Antioxidants in the treatment & prevention of oral cancer

Dr.Beenadas

TAKEN FROM KERALA DENTAL JOURNAL VOL-31   NO.4    OCTOBER 2008.

KDJ :- Quaterly publication of Indian Dental Associassion, Kerala State Branch.

Contents

• PRESIDENT”S MESSAGE
• EDITORIAL
• BUSINES MANAGER SPEAKS
• SCIENTIFIC ARTICLES
• PRACTITIONER’S COLUMN
• ASSOCIATED NEWS
• BOOK REVIEW
• EVENT/NEWS
• QUIZ

ABSTRACT : The objective of this review is to emphasize the important of the chemo preventive role of antioxidant nutrients like Beta-carotene, Vitamin C, Vitamin E (tocopherol succinate) etc. against oral cancer. 

INTRODUCTION : Oral cavity cancer is one of the ten most frequent cancer in the world; some of the highest rates are in developing countries, where up to 25% of all malignancies are found in the oral cavity. Cancer is the product of interaction of genetic factors and environment exposures like ionizing radiation, smoking, specific infectious agents and dietary factors which develops over a long time and progresses through many stages. Tobacco is the predominant case of this disease. Alcohol use is a risk factor that acts synergistically with tobacco. Thus, the major risk factor for oral cancer is the same as that of some other common diseases. (Eg: emphysema, lung cancer and heart disease). Consequently, prevention strategies for oral cancer, such as discontinuing tobacco use, can affect many life threatening diseases; other prevention modalities, such as nutritional agents, may similarly be beneficial for several chronic diseases.  

CARCINOGENESIS AND THE EFFECT OF ANTIOXIDANTS
Carcinogenesis involves several sequential stages: Initiation, promotion and progression. Clinical efforts in cancer therapeutics have been mainly concentrated on the final stage of this disease (i.e, invasive cancer). Such an approach has limited effect especially when the goal is prevention.

Abuse of a alcohol and tobacco has serious nutritional implication for the host and generates increased production of reactive free radicals as well as eliciting immunosuppresion. Smoking also results in lower B-carotene concentrations in plasma and oral mucosal cells. A chemo preventive role exists for the so called antioxidant nutrients (Beta-carotene, Vitamin E) against oral cavity cancer. In several epidemiologic studies; low intake of Vit.E, carotinoids or both, like in starvation or malnutrition have been associated with a higher cancer risk. Cancer chemoprevention is a new promising strategy for prevention, inhibition or reversal of carcinogenesis.

Active oxygen species and other reactive free radicals mediate phenotype and genotype alterations that lead from mutation to neoplasisa. Antioxidants or free radical scavengers, both nature and synthetic, neutralize metabolic products, interfere with activation of procarcinogens, prevent binding of carcinogens to DNA, inhibit chromosome aberrations, restrain replication of the transformers cells, suppress action of precancerous oral lesions such as leukoplakia and erythroplakia. The main types of free radicals include the hydroxyl radial (OH), the nitric oxide radical (NO) and the lipid peroxyl radical (LOO). 

EPIDEMIOLOGIC EVIDENCE
Epidermological studies conducted world wide, point to the fact that a low intake of fruits and vegetables of high carotenoid content is directly proportional with  increased risk of cancer  especially head and neck cancer. Few studies are quoted underneath.

• Assessment of oxidative DNA damage  in 24 vegetarians, compared to 24 non-vegetarians showed that DNA strand breaks oxidized purine were significantly lower in vegetarians. Sufficient antioxidative status is crucial in free radical defense. Intake of protective food commodities were  significantly higher in vegetarians; thus less risk to oral cancer.
• In a case control study done  in Italy on 105 cases; besides significant and strong correlation of oral cancer with tobacco and  its products, alcohol etc.  It was also found out that consumption of 6 food items – milk, meat, cheese, carrot, green vegetables and fruits – were inversely correlated with the development of oral cancer.
• Stitch et al and more recently Peng et al found that cigarette smokers who are always at risk for oral malignancy, have lower plasma concentrations of  carotinoids and  beta-carotene than do non- smokers.
• Another case control study on 227 women North Carolina, USA with oral cavity or pharyngeal cancer  and 405 matched controls  showed the protectve effect of diet rich in fruits and vegetables.

 

LABORATORY EVIDENCE.

Few laboratory evidence are stated below :-

1. Stitch et  al has demonstrated the capacity of carotinoids to block genotoxic damage in Chinese Hamster ovary cells caused by oral carcinogens such as extracts of areca nut.

2. In another study, oral squamous carcinoma was developed in the buccal pouch of Syrian GoldHamsters, by painting 0.5 %  7, 12- dimethylbenz anthracene, thrice a weak for 14 weeks. Results showed that a antioxidant (antilipidperoxidative),  extract of Tephrosia Purpurea had the chemopreventive  potential in such

Hamsters.

3. In malnutrition there is marked depletion of the key antioxidant  nutrients as well as reduced glutathions in the human  and in  experimented animals. GSH status has been shown protective against  chemically produced oral cancers and leukoplakia in adult Hamsters.

4.  Studies showed a pronounced reduction in cancer risk with the use of  13 cisretinoic acid, the provitamin A antioxidant. Antioxident   supplements (30mg beta carotene, 1000mg ascorbic acid and 800 IU  of  alpha tocopherol) were given to 79 patients with oral leukoplakia   with  improvement noted in 55.7%  of patients. The supplement was  intended to increase  tissue levels of beta carotene, ascorbic acid and  alpha tocopherol.

ROLE OF ANTIOXIDANTS.

The role of antioxidants in cancer  chemoprevention can be summarized as :

1. inhibits oral cavity carcinogenesis
2. reduces the risk of developing oral cancer.
3. causes reversal of premalignent lesion like oral leukoplakia.

Oxidative damage is recognized as playing a role in the pathogenesis of cancer  which could arise from incorrect nutritional habits and lifestyle practices. This process can cause DNA damage, which is a basic mechanism in cancer induction. Sufficient antioxidative status is crucial in free radical defense.  To reduce the risk of oral and pharyngeal cancer, especially oral cell carcinoma, diet must be optimized, primarily to reduce calorie intake, monosaturated fat and red or processed  meat. Optimal levels of daily allowance of micronutrients like vitamin C, E, antioxidants, alpha-carotene and folate are effective in prevention of oral cancer. Antioxidants can be mainly alpha-carotene, tea, fresh fruits and vegetables. The strongest protection was apparently attributed to the frequent consumption of fruits (antioxidants and fibre ), which appears to be a particulatly important proactive factor against oral cancer.

Consumption of fried or broiled foods and employment of microwave cooking ( formation of heterocyclic amines ) must be avoided because of increasing risk of oral cancer including salivary gland tumours. Antioxident can inhibit or decrease the production of compounds, which can induce cancer caused by frying or broiling proteins and food that generate heterocyclic amines.

Abuse of alcohol and tobacco (both smoking and smokeless) has serious nutritional implications for the host and generates increased production of reactive free radicals as well as  eliciting immunosuppression. Antioxidant can also inhibit reactions of the tobacco specific nitrosamine, which undergo specific activation and detoxification process and may be important carcinogens.

Antioxidants such as quercetin  in garlic and onion, genistein on soy, sulforaphone in broccoli can control activation reactions that promote carcinogenesis. The beverage tea can also act as an antioxidant and inhibit  the  carcinogenic effect  of cigarette and tobacco.

The important dietary micronutrients that  are antioxidant in action include vitamin A, vitamin E (alpha- tocopherol), precursors of Vit. A (beta- carotene), Vitamin C,  lycopene,  folate and Zinc.

Recommended dailyrequirments:-

Vitamin C (males) – 90mg/day to 2000mg/day.

Females – 75mg/day to 2000mg/ day.

Vitamin E  – 15mg/day to 1000mg/day.

Dietary  essential mineral elements are constituents of several important anti-oxidant enzymes. These include selenium, copper, zinc, manganese and iron. Ascorbic acid spares GSH  and also regenerates the active reduced form of vitamen E from the Vitamin E radical. It protects alpha- 1- protease inhibitor from inactivation by the free radicals generated during oxidative burst in neutrophils. Vitamin E is a very important antioxidant in the lipid domain and together with vitamin C it is an excellent nitrite trapping agent.

Carotenes are excellent antioxidants and radical trapping agents, particularly for peroxyl and hydroxyl radicals. Vitamin A has antioxidant activity on singlet oxygen.

REVERSAL OF  LEUKOPLAKIA
The reversal or regression of premalignent regions such as leukoplakia is an important stategery  for cancer prevention. Any agents selected for trials in premalignent lesion  the ultimate goal of which is application for cancer prevention, should have minimal or preferably no toxicity because many subjects whose lesions are unlikely to progress to cancer will be exposed to be the intervention. If the objects is to develop agents for use by general population to reduce the incidence of oral cancer, then agents preferred are antioxidants such as beta- carotene and vitamin E. Intervention trails on betel, quid-tobacco chewers show that administration of Vitamin A cause complete remission of leukoplakia. The most commonly used synthetic retinol, 13 cis- retinoic acid, is toxic even when given at very low dose. There is therefore increasing emphasis on the use of relatively non-toxic antioxidants such as beta-carotene and Vit.E.

Conclusion.
Numerous lines of evidence suggest a potential role of beta- carotene and other antioxidants in preventing oral cavity malignancy. The evidence in favour of these agents is derived from a wide range of specialities, including epidermology, laboratory studies and clinical trails. We can reduce the risk of oral cancer through changing diet by

1. avoiding formation of carcinogens
2. reducing their metabolic activation
3.  increasing their detoxification

Diets high in antioxidants can perform the above said actions. Consuption of alcohol and diets rich in monosaturated fat, fried or broiled foods, microwave cooking all these increases the risk of oral cancer. Micronutrients also have important role in prevention of oral cancer.

Various positive results exists concerning the chemopreventive role of antioxidants. So, such dietary improvements not only reduce the risk of oral cancer but also contribute to a healthy life to be advanced age.

Antioxidant
An antioxidant is a molecule capable of slowing or preventing the oxidation of other molecules. Oxidation is a chemical reaction that transferselectrons from a substance to an oxidizing agent. Oxidation reactions can produce free radicals, which start chain reactions that damage cells. Antioxidants terminate these chain reactions by removing free radical intermediates, and inhibit other oxidation reactions by being oxidized themselves. As a result, antioxidants are often reducing agents such as thiols or polyphenols.

Antioxidant activity could be measured simply by placing the fat in a closed container with oxygen and measuring the rate of oxygen consumption. However, it was the identification of vitamins A, C, and E as antioxidants that revolutionized the field and led to the realization of the importance of antioxidants in the biochemistry of living organisms.

Although oxidation reactions are crucial for life, they can also be damaging; hence, plants and animals maintain complex systems of multiple types of antioxidants, such as glutathione, vitamin C, and vitamin E as well as enzymes such as catalase, superoxide dismutase and variousperoxidases. Low levels of antioxidants, or inhibition of the antioxidant enzymes, causes oxidative stress and may damage or kill cells.

As oxidative stress might be an important part of many human diseases, the use of antioxidants in pharmacology is intensively studied, particularly as treatments for stroke and neurodegenerative diseases. However, it is unknown whether oxidative stress is the cause or the consequence of disease. Antioxidants are also widely used as ingredients in dietary supplements in the hope of maintaining health and preventing diseases such as cancer and coronary heart disease.

Research into how vitamin E prevents the process of lipid peroxidation led to the identification of antioxidants as reducing agents that prevent oxidative reactions, often by scavenging reactive oxygen species before they can damage cells.

Oxygen is a highly reactive molecule that damages living organisms by producing reactive oxygen species.  Consequently, organisms contain a complex network of antioxidant metabolites and enzymes that work together to prevent oxidative damage to cellular components such as DNA,proteins and lipids.

The reactive oxygen species produced in cells include hydrogen peroxide (H₂O₂), hypochlorous acid (HOCl), and free radicals such as thehydroxyl radical (OH) and the superoxide anion (O₂⁻).  The hydroxyl radical is particularly unstable and will react rapidly and non-specifically with most biological molecules. These oxidants can damage cells by starting chemical chain reactions such as lipid peroxidation, or by oxidizing DNA or proteins. Damage to DNA can cause mutations and possibly cancer, if not reversed by DNA repair mechanisms, while damage to proteins causes enzyme inhibition, denaturation and protein degradation.

The use of oxygen as part of the process for generating metabolic energy produces reactive oxygen species. In this process, the superoxide anion is produced as a by-product of several steps in the electron transport chain. Particularly important is the reduction of coenzyme Q in complex III, since a highly reactive free radical is formed as an intermediate (Q·⁻). This unstable intermediate can lead to electron “leakage”, when electrons jump directly to oxygen and form the superoxide anion, instead of moving through the normal series of well-controlled reactions of the electron transport chain.

Antioxidants are classified into two broad divisions, depending on whether they are soluble in water (hydrophilic) or in lipids (hydrophobic). In general, water-soluble antioxidants react with oxidants in the cell cytosol and the blood plasma, while lipid-soluble antioxidants protect cell membranes from lipid peroxidation. These compounds may be synthesized in the body or obtained from the diet.

The relative importance and interactions between these different antioxidants is  very, with the various metabolites and enzyme systems havingsynergistic and interdependent effects on one another. The action of one antioxidant may therefore depend on the proper function of other members of the antioxidant system. The amount of protection provided by any one antioxidant will also depend on its concentration, its reactivity towards the particular reactive oxygen species being considered, and the status of the antioxidants with which it interacts.

Some compounds contribute to antioxidant defense by chelating transition metals and preventing them from catalyzing the production of free radicals in the cell. Particularly important is the ability to sequester iron, which is the function of iron-binding proteins such as transferrin andferritin.  Selenium and zinc are commonly referred to as antioxidant nutrients, but these chemical elements have no antioxidant action themselves and are instead required for the activity of  some antioxidant enzymes.

Dr.Beenadas
Lecturer, Department of MM
Govt. Homeopathic Medical College. Calicut