**10. Chemoprevention**

Chemoprevention is defined as a usage of a medication or natural substances, which can prevent occurrence of benign or malignant tumor (Hakama, 1998). Chemoprevention is used in every stage of CRC prevention and includes three major groups: medications, nonmedications and biologically active substances. Medications include non-steroidal antiinflammatory drugs (NSAIDs), acetylsalicylic acid, inhibitors of cyclooxigenase-2 (СОХ-2), 5-aminosalicylic acid (5-ASA), folic acid, ursodeoxycholic acid, difluoromethylornithine (DFMO), dithiolethionine (oltipraz), acetilcystein, etc. Non-medications are: selenium, fibers, calcium, vit A, B, C, D, β-carotene, other retinoids, minerals, etc. Biologically active substances include: limonene and perillyl alcohol (in citruses), resveratrol (red grape), diallyl disulfide (garlic), lycopene (tomatoes), flavanols (green tea), isoflavones – genistein (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 and possible role, are needed.

#### **10.1 NSAIDs**

194 Cancer Prevention – From Mechanisms to Translational Benefits

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

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

Chemoprevention is defined as a usage of a medication or natural substances, which can prevent occurrence of benign or malignant tumor (Hakama, 1998). Chemoprevention is used in every stage of CRC prevention and includes three major groups: medications, nonmedications and biologically active substances. Medications include non-steroidal antiinflammatory drugs (NSAIDs), acetylsalicylic acid, inhibitors of cyclooxigenase-2 (СОХ-2), 5-aminosalicylic acid (5-ASA), folic acid, ursodeoxycholic acid, difluoromethylornithine (DFMO), dithiolethionine (oltipraz), acetilcystein, etc. Non-medications are: selenium, fibers, calcium, vit A, B, C, D, β-carotene, other retinoids, minerals, etc. Biologically active substances include: limonene and perillyl alcohol (in citruses), resveratrol (red grape), diallyl disulfide (garlic), lycopene (tomatoes), flavanols (green tea), isoflavones – genistein

diet.

certain exogenous factors.

**10. Chemoprevention** 

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 fatty acids in the fish.

#### **10.2 Folic acid**

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 acid.

Risk and Protective Factors for Development of Colorectal Polyps and Cancer 197

modification of the established risk factors for colorectal polyps. These are: limitation of certain foods, beverages and habits; improved physical activity; consumption of protective foods; eradication of *H. pylori*. Important question is whether it is possible to apply primary prophylaxis in CRC and its precursor – adenomatous colorectal polyposis and if risk factors for CRC and CRP are avoidable and at what extent? Considering the growing epidemic of CRC this issue is waiting its prompt answer. What kind of healthy style of life we can offer to threatened people, similarly to the primary prevention in other diseases like cardiovascular disease, ischaemic heart disease and arterial hypertension, and distinct type of cancers? A great part of risk factors for CRC and CRP are associated with the diet, the lifestyle, exogenous carcinogens, some diseases and disease-like conditions. However, some protective factors for CRC and CRP are famous and could be recommended. As a primary prevention in healthy persons change of diet habits, reduction of body weight, refusal of tobacco smoking and alcohol intake are recommended. Preventive role of calcium, magnesium, β-carotene, vitamins, folic acid and selenium for CRC and CRP is still disputable. Acetylsalicylic acid and other NSAIDs for this purpose are not commonly used, because of their adverse side effects (Sandler, 2004). However, if new and convincing data are available, we can try to restrict influences of known risk factors and to cure precancerous conditions and will be able to perform proper primary prevention for CRC and colorectal

**12. Secondary prophylaxis of colorectal adenomatous polyps and CRC** 

Secondary CRC prevention is used for early detection of premalignant adenomas and cancer in its curative stage. It includes: screening colonoscopy; polypectomy; optimal treatment of IBD patients; chemoprevention and follow-up (Hawk, 2004; Rex, 2000). The aim of secondary prophylaxis or screening is to diminish the mortality of CRC by early detection and treatment of premalignant adenomas and cancer in its curable stage. European and national gastrointestinal and digestive endoscopy societies recommend screening to comprehend all healthy and risk groups of people. CRC screening consists of: digital rectal examination, fecal occult blood test, fecal immunochemical test for haemoglobin/haptoglobin, barium enema, sigmoidoscopy, sigmoidoscopy with fecal occult blood test, colonoscopy (with polypectomy), chromoendoscopy, NBI and high-resolution colonoscopy, virtual colonoscopy - CT or MRI, fecal DNA test (Geissler & Graeven, 2005). A useful test is invented for early detection and follow-up of CRC, similar to the noninvasive serological and fecal tests used for detection of infection with *H. Pylori*. This test is based on the idea, that proliferating cells, especially malignant cells, are expressing special isoenzyme of pyruvate kinase (PK), which plays a significant role in glycolysis. This isoenzyme consists of 4 subunits in healthy cells, while in neoplastic cells there are 2 subunits. This dimeric form M2-PK is found in gastrointestinal neoplasms. Tumor marker M2-PK is found in the blood of 47.8% of patients with CRC, while fecal test is sensible in 80% of cases with CRC

We propose stratification of healthy population in *three* groups: patients with *moderate risk* for development of colorectal polyps and cancer; patients with *elevated risk* for development of colorectal polyps and cancer; patients with *extremely high risk* for development of

adenomatous polyposis.

(Hardt et al., 2004).

colorectal polyps and cancer;
