Carcinogenblocking Activities Antimutagenicity

Inhibition of carcinogen uptake into cells, inhibition of carcinogen formation or activation, carcinogen deactiv-ation or detoxification, preventing carcinogen binding to DNA, and enhancing the level or fidelity of DNA repair are all carcinogen-blocking activities and potential chemo-preventive mechanisms (Wattenberg, 1978; Kelloff et al., 1995b). (See the chapter on Antigenotoxins and Cancer.)

Table l Mechanisms for chemoprevention with possible molecular targetsa

Mechanism

Possible molecular targets

Representative agents

Inhibit carcinogen uptake

Bile acids (bind)

Calcium

Inhibit formation/activation of

Cytochromes P450 (inhibit)

PEITC, tea, indole-3-carbinol

carcinogen

PG synthase hydroperoxidase,

NSAIDs, COX-2 inhibitors,

5-lipoxygenase (inhibit)

LOX inhibitors, iNOS inhibitors

Bile acids (inhibit)

Ursodiol

Deactivate/detoxify carcinogen

GSH/GST (enhance)

Oltipraz, NAC

Prevent carcinogen-DNA binding

Cytochromes p450 (inhibit)

Tea

Increase level or fidelity of DNA repair

Poly(ADP-ribosyl)transferase (enhance)

NAC, protease inhibitors

Modulate hormone/growth factor activity

Oestrogen receptor (antagonize)

SERMs, soy isoflavones

Androgen receptor (antagonize)

Bicalutamide, flutamide

Steroid aromatase (inhibit)

Exemestane, vorozole, letrozole

Steroid 5-reductase (inhibit)

Finasteride

IGF-I (inhibit)

SERMs, retinoids

Inhibit oncogene activity

Farnesyl protein transferase (inhibit)

Perillyl alcohol, limonene, DHEA, FTI-276

Inhibit polyamine metabolism

ODC activity (inhibit)

DFMO

ODC induction (inhibit)

Retinoids

Induce terminal differentiation

TGF (induce)

Retinoids, vitamin D, SERMs

PPAR (activate)

GW7845

Restore immune response

COX (inhibit)

NSAIDs

T, NK lymphocytes (enhance)

Selenium, tea

Langerhans cells (enhance)

Vitamin E

Increase intercellular communication

Connexin 43 (enhance)

Carotenoids, retinoids

Restore tumour-suppressor function

p53 (stabilize)

CP-31398

Induce apoptosis

TGF (induce)

Retinoids, SERMs, vitamin D

RAS farnesylation (inhibit)

Perillyl alcohol, limonene, DHEA, FTI-276

Telomerase (inhibit)

Retinoic acid

AA (enhance)

NSAIDs, COX-2 inhibitors, LOX inhibitors

Caspase (activate)

Retinoids

PPAR (activate)

Phenylacetate

PPAR (inhibit)

NSAIDs

Inhibit angiogenesis

FGF receptor (inhibit)

Soy isoflavones, COX-2 inhibitors

Thrombomodulin (inhibit)

Retinoids

Correct DNA methylation Imbalances

CpG island methylation (enhance)

Folic acid

GSH/GST (enhance)

Oltipraz, NAC

Inhibit basement membrane degradation

Type IV collagenase (inhibit)

Protease inhibitors

Inhibit DNA synthesis

Glucose 6-phosphate

DHEA, fluasterone

dehydrogenase (inhibit)

Abbreviations: AA, arachidonic acid; COX, cyciooxygenase; CpG, cytosine-guanosine; DFMO, 2-difiuoromethylornithine; DHEA, dehydroepiandrosterone; GSH, glutathione; GST, glutathione-S-transferase; FGF, fibroblast growth factor; IGF, insulin-like growth factor; iNOS, inducible nitric oxide synthase; LOX, lipoxygenase; NAC, N-acetyl-L-cysteine; NK, natural killer; NSAID, nonsteroidal anti-inflammatory drug; ODC, ornithine decarboxylase; PEITC, phenylethyl-isothiocyanate; PG, prostaglandin; PPAR, peroxisome proliferator-activated receptor; SERM, selective oestrogen receptor modulator; TGF, transforming growth factor. See also Kelloff, G. J. (2000). Advances in Cancer Research, 278, 199-334.

Abbreviations: AA, arachidonic acid; COX, cyciooxygenase; CpG, cytosine-guanosine; DFMO, 2-difiuoromethylornithine; DHEA, dehydroepiandrosterone; GSH, glutathione; GST, glutathione-S-transferase; FGF, fibroblast growth factor; IGF, insulin-like growth factor; iNOS, inducible nitric oxide synthase; LOX, lipoxygenase; NAC, N-acetyl-L-cysteine; NK, natural killer; NSAID, nonsteroidal anti-inflammatory drug; ODC, ornithine decarboxylase; PEITC, phenylethyl-isothiocyanate; PG, prostaglandin; PPAR, peroxisome proliferator-activated receptor; SERM, selective oestrogen receptor modulator; TGF, transforming growth factor. See also Kelloff, G. J. (2000). Advances in Cancer Research, 278, 199-334.

Inhibition of Carcinogen Uptake

Agents which inhibit carcinogen uptake appear to react directly with putative carcinogens, both initiators and promoters. For example, calcium inhibits the promotion of carcinogen- and dietary fat-induced colon tumours in rats. It also inhibits carcinogen-induced hyperproliferation induced in rat and mouse colon, including that induced by a Western 'stress' diet, i.e. a diet low in calcium and vitamin D and high in fat and phosphate. A partial explanation of these effects is that calcium binds to excess bile and free fatty acids that irritate the colon lumen and promote the formation of tumours. Such data suggest a potential for other sequestering and chelating agents as chemopreventives, particularly in the colon.

Inhibition of Carcinogen Formation/Activation

Vitamin C prevents the biosynthesis of carcinogenic ^-nitroso compounds. Other chemopreventive antioxidants such as vitamin E prevent the formation of nitrosamines from their precursors by scavenging nitrite. Many putative chemopreventive agents interfere with metabolic activation of a procarcinogen (Wattenberg, 1978; De Flora and Ramel, 1998; Hartman and Shankel, 1990; Kelloff et al., 1995b). Examples are allylic sulfides, arylalkyl iso-thiocyanates, carbamates and flavonoids and other polyphenols. Usually this activity involves inhibition of the cytochrome P-450 enzymes responsible for activating various classes of carcinogens such as polycyclic aromatic hydrocarbons (PAHs).

Steroid aromatase, a cytochrome P-450-dependent enzyme, catalyses the first step in oestrogen biosynthesis in humans: C19 hydroxylation and subsequent oxida-tive cleavage of the androgens androstenedione and testosterone to oestrone and oestradiol, respectively. Both steroidal (e.g. 4-hydroxyandrostenedione) and non-steroidal (e.g. vorozole) aromatase inhibitors also inhibit carcinogenesis in oestrogen-sensitive tissues.

Enhancement of Carcinogen Deactivation/Detoxification

Enhancement of carcinogen deactivation/detoxification is potentially a very important strategy for chemoprevention (De Flora and Ramel, 1998; Kelloff et al, 1995b). Two metabolic pathways are critical. The first is the introduction or exposure of polar groups (e.g. hydroxyl groups) on procarcinogens/carcinogens via the phase I metabolic enzymes, which are primarily the microsomal mixed-function oxidases. These polar groups become substrates for conjugation. The second pathway is via the phase II metabolic enzymes responsible for conjugation and the formation of glucuronides, glutathione (GSH) conjugates and sulfates. In both cases, the conjugates are more likely to be excreted from the body than they are to reach sensitive tissues in activated form. Agents that affect phase II enzymes probably hold more promise than those which induce phase I enzymes, since phase I oxidation also can result in carcinogen activation. (See the chapter on Mechanisms of Chemical Carcinogenesis.)

GSH is a prototype carcinogen scavenger (see also under the more general mechanism of electrophile scavenging below). It reacts spontaneously or via catalysis of GSH-S-transferases with numerous activated carcinogens including some N-nitroso compounds, aflatoxin B1 (AFB1) and PAHs. GSH protects against mouse skin tumours induced by PAHs, rat forestomach tumours induced by nitrosamines and rat liver tumours induced by AFB1. A number of promising chemopreventive agents are potent inducers of GSH and GSH-S-transferases, including allylic sulfides, which are natural products found in onion, garlic and other members of the Allium genus as well as the sulfur-containing compounds found in cruciferous vegetables. Oltipraz (a dithiolthione similar to those found in cruciferous vegetables) is a potent GSH-S- transferase inducer with a wide spectrum of che-mopreventive activity. Sulforaphane, an isothiocyanate found in broccoli sprouts, induces phase II enzymes and has chemopreventive activity in rat colon (prevents formation of nitrosamine-induced ACF) and mammary gland (PAH-induced carcinoma). N-Acetyl-L-cysteine (NAC) is essentially a precursor of GSH. NAC shows inhibitory activity in mouse lung and bladder and rat colon and mammary gland against nitrosamine-induced tumours.

GSH-peroxidases (GSH-Px) catalyse the reduction of hydrogen peroxide (H2O2) and organic hydroperoxides; the antioxidant effects of selenium may be related to its function in the enzyme's active site. Although several studies show that the anticarcinogenic activity of selenium in mouse and rat mammary glands is not mediated by GSH-Px, in tissues such as colon, glandular stomach and skin, GSH-Px are thought to play a role.

Another type of carcinogen deactivation is modulation of the mixed-function oxidases involved in the metabolism of oestrogens. Indole-3-carbinol, a compound which occurs naturally in cruciferous vegetables, inhibits the induction of mammary tumours in rats and induces mixed-function oxidases. Particularly, it induces the activity of the enzymes responsible for 2-hydroxylation of oestradiol, leading to increased excretion of oestradiol metabolites.

Inhibition of DNA-Carcinogen Adduct Formation

DNA--carcinogen adduct formation can be considered a biomarker of carcinogen exposure. In most cases, it is probably secondary to other mechanisms of carcinogen-esis, such as carcinogen activation and formation. Likewise, inhibition of DNA adduct formation is typically an indirect measure of other mechanisms of chemopreven-tion, particularly inhibition of carcinogen formation and activation and enhancement of carcinogen detoxification (Hartman and Shankel, 1990; Kelloff et al, 1995b). For example, oltipraz prevents the formation of AFB1-DNA adducts, an effect which has been attributed to increased rates of aflatoxin detoxification by GST. Nonetheless, inhibition of DNA adduct formation is a convenient assay for screening potential chemopreventive agents which are expected to modulate carcinogen metabolism. There is also limited evidence of chemopreventive agents directly obstructing adduct formation. For example, ellagic acid appears to inhibit the carcinogen adduct formation by itself binding to the duplex form of DNA. (See also chapter on The Formation of DNA Adducts.)

Enhancement of DNA Repair

There are three possible chemopreventive mechanisms that involve DNA repair (Kelloff et al., 1995b). First is an increase in the overall level of DNA repair. Second, the enzyme poly(ADP-ribosyl)transferase (ADPRT) is known to be involved in modulation of DNA damage, and the level of this enzyme is decreased in the presence of carcinogens. The chemopreventive agent NAC prevents carcinogen-induced decreases in ADPRT. The third mechanism is suppression of error-prone DNA repair. It is known that protease inhibitors depress error-prone repair in bacteria, and it has been suggested that they might prevent carcinogenesis by inhibiting an error-prone repair system activated by proteases that, in turn, are induced by tumour promoters. The protease inhibitor best studied as a chemopreventive is Bowman-Birk soybean trypsin inhibitor (BBI), which inhibits nitrosamine-induced tumours in mouse colon and liver and in rat oesophagus.

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