Chemopreventive activity model

In addition to their possible prooxidant activity (see above) polyphenols and flavonoids may influence cancer cells via their antioxidant properties. Recently, Jang et al. [219] studied cancer chemopreventive activity of resveratrol, a natural polyphenolic compound derived from grapes (Chapter 29). These authors showed that resveratrol inhibited the development of preneoplastic lesions in carcinogen-treated mouse mammary glands in culture and inhibited tumorigenesis in a mouse skin cancer model. Flavonoids silymarin and silibinin also exhibited antitumor-promoting effects at the stage I tumor promotion in mouse skin [220] and manifested antiproliferative effects in rat prostate cancer cells [221]. 

Several studies have shown the ability of DNMT inhibitors to prevent cancer using different pathways [101-104]. Genistein demonstrated cancer chemopreventive activities in animal models [105]. It has been studied in different cancer cell lines and inhibition of cancer cell growth has been shown [106]. But several mechanisms, such as antihormonal effects, are discussed to explain this activity and the exact contribution of DNMT inhibition to in-vivo activity in cancer chemoprevention remains to be determined. 

Selective COX-2 inhibitors have also been shown to prevent early and late forms of colorectal neoplasia in rat models. Reddy et al. showed that administration of celecoxib inhibited aberrant colonic crypt foci (ACF) induction and multiplicity by about 40-49% in an azoxymethane-induced ACF rat model (81). Later the same investigators also showed that dietary administration of celecoxib can inhibit both the incidence and multiplicity of colon tumors by about 93 % and 97 %, respectively in the same rat model (82). Other researchers reported similar results with the Min mouse model (52). There is little data on human clinical trials with selective COX-2 inhibitors for colorectal tumor prevention. Recently Steinbach et al. conducted a double-blind, placebo-controlled study with 77 patients with FAP, and reported that treatment with celecoxib, a selective COX-2 inhibitor, for 6 mo led to a significant reduction (28%) in the number of colorectal polyps in these patients (50). Collectively, COX-2 nonspecific or specific NSAIDs appear to have chemopreventive activity against colorectal cancer development. Selective... 

Synthetic 13-m-retinoic acid not only inhibited the incidence but also reduced the severity of bladder neoplasms induced by the intravesical administration of MNU of female Wister-Lewis rats [113]. In an experimental model with mice treated with TV-butyl-A -(4-hydroxybutyl)-nitrosamine (OH-BBN), retinoic acid (Re5), 13-cw-retinoic acid, and retinol acetate (Re2) show chemopreventive activity. In addition, a quite large number of synthetic -alkyl amide derivatives of Re2 have a greater activity to toxicity ratio than 13-cw-retinoic acid [113]. 

Arachidonic acid metabolites have received tremendous attention for their role in carcinogenesis. A link among the enzymes, metabolites, and receptors involved in the Cox and Lox pathways has been established to inflammation and a variety of cancers. Aberrant arachidonic acid metabolism has been shown to play a major role in the development and progression of several cancers. Both the Cox and Lox pathways have been linked to cell proliferation, inhibition of apoptosis, and promotion of angiogenesis. In addition, several clinical, in vitro, and in vivo studies have been conducted to demonstrate the chemopreventive activity of several Cox-2 and 5-Lox inhibitors on several models of cancer. - ... 

Recently garcinol (46), also called camboginol, has attracted considerable interest because of its associated beneficial health properties, including antiulcer activity [59], anti-glycation activity [60], cancer chemopreventive activity against colonic aberrant crypt foci (ACF) in an animal model [63], induction of apoptosis through cytochrome c release and activation of caspases in human leukemia cells [61]. It also showed strong antioxidant activity [59,60]. 

Cancer chemopreventive activity of garcinol have been also demonstrated in animal model dietary administration of garcinol significantly inhibited azoxymethane(AOM)-induced aberrant crypt foci (ACF) formation in male F344 rats without causing any adverse effects [63], ACF are precursor lesions for colon carcinoma. 

Following this experimental design, approximately 700 plant materials have been evaluated and this has resulted in over 6,500 bioassay results. A number of active principles have been obtained that are active with the in vitro test systems, and several of the isolates have retained activity by preventing formation of preneoplastic lesions in mammary organ culture. Thus far, three lead compounds have been shown to mediate considerable cancer chemopreventive activity in full-term tumorigenesis models (28,34,45,46) and are being studied in more advanced test systems. We remain hopeful that one or more discoveries resulting from this project will be deemed worthy of human intervention trials. 

Scolastici, C., Ong, T.P., and Moreno, F.S., Squalene does not exhibit a chemopreventive activity and increases plasma cholesterol in a Wistar rat hepatocarcinogenesis model, Nutr. Cancer, 50,101-109, 2004. 

The monocyclic monoterpene (+)- and (-)-limonene enantiomers have been shown to be present in orange peel Citrus aurantium L. sp. aurantium) and other plants and are extensively used as fragrances in household products and components of artificial essential oils. The (+)-limonene isomeric form is more abundantly present in plants than the racemic mixture and the (-)-limonene isomeric form (Wichtel, 2002). It has previously been shown that (+) limonene has chemopreventive activities in experimental animal models including rats and mice (Crowell et al., 1992). Because of the greater importance of (-i-)-limonene in the food and fragrance industry, only its metabolism and not that of (-)-limonene is described below. Several research groups have successfully described the biotransformation of ( f)-limonene in vitro (rat and human liver microsomes) and in vivo (rat, mice, guinea... 

The evidence supporting the chemopreventive activity of retinoids in mammary tumor models in rats is substantial. However, only three studies describing the use of retinoids in mammary tumorigenesis in mice have been reported. In the initial study, Maiorana and Gullino (1980) found that retinyl acetate did not influence (neither inhibited nor enhanced) tumor incidence, latency, or tumor number in C3H-A y female mice positive for the mammary tumor virus (MTV). Moon et al. (1983a) using C3H mice negative for the MTV found that the... 

It has been shown that tannic acid (TA) exerts cancer chemopreventive activity in various animal models (61). TA induced either growth arrest or apoptotic death (62). TA induced apoptosis more in human oral squamous cell carcinoma and salivary gland tumor cell lines than in normal human gingival fibroblasts, whereas gallic acid, a component unit of TA, showed much weaker selective cytotoxicity (63). Recently, it was shown that inhibition of the proteosome of living Jurkat cells results in accumulation of two natural proteosome substrates, the cyclin-dependent kinase inhibitor p27 and the proapoptotic protein Bax, followed growth arrest in G1 and induction of apoptotic cell death (d ). 

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