**6.3.3 Whole foods**

Water extracts of Salvia species increased rejoining of strand breaks after treatment with H2O2 in Caco-2 cells. These water extracts also increased incision activity of a Caco-2 cell extract on a DNA substrate containing specific oxidative damage (8-oxoGua) (Ramos *et al.*, 2010a). Nakamura et al., (2000) reported that aqueous fractions of Fushimi sweet pepper increase repair against ultraviolet-induced cyclobutane pyrimidine dimers in human fibroblasts.

Collins et al., (2003), in a human intervention study, showed that 3 weeks of a dietary supplementation with kiwifruit increased DNA repair capacity measured by "in vitro repair assay". Also Freese, (2006) showed that kiwifruit consumption increased DNA repair capacity in human lymphocytes. Brevik *et al.*, (2011) in a human biomonitoring study, reported that consumption of kiwifruits and antioxidant-rich plant products reduced DNA strand breaks in lymphocytes. Increase of BER activity was observed in the group that consumed antioxidant-rich plant products. However, a reduction of NER activity was observed in both groups. No explanations have been found for this decrease in NER pathway. Diet supplementation with cooked carrots, during 3 weeks, increased in vitro repair activity and strand break rejoining in lymphocytes (Astley *et al.*, 2004).

High dietary folate intake has been associated with a decreased risk of cancer development, such as colorectal cancer. In vitro, rodent and human studies demonstrated that low folate intake increases uracil misincorporation leading to increase of DNA damage, chromosomal breakage and malignant transformation; modulates DNA repair by inhibiting thymidine

DNA Damage Protection and Induction of Repair

alkylating drugs more studies are need.

concentrations can be toxic at higher concentrations.

**8. Conclusion** 

by Dietary Phytochemicals and Cancer Prevention: What Do We Know? 257

breaks may activate apoptotic pathways, leading to cell death. In some cells, resistance to alkylating agents can be mediated by MGMT and MMR. Active MGMT and loss of MMR pathway protect cells against the cell death induced by methylating chemotherapeutic drugs (Allan and Travis, 2005). Depletion of MGMT activity (for example, by O6-BG or by epigenetic silencing of the MGMT gene) and intact MMR system results in reversion of resistance with high sensitivity to the cytotoxic effects of alkylating drugs (Casorelli et al., 2008; Esteller et al., 2000; Hegi et al., 2005). Tumors with low MGMT level are more sensitive to alkylating chemotherapy (Bandres et al., 2005). Therefore,DNA repair mechanisms may be understood as a promising target to develop new cancer treatments (Helleday *et al.*, 2008; Jiricny, 2006). Different strategies have been developed to enhance the efficacy of chemotherapy using alkylating agents. In tumor cells, inhibition of MGMT activity and/or BER pathway decreases resistance to alkylating drugs (Drablos et al., 2004; Jaiswal et al., 2011; Middleton and Margison, 2003). Downregulation of DNA repair pathways (except MMR) may increase efficacy of alkylating agents, decreasing the amount of drug needed for

chemotherapy and consequently reduction of the side effects (Kondo et al., 2010).

Dietary agents that modulate MGMT expression and/or BER pathway may play an important role in chemotherapy when in combination with alkylating agents. However this subject, in contrast to chemoprevention, has received little attention. Some studies have been that dietary agents may increase MGMT activity. Niture *et al.*, (2006), investigated the potential ability of some Indian medicinal plants extracts to modulate MGMT activity and expression in human peripheral blood lymphocytes and cancer cell lines. The results showed that both the ethanolic and aqueous extracts from neem (*Azadirachta indica*), holy basil (*Ocimum sanctum*), winter cherry (*Withania somnifera*), and oregano (*Origanum majorana*) increased MGMT expression and its activity. Extracts from gooseberry (*Emblica officinalis*), common basil (*Ocimum basilicum*), and spearmint (*Mentha viridis*) also increased MGMT levels, however to a smaller extent. Later, the same author reported that some phytochemicals such as curcumin, silymarin and resveratrol increase protein expression as well as activity of MGMT in lymphocytes and cancer cell lines (Niture *et al.*, 2007). In tumor cells a number of genes are abnormally methylated. Some dietary agents, such as genistein and epigallocatechin-3-gallate showed the ability to reactivate some methylation-silenced genes in cancer cells like MGMT due to a direct inhibition of DNA methyltransferase (Fang et al., 2005; Fang et al., 2003). Recently, Billson et al., (2009), demonstrated that a high vegetable intake in humans decreases MGMT activity in normal colorectal mucosa. To understand the real role of dietary agents on chemotherapy when in combination with

Prevention of DNA damage and/or enhanced DNA repair activity by dietary agents constitute an important strategy to prevent mutations and consequently inhibit the carcinogenic process. Diet supplementation with phytochemicals, with beneficial effects, increases their concentrations in the organism. However, effects of supra-physiological concentrations need to be evaluated in each case since a safe phytochemical at physiological

The comet assay is a powerful tool to assess the effects of diet on DNA. The immense literature (more than 5500 papers in Pubmed since 1995) that use comet assay (standard and modified versions) demonstrates the real potential of this assay. Some dietary agents have

and purine biosynthesis and induces epigenetic changes leading to global DNA hypomethylation and/or changes in gene-specific methylation and protooncogene activation (Duthie and McMillan, 1997; Duthie, 2010; Duthie *et al.*, 2000; Melnyk et al., 1999). In vivo, folate deficiency induced DNA repair, such as increase of OGG1 and MGMT (Duthie *et al.*, 2010). However, remains unclear if increasing folate intake improve DNA repair. Generaly, the protective role of folate against carcinogenesis is not completely understood.
