bowel. The secondary products of bile metabolism and by-products of some foods, which are cooked in certain way, could act like carcinogens, especially in persons with genetic predisposition for development of CRC. The food exerts effect upon intraluminal content and wall of the large bowel, but also part of the digested substances are absorbed and release of the local

**9.3.9 Cereals** 

gram per day.

al., 2002).

1997).

**9.3.11 Dairy products** 

**9.3.10 Fruit and vegetables** 

hormones and peptides, like insulin and gastrin, is induced. These hormones and peptides could also promote epithelial hyperploliferation. Apoptosis and cell differentiation are suppressed too, and DNA abnormalities could occur (Fig. 1). Adenomatous, hyperplastic or mixed colorectal polyps are morphological sign of the blended influence of genetic and exogenous factors upon the colorectal epithelium. Occurrence and progression of these polyps are evidence for the readiness of the colorectal epithelium to react in this distinct way under the influence of exogenous risk factors and inherited predisposition. Diet fibers by their volume and fluids dilute large bowel content, shorten the bowel transit time and do not permit a long contact of large bowel content with large bowel wall. As a result of bacterial fermentation of the cereal fibers, short-chain fatty acids are produced, which are very important for the metabolism and proper state of large bowel epithelium and contribute to large bowel integrity (Hague et al., 1995). Changed low pH in the large bowel inhibits dehydroxylation and dehydrogenation of bile acids. Changed low pH in the large bowel plays protective role for occurrence of CRC, because dehydroxylation and dehydrogenation of bile acids could result in formation of carcinogenic substances.

Fig. 1. Possible mechanisms of influence of diet and lifestyle upon pathogenesis of colorectal cancer. IFG-1, insulin-like growth factor-1; COX-2, cyclooxygenase-2.

Risk and Protective Factors for Development of Colorectal Polyps and Cancer 195

(soya), dithiolthiones, squalene (olive oil), ferulic and phytic acids (rice). Chemoprevention plays a substantial role in secondary and tertiary prevention of CRC. Also, it could be used for prophylaxis in patients after polypectomy of adenomas with high-grade dysplasia, polyps with invasive carcinomas, patients with familial history for cancer. Patient with IBD and inflammatory pseudopolyposis and require constant chemoprevention with 5-ASA. The most widely used medications include: acetylsalicylic acid, polyvitamins, folic acid, selenium, NSAID. So far, the most consistent data for reduction of polyp recurrence exist for acetylsalicylic acid and folic acid. Still, more large studies, examining the exact medications

Mechanisms of chemoprevention with NSAIDs include: inhibition and deactivation of possible carcinogens, inhibition of cell proliferation, promotion of cell differentiation and apoptosis, correction of genetic damages and inhibition of angiogenesis (Gustafson-Svard et al., 1996). Epidemiological studies have shown that NSAIDs and especially acetylsalicylic acid have chemopreventive properties (Lang, 2003). Regression of polyps to 28% is detected in FAP patients, who are treated in a long period with NSAIDs (Steinbach et al., 2000). The regular intake of acetylsalicylic acid and other NSAIDs reduce the incidence of CRC with 30- 50% according to retrospective and prospective studies (Janne & Mayer, 2000). However, adenomas are observed in some patients, who are treated with acetylsalicylic acid, which means that chemoprevention cannot substitute completely screening colonoscopy (Sandler et al., 2003). The dose of acetylsalicylic acid is still debatable. Some studies show that reduction of the risk for colorectal polyp occurrence is achieved with lower doses of acetylsalicylic acid (Baron et al., 2003). Side effects of long intake of acetylsalicylic acid, like gastrointestinal hemorrhage and brain hemorrhage restrict the usage of acetylsalicylic acid. There is a need for development and usage of new forms of acetylsalicylic acid and NSAIDs agents, which are much safer, like NO-acetylsalicylic acid (Fiorucci & Del Soldato, 2003). Another possibility is the usage of products and substances of natural origin. For example, natural COX-2 inhibitors are yellow pigment curcumin, resveratrol (in grapes) and omega 3-

The presumable protective mechanism of folic acid is not clear, but it is supposed, that the lack of folic acid is associated with hypomethylation of DNA and oncogenic activation. Regular intake of folic acid for at least 15 years reduces the risk of development of CRC (Giovannucci et al., 1998). A study showed reduction of CRC incidence in genetically predisposed persons who use folic acid in high doses. Probably, these persons are vulnerable to methyl group deficiency, as a result of DNA aberrations with low penetration (Fuchs et al., 2002). The risk for CRC is vastly reduced if folic acid is used for a prolonged time, especially from smokers (Scottish Intercollegiate Guidelines Network. Management of Colorectal cancer. A national clinical guideline. 2003). However, there are data from animal studies that folic acid can promote the impact of some carcinogens (Kim, 2003). Moreover, no large studies are available to sustain the chemopreventive role of folic

and possible role, are needed.

**10.1 NSAIDs** 

fatty acids in the fish.

**10.2 Folic acid** 

acid.

Micronutrients and bioactive compounds complete their protective role by several mechanisms – in systemic way promote cell differentiation and apoptosis, and support the large bowel integrity, while intraluminally, micronutrients and bioactive compounds participate actively in detoxification of diet and metabolite carcinogens. Influence of the environmental risk factors, especially diet risk factors, could facilitate the clinic expression of recessive alleles for CRC or alleles with low penetration. Diet risk factors could also modulate the time of expression of recessive alleles for CRC. This statement could explain some of the cases of CRC in patients from a generation, which has been migrated from countries with low incidence of CRC in countries with high incidence of CRC (USA, Australia). Often, systemic genetic variations (polymorphisms) could affect the speed of detoxification or the activation of environmental carcinogens. This is happening in the process of the culinary food treatment, during tobacco smoking or from the alcohol metabolites. At the same time, shortage of anticarcinogens could be available in the regular diet.

We must not forget that from the two known etiological risk factors, the first is acquired – diet and lifestyle, and the second one is inheritable – susceptibility. Large bowel polyposis is a very good example of the interactions between exogenous and endogenous factors that take part in large bowel carcinogenesis with different rate of progression. In patients with FAP the progression from benign adenomas to cancer is rapid (2-4 years) due to inherited genetic changes; in other cases longer exposure to certain exogenous factors is needed to cause genetic changes that lead to cancer (the mean age of CRC patients in оur group was 64 years); however, in certain subjects the time for neoplastic transformation exceeds life duration. Therefore a good differentiation between these groups and early prophylaxis and screening methods are needed. The most frequently used screening methods include: flexible sigmoidoscopy, fecal occult blood test, large bowel capsule endoscopy (if cheaper), double contrast barium enema, virtual colonoscopy, fibrocolonoscopy, endoscopic polypectomy, histological evaluation of all removed polyps, assessment of risk factors, and genetic testing if possible. In conclusion about 15% of the cases with CRC are hereditary, while the remaining 85% are sporadic. However, in 30% of cases a stronger correlation with dietary habits and lifestyle is suspected, while in 55% a close interaction between host susceptibility and environmental factors is more probable. The above fact leads us to the hypothesis that prevention of CRC is a possible task, which can be achieved by correction of certain exogenous factors.
