MATERNAL AND FETAL OUTCOMES IN PREGNANCY INDUCED HYPERTENSION-A RETROSPECTIVE, OPEN LABELED STUDY

To find the maternal and foetal outcomes in Pregnancy induced hypertension (PIH).

Primary objective: To study the maternal and foetal outcomes in PIH.
Secondary objective:
* To compare these outcomes in primiparous and multiparous PIH women.
* To find prevalence of different types of PIH and to study their outcomes

Medical records of one year were reviewed. A total of 791 cases were present as per the medical records. Out of these, 245 cases had PIH.
Statistical methods: Chi square test was used to compare variables. Descriptive analyses were used to study maternal foetal outcomes.
Result: The commonly seen maternal outcomes were higher rates of caesarian section, maternal deaths and post partum hemorrhage in PIH women. The foetal outcomes were live births, still births, deaths, low birth weight and low APGAR scores. There was a strong association between maternal outcomes and parity. The rate of caesarian was higher in primiparous women. The association between foetal outcomes and parity was not statistically significant. Preeclampsia was the most common type of PIH and these women were more prone to hypertensive complications.

Conclusion: In the present study most commonly seen outcomes in PIH women were in agreement with data obtained from previous studies. Majority of PIH cases went for caesarean delivery in present study .Many studies conducted previously also showed similar outcome with increased rate of caesarian section. The incidence of PIH is higher in developing countries due to poor socio-economic condition.The common maternal complications were deaths, higher caesarian rates and foetal complications were still birth, deaths and low birth weights. Primiparous women were more prone to adverse outcomes. Preeclampsia was the most common type of PIH seen in present study.

COPY CODE SNIPPET

Introduction
Hypertension is disorder of Blood Pressure. A person is said to be hypertensive if the systolic BP is greater than 140 mm of Hg and diastolic BP is greater than 90mm of Hg. The exact etiology of hypertension is not known. A number of factors like Obesity, aging, stress, sedentary life style are said to play role in its etiology.Hypertension is seen even during pregnancy. This hypertension is said to be pregnancy induced. This is due to the stress during pregnancy. Pregnancy induced hypertension is one of the most common and dangerous disorder in mothers during pregnancy ⁽¹⁾. Low serum calcium levels are found to play a vital role in etiology of PIH. Many opine that insulin resistance is involved in pathogenesis of PIH. Pregnancy induced hypertension is known to affect 5% of the pregnancies ⁽²⁾ . There are 3 clinical types of PIH. They are Preeclampsia, Eclampsia and Gestational hypertension ⁽¹⁾.

Preeclampsia: It occurs in about 10% of primiparous women and in 5% of multiparous women. There is raise in BP at least twice with a time gap of 6 hours. ⁽³⁾

Eclampsia: This is a condition where preeclampsia is accompanied by coma or convulsions. The incidence if eclampsia varies in different countries. The cause of convulsion is not known. ⁽³⁾.

Gestational hypertension (BP >140/90): This is a condition in which hypertension is seen only during pregnancy and blood pressure comes back to normal after delivery.⁽³⁾

Complications of PIH: Maternal complications (outcomes):

• Higher rates of caesarian section
• Maternal deaths
• Post partum hemorrhage ⁽³⁾

Fetal complications (outcomes):⁽¹⁾

• Intrauterine death
• Asphyxia
• Prematurity
• low birth weight

Diagnosis: PIH can be diagnosed by any of the following examinations:

• Urine test
• Measuring blood pressure
• Weight checks

There are many risk factors for PIH. It is very commonly seen in:

• Primigravidae ⁽⁴⁾
• Women aged above 40
• Women with high BP just before pregnancy
• Genetic factors ⁽²⁾

Treatment: The treatment of PIH depends on severity of disease, patient’s opinion, due date and also tolerance to antihypertensive drugs ⁽⁶⁾. Different treatment strategies followed are bed rest either at home or hospital and antihypertensive medications ⁽⁵⁾. Health care provider decides upon the treatment based on due date. There is a need for continuous maternal and foetal monitoring in PIH.
Prevention is always better than to cure. PIH can be prevented by exercising, proper Rest, proper diet, avoiding oily food, reducing intake of caffeine
The aim of this study was to find the maternal and foetal outcomes in PIH. The secondary aims were to compare these outcomes in primiparous and multiparous women. The prevalence and outcomes of different types of PIH was also studied.

Materials and methods
One year medical records of Obstetrics and Gynecology department were reviewed from May 2005 to April 2006 to find the PIH cases ⁽¹⁾. The medical records reviewed had details of patients, their demographic data, age, gestational age, parity, obstetric history, diagnosis and outcome. It also had details of foetal sex, birth weight, APGAR scores at 1st and 5th minute, foetal outcomes. APGAR scores indicates activeness of newborns in terms of its respiratory rate, muscle tone etc. Primigravidae (primiparity) was defined as the first pregnancy. The subsequent pregnancies were called as multigravidae (multiparity). Gestational age was determined based on last menstrual cycle. Here new borns were classified as low birth weight cases based on definition of World Health Organization. As per World Health Organization’s definition new borns with low birth weight are those born with a weight less than 2500g⁽¹⁾. The outcomes in mother and foetus were studied. The complications were studied in both primiparous and multiparous women. All singleton pregnancies with mild or severe eclampsia, preeclampsia and gestational hypertension were included in study. All twin pregnancies were excluded. Prevalence of different types of PIH and their outcomes was studied separately. The age of the women in this study was ranging between 18 to 35 years in both the groups as per medical record. There was no variation in demographic and obstetric characteristics of women in both the parity group. The cases marked as hypertensive on record were included in the study.

Table: Population studied and control

Attributes	Total pregnant cases studied	PIH cases	Non PIH cases
Number	791	245	546

There were 794 pregnant cases present in the year 2005- 06 as per medical record. Out of these, 3 twin pregnancies were excluded. In remaining 791 cases, 245 cases had PIH as shown in table 1. The outcomes studied were type of delivery, death and post partum hemorrhage in mothers. The main outcomes studied in newborns were low birth weight, low APGAR scores, still birth and death. The complications were compared in primiparous and multiparous women. PIH was classified as Preeclampsia, Eclampsia and Gestational hypertension.

Parity and age distribution of women in both groups are represented in table and respectively

Parity distribution cases

Age distribution in PIH and non PIH

Statistical methods:
The data was stored in excel sheet. Statistician was approached for analysis of the data. Descriptive analysis was performed. Comparative analyses were performed using Chi square test to see the homogeneity of thequantitative variables. The student’s t test was used to compare the means of the quantitative variables. SPSS software 11.0 version was used for statistical analyses. The output generated was decoded and resultswere interpreted in the form of table or graphs.

Results
The most common maternal outcomes were aesarian, induced and normal deliveries. The majority of the PIH cases went for caesarian deliveries (46.1%), followed by normal (25.3%) deliveries and induced deliveries (15.9). Two maternal deaths were reported (0.816%).Two cases with post partum hemorrhage were reported (0.816%). The most commonly seen foetal outcomes were live births, stillbirths and deaths. The rate ofstillbirths and death were 18% and 4.1% respectively. 78% 0f the live births were seen in PIH cases. Other complications like Asphyxia, IUGR, foetal distress was seen .Asphyxia was seen in 1 case which died after some time. FD was seen in 7 births (2.9%), 2 of which died. IUGR was seen in 20 cases (8.2%).

The association between the parity and maternal outcomes are found to be statistically significant (P<0.05). The results of this study show that the rate of caesarian deliveries is 36.2% and 27.2% in primiparous than multiparous cases respectively. The rate of caesarian deliveries is comparatively higher in primiparous than multiparous cases. The rate of induced delivery was 20 and 22.7% in primiparous than multiparous cases. The rate of normal delivery was 43.8% and 50% respectively in primiparous than multiparous cases. Hence majority of the primiparous cases went for caesarian section. There were 2 maternal deaths (1.48%) and two cases of PPH (1.48%) reported in primiparous women.

There is no association between foetal outcomes and parity. (P>0.05) .The rate of still births in primiparous and multiparous cases was 9.6% and 11.8% respectively. The death rates were 5.3% and 5.5% in primiparous and multiparous cases respectively. Here there is no much difference in rates of foetal complications in primiparous and multiparous cases. The live birth rates were 85.1% and 82.7% respectively in primiparous and multiparous cases. The other complications like asphyxia and fetal distress were seen in primiparous cases. IUGR were reported in 12 primiparous cases, rest 8 cases were seen in multiparous women.

Table

Mean, SD of APGAR score at 1st minute of new born, t-value, d.f and significance level between primiparous and multiparous women in PIH group

Student’s t test is used to test the difference between the two means i.e. between primiparous and multiparous women. The mean APGAR score at 1st minute is 4.0 and 3.8 in primiparous and multiparous women respectively as show in table. This difference is not statistically significant.

Table

Mean, SD of APGAR score at 5^th minute of new born, t-value, d.f and significance level between primiparous and multiparous women in PIH group

Student’s t test is used to test the difference between the two means i.e. between primiparous and multiparous . The mean APGAR score at 5th minute is 7.02 and 6.96 in primiparous and multiparous respectively as show in table. This difference is also not statistically significant. Here there is no difference between mean APGAR score of primiparous and multiparous .

Table

Mean, SD of birth weight, t-value, d.f and significance level between primiparous and multiparous women

Student’s t test is used to test the difference between the two means i.e. between primiparous and multiparous. There is no significant difference between the two means as show in table. The mean birth weightin primiparous and multiparous is 2.2 Kgs and 2.1 Kgs respectively.

Table: Type of PIH and its prevalence

Preeclampsia, eclampsia and gestational hypertension were seen in 21.3%, 8.7%and 0.88% of the PIH cases respectively as shown in table. Preeclampsia was found to be more prevalent when compared to other types of PIH.

Discussion
It was seen that the majority of the PIH cases went for caesarian delivery. The rate of caesarian delivery was (46.1%) followed by normal (38.1%) and induced (15.9%) deliveries. The results obtained in this study are in consistency with the data generated from other studies. A study was conducted at teaching hospital and also at few medical colleges in India to find out the major indications of caesarian deliveries. It was seen that PIH was one of the major indications of caesarian deliveries. Caesarian is the most common type of deliveries recommended in PIH. ⁽⁷⁾ . Here the rate of maternal deaths reported was higher compared to previous studies (0.816%).There was one (0.08%) maternal death in previous study ⁽⁸⁾ . As to the rate of caesarian deliveries in PIH cases, its frequency was slightly lower in present study than earlier study conducted ⁽⁹⁾. The rate of caesarian was 59.9% in this study done to see the case profiles of maternal mortality in Saul Paulo.The fetal outcomes seen in the study were live births (78%), still birth (18%), death (4%) in this study. The outcomes studied were low birth weight, pre maturity, still birth, low APGAR scores, deaths. The mean birth weight of neonates born to PIH cases was 2.1 Kgs. These results are in agreement with foetal outcomes seen in other studies. In a study conducted earlier to see foetal outcomes in PIH, it was seen that 19% of the cases had low birth weight ⁽¹⁾. PIH is said to increase the rate of foetal deaths. ⁽¹⁰⁾ A study conducted to find the levels of serum lipids on PIH cases revealed that neonates born to PIH cases had lower birth weights than those born to normal ones. ⁽⁶⁾.The mean APGAR value was 4 and 6.41 at 1st and 5th minute respectively in present study. In a previous study conducted to assess the foetal outcomes in PIH, APGAR score was found to be greater than or equal to 7 at 1st minute in 84.1% of the cases and it was less than 7 in 15.9% of the cases .It was greater or equal to 7 and less than 7 at 5^th minute in 99.2 and 0.8% of the cases respectively ⁽¹⁾. The rate of cesarean section was higher in primiparous women. It is said that primiparous women were more prone to PIH⁽¹¹⁾. They had higher frequency of preeclampsia, eclampsia and gestational hypertension (95%, 98% and 98%). There are no many studies done to see the severity or effect of parity in PIH. . A study conducted to see the maternal and perinatal outcomes in eclampsia said that primiparous women were more prone to eclampsia than multiparous women. ⁽¹²⁾.There are many studies which say that primiparous women are more pone to PIH or any hypertensive complication than multiparous women.^{(12) (13)}.

In a study carried out to see the effect of smoking on PIH, it was seen that there was no variation in complications in both primiparous and multiparous women ⁽¹⁴⁾. Here there was no association between foetal outcomes and parity. Hence null hypothesis was accepted at P<0.05. But there was a strong association between maternal complications and parity. Hence null hypothesis was rejected at P<0.05. The rate of caesarian deliveries was higher in primiparous women. Two maternal deaths were seen in primiparous women. The other complications like asphyxia, IUGR and foetal distress were more prevalent in primiparous cases in present study.A study conducted to see the outcomes of PIH showed that there was no difference in caesarian rates in primiparous and multiparous women. ⁽¹⁵⁾ But perinatal death, foetal death on admission was seen mostly in multiparous and two foetal deaths were seen in primiparous cases during hospital stay. There was no difference in the means of APGAR scores of new born at 1st and 5th minute between primiparous and multiparous cases in the present study .The difference in mean weights of the neonates between primiparous and multiparous cases were also not very significant.Hence null hypothesis was accepted at P>0.05.Here preeclampsia was the most common type of PIH in the present study. Caesarian rate was higher in eclampsia. There was no much difference in foetal outcomes in different types of PIH. Caesarian is said to be the most common type of delivery in preeclampsia. Incidence of eclampsia was found to be 1.66% in a study conducted at Lagos State University Teaching Hospital ⁽¹⁶⁾. In the present study it was 5 times more than this. The rate of caesarian was 53.7% in women with eclampsia in previous study. In the present study it was found to be 52.2%. Maternal complications were more common in preeclampsic cases. Hence this data obtained is in agreement with previous study.

It was seen that the infant complications were more prevalent in preeclampsia than other types of PIH. The still birth of foetus was more common in gestational hypertension and preeclamsia. The death rate of new born was also higher in preeclamsia. Many complications and fatal outcomes were reported in preeclampsic women in earlier studies also. The low birth weights and preterm births were higher in preclampsia in earlier studies ⁽¹¹⁾ . In the present study preeclampsic women were more prone to various complications as in previous studies ⁽¹⁷⁾. PIH may head to severe complications in later life. It is found to be associated with coronary heart disease in later stages of life in women with PIH. Hence necessary steps have to be taken to ensure proper diagnosis, care and treatment. This will ensure decrease in occurrence of PIH. The incidence of preeclampsia was 15% in previous studies ⁽¹⁸⁾. This is slightly lower when compared to incidence rate in present study. The rate ofmaternal mortality is high in developing countries due to poor socio economic condition. Improving standard of living might help to prevent these complications. PIH is the third most common cause of maternal death in developing countries. 68% of the total deaths due to hypertensive complications occur in South Asia. The prevalence of hypertension is 31.8% and 42.2% among males and females respectively ⁽¹⁹⁾. The maternal and foetal complications due to PIH, mortality and morbidity rates are lesser in developed countries due to appropriate care ⁽¹⁾ .The proper identification and management of PIH, regular maternal and foetal monitoring will help in reducing the maternal and foetal mortality and morbidity. ⁽¹²⁾

PIH is one of the leading causes of maternal, foetal mortality and morbidity. Hence there is a need for more researches and studies in this area. This study indicates that the prevalence of PIH is high in India. It has major effect on both mothers and new born. This study also recommends for a better maternal and foetal monitoring along with standard therapy as the lack of these have been reported to be the main cause of high prevalence. Hence this a study in this area would surely help in understanding the present situation of PIH in India. The higher rates of prevalence indicate the absence of standard antenatal and perinatal monitoring. Many government hospitals are providing treatment and medications free of cost. The prevalence of poor economic condition is higher in India. Hence cost constraints will not allow them to afford private hospitals. Hence they are devoid of a standard care and treatment. This case control comparative study gave an insight upon of maternal and foetal outcomes in PIH. The data generated in this study is in agreement with other studies. There are many studies conducted and being conducted in this area. This is one of the leading causes of maternal and foetal deaths in majority of the developing countries. The rate of PIH has reduced in developed countries due to proper precautionary measures taken during pregnancy. This study would help in understanding of loopholes in treatment, management strategy of PIH. This might also encourage others to conduct further studies in this aspect. This might provoke hospital administration and other authorities to take up necessary actions to prevent this raise in the incidence of PIH. Retrospective study was carried out due to time constraints. Non availability of adequate time is the limitation of this study. Other details of the patients like previous medical history and other complications present in women during pregnancy along with hypertension were not recorded in medical record for all cases.

Conclusion and future work
The present study shows that PIH is on of the major indication of caesarian section. It is one of the major causes of maternal mortality and morbidity. PIH was found to be associated with the larger number of maternal and foetal complications.This study talks about the most common maternal and foetal outcomes in PIH. However retrospective study was carried out mainly because of time constraints. The most common maternal outcome in the present study was higher rates of caesarian section in PIH cases. This is in agreement with data generated from previous studies. In addition to this there were maternal deaths and complications like PPH. The most common foetal complications were still births, deaths and low birth in the present study.There was a significant association between maternal outcomes and parity in PIH. But the association between foetal outcomes and parity was not significant. Preeclampsia was the most common type of PIH seen in present study followed by eclampsia and gestational hypertension. Caesarian was common outcome in all types of PIH. The rate of still birth was higher in preeclampsia even though it was common in all types of PIH.This study would help in understanding most frequently occurring maternal and foetal complications. PIH is said to be the one of the four main causes of maternal death in Brazil. ⁽¹⁾. Hence conducting study in this area will contribute the better understanding of this aspect. These complications are fatal if not treated. Hence appropriate care must be taken to diagnose and identify PIH at initial stage and provide appropriate treatment. This would ensure the reduction in incidence of PIH. This would in turn reduce the rate of maternal and foetal mortality and morbidity. The rate of maternal mortality and morbidity due to PIH has reduced in recent years with increased care towards mothers and newborns and by providing appropriate treatment in US. The prevalence of PIH is found to be higher in developing country like India. This is due to the poor socioeconomic strata. This prevents patients with PIH from obtaining a proper perinatal and antenatal care. Proper maternal and foetal monitoring and a good management of hypertension with antihypertensive medication are recommended. This would bring down the rate of PIH in India.

Future work
There is a need for more work in this area as PIH is one of the most common disorders during pregnancy. If there was no restriction on time the present study could have focused on after effects of PIH by following up these women. There are many studies which say that these women are more prone to various diseases in later stages of their life. Hence this could have been possible if these subjects were contacted and followed up. Other areas like treatment or most common medications used in PIH and pharmacoeconomic study would have been conducted. Low socioeconomic condition is highly prevalent in India. Hence conducting pharmacoeconomic study will enlighten upon amount spent on medication and other economic aspects related to their treatment. PIH is highly prevalent in India. This can be attributed mainly to poor socio economic condition, lack of standard treatment strategy, lack of awareness of PIH among women. Hence a good standard treatment strategy and educating programmes for women regarding various aspects of PIH like diagnosis, treatment and prevention is needed.

References
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2. Irgens H U, ReisÊter L, Irgens L M , Lie RT, Long term mortality of mothers and fathers after preeclampsia: population based cohort study, November 2001 ,BMJ ,Vol 323 , pp:1213 ,www.bmj.com
3. Book: Dutta; Hypertensive disorders in pregnancy. Text book of obstetrics in pregnancy; pp: 235-255
4. Rasmussen S, Irgens L M , Predicting Preeclampsia in the Second Pregnancy from Low Birth Weight in the First Pregnancy ,Obstetrics & Gynecology,pp: 696-700
5. Shen J. J., Tymkow C, MacMullen N, Disparities in maternal outcomes among four ethnic populatios. Ethnicity & Disease. 2005 vol 15,: pp:492-497
6. Mohanty,S., Nayak N, Nanda NN, Rao P.Serun lipids and malondialdehyde levels in primiparous patients with pregnancy induced hypertension. Indian Journal of Clinical Biochemistry, 2006, vol 21, no 1,pp: 189-192
7. Kambo I, X Bedi N, Dhillon B S, Saxena N C.A critical appraisal of cesarean section rates at teaching hospitals in India. International Journal of Gynecology & Obstetrics. 2002, Vol 79, Issue 2, November, pp:151-158
8. Lydakis, C., Obstetric and neonatal outcomes following chronic hypertension in pregnancy among different ethnic groups, 1998,Q J Med,vol 91,pp: 837-844
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10. KnightK B , Keith R E., Calcium supplementation on normotensive and hypertensive pregnant women, Am J C/in Nuir, 1992, vol 55, pp: 89l-895
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12. Naib, J M., Siddiqui M L , Ajmal W. Maternal and perinatal outcome in eclampsia,a one year study. J pakmed ,2004, Vol 18 No 3 :: Page 470 – 476,
13. Badria, L. F, Amarin Z. O. Pre-eclampsia: is it a different disease in primiparous and multiparous women?. Archives of Gynecology & Obstetrics :2005: 273(1): 26-31.
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16. Akinola O, Fabamwo A, Gbadegesin A ,Ottun A, Kusemiju O. Improving The Clinical Outcome In Cases Of Eclampsia: The Experience At Lagos State University Teaching Hospital, Ikeja, The Internet Journal of Third World Medicine , 2008: Vol 6:no 2.
17. Rasmussen S, Irgens L M. Fetal Growth and Body Proportion in Preeclampsia, Obstetric & Gynecology : Vol. 101, No. 3, March 2003,pp:575-583
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ROLE OF ANTIOXIDANT IN CANCER TREATMENT: A REVIEW

Abstract:
Antioxidants are essential and important for plants and animals’ sustenance. They are substances that protect cells from the damage caused by unstable molecules known as free radicals. Cancer develops when cells multiply in the presence of oxidation and other damage. Certain "antioxidant" substances, such as vitamin C, are able to exploit the differences between cancer and healthy cells; they kill cancer cells while helping healthy cells. Antioxidants are substances that may protect cells from the damage caused by unstable molecules known as free radicals. Free radical damage may lead to cancer. Antioxidants interact with and stabilize free radicals and may prevent some of the damage free radicals Examples of antioxidants includeQuercetin Curcumin Beta-carotene, Lycopene, Vitamins C, E, and A, and other substances. Epidemiological studies have consistently shown that regular consumption of fruits and vegetables is strongly associated with reduced risk of developing chronic diseases, such as cancer and cardiovascular disease.

Introduction:
Antioxidants neutralize free radicals as the natural by-product of normal cell processes.

Free radical formation can leads due to the Exposure of various environmental factors, including tobacco smokeand radiation and etc.  The most common form of free radicals in Humans is oxygen. When an oxygen molecule  becomes electrically charged causing damage to the DNA and other Cell such damage may be irreversible and may be causes many disorders like as Cancer. Antioxidants are neutralize the electrical charge and prevent the transportation of electrons from other molecules to free radicals.

DNA is a major target of free radical damage. The types of damages induced are many and include strand breaks (single or double strand breaks) damage yielding products such as 8-hydroxyguanosine, thymine glycol or abasic sites. These damages can result in mutations that are heritable change in the DNA that can yield cancer. The involvement of free radicals with tumor suppressor genes and proto-oncogenes suggest their role in the development of different human cancer.[2]

produced in the body (endogenous) and others  obtained from the diet (exogenous Humans have evolved with antioxidant systems for protection against free radicals and ROS. These systems include some antioxidants).

Many clinical trials published and  reached differing conclusions about the effect of antioxidants on cancer.

1. The first large randomized trial on antioxidants and cancer risk was the Chinese Cancer Prevention Study, published in 1993. This trial investigated the effect of a combination of beta-carotene, vitamin E, and selenium on cancer in healthy Chinese men and women at high risk for gastric cancer. The study showed a combination of beta-carotene, vitamin E, and selenium significantly reduced incidence of both gastric cancer and cancer overall. [3]

2. A 1994 cancer prevention study entitled the Alpha-Tocopherol (vitamin E)/ Beta-Carotene Cancer Prevention Study (ATBC) demonstrated that lung cancer rates of Finnish male smokers increased significantly with beta-carotene and were not affected by vitamin E. [4]

Cancer development can be described by three stages: initiation, promotion and progression, and ROS can act in all these stages of carcinogenesis [5] . It is also well established that free radicals are known to react with all components of DNA, thus damaging its bases and the deoxyribose backbone [6] causing mutations in crucial genes, which ultimately may lead to cancer. [7]

A high level of oxidative stress can induce apoptosis or even necrosis; however, a low level of oxidative stress can stimulate cell division and thus promote tumor growth. [8] ROS probably enhance the final irreversible stage of carcinogenesis, which is characterized by accumulation of additional genetic damage, leading to the transition of the cell from benign to malignant.

Three large-scale clinical trials continue to investigate the effect of antioxidants on cancer
1. The Women’s Health Study (WHS) is currently evaluating the effect of vitamin E in the primary prevention of cancer among U.S. female health professionals age 45 and older. The WHS is expected to conclude in August 2004

2. The Selenium and Vitamin E Cancer Prevention Trial (SELECT) is taking place in the United States, Puerto Rico, and Canada. SELECT is trying to find out if taking selenium and/or vitamin E supplements can prevent prostate cancer in men age 50 or older. The SELECT trial is expected to stop recruiting patients in May 2006.

3. The Physicians' Health Study II (PHS II) is a follow up to the earlier clinical trial by the same name. The study is investigating the effects of vitamin E, C, and multivitamins on prostate cancer and total cancer incidence. The PHS II is expected to conclude in August 2007.[9_11]

Last stages cancer can’t treated with antioxidants suppliments. So ant oxidative nutritional supplements as cancer preventatives is not actual therapies [14].The great Caltech chemist, Linus Pauling, who near the end of his illustrious career wrote a book with Ewan Cameron in 1979, Cancer and Vitamin C, about vitamin C's great potential as an anti-cancer agent.[12]. But At the time of his death from prostate cancer in 1994, at the age of 93, Linus was taking 12 g of vitamin C every day. late-stage cancer'. vast number of nutritional intervention trials using the antioxidants β-carotene, vitamin A, vitamin C, vitamin E and selenium have shown no obvious effectiveness in preventing gastrointestinal cancer.[13].

The cytotoxic action (side/adverse effect of anti cancer agents) of many anticancer drug including like as 5-fluorouracil, vincristine, doxorubicin, cisplatin and   were found to be increased with co administration or in presence of vitamin E and the cytotoxic effect of  Antineoplastics agents Bleomycin, Paclitaxel and darcarbazine were found to be increased with co administration or in presence of vitamin C during in vitro studies through inhibition of the effects of lipid peroxidise on cell growth. [15].

Molecular Studies of Natural Antioxidants: 
Different types of natural antioxidants are present in fruit and vegetables they have synergistic interactions that are important due to their activity and regenerative potential. For example,ascorbate can regenerate into α-tocopherol. [16] Interactions is known as the “antioxidant network”.

Tumor necrosis factor-alpha (TNF-α) is a cytokine that, under normal conditions, induces inflammation, tumor inhibition, and apoptotic cell death. However, when the former undergoes deregulation, it acts as a breast tumor promoter, enhancing the proliferation of chemically induced mammary tumors. [17].

Phenolic antioxidants can block the increase of TNF- α at the transcriptional level in the nucleus, which suggests the molecular mechanism of phenolic antioxidants through control of cytokine induction. [18].

Nomenclature and Classification of Antioxidants:

Table 1 lists categories in which various antioxidants have been characterized.

ANTIOXIDANT AGENTS:

1.) QUERCETIN:
Quercetin (3,3’,4’,5,7-pentahydroxyflavone)is one of the most frequently studied bioflavonoid. Flavonoids are polyphenolic compounds possessing 15 carbon atoms, two benzene rings joined by a linear three carbon atom chain (structure A). The chemical structure of flavonoids are based on a C15 skeleton with a chromane ring bearing a second aromatic ring B in position 2, 3 or 4 (structure B). Quercetin have multiple pharmacological and medicinal action and uses as anti-inflammatory, anti-allergic, antiviral, antithrombotic, anti-mutagenic and  antineoplasti agents. [20]

A number of its actions make it a potential anti-cancer agent, including cell cycle regulation, interaction with type II estrogen binding sites, and tyrosine kinase inhibition. [21].

Its reputation as an antioxidant stems from the reactivity of phenolic compounds with free radical species to form phenoxy radicals which are considerably less reactive.

Properties, Occurrence and Production of Quercetin:
Quercetin is a yellow, crystalline solid with a bitter taste, which is insoluble in water, slightly soluble in alcohol, and soluble in glacial acetic acid and aqueous alkaline solutions.[22_23]. Quercetin is usually obtained from the hydrolysis of rutin (quercetin-3- rutinoside), a naturally occurring flavonoid glycoside. [24] although it can also be synthesized.[25] Quercetin glycosides are relatively poorly absorbed by the small intestine. Micro flora of the lower bowel hydrolyze the flavonide-glycoside to quercetin and the sugar, and quercetin is then absorbed into the enterohepatic system [26-28]. A 100 mg single dose was found to create a serum concentration of 0.8 microM quercetin, The serum quercetin concentrations required for anti-cancer activity (upwards of 10 microM,[29]. Quercetin interfere by reacting with the radicals formed in the process of lipid peroxidation[30]

Table 2. Quercetin Content in Selected Foods:

Food Source	Quercetin Content (mg/100g)
Apple with skin	4.42
Raw Onions	13.27
Black Tea Leaves, dry	204.66
Green Tea Leaves, dry	255.55

Quercetin have a ability to scavenge free radicals and bind transition metal ions. These properties of quercetin allow it to inhibit lipid peroxidation [31-32].

ANTI-CANCER EFFECTS OF QUERCETIN:
Oxidative DNA damage is a known risk factor of cancer. Antioxidants, such as quercetin, are thought to play an important role in protecting cells from oxidative stress induced by reactive oxygen species(ROS). ROS and RNS (reactive nitrogen species) play a vital role in development of Cancer in Human. ROS is collective term of various oxidizing agents.[33]

Fig. : Role of ROS/RNS in cancer development [33]

MOLECULAR MECHANISM OF ACTION OF QUERCETIN:
1.) Down Regulation of Mutant P53 Protein:
Quercetin (248 microM) was found to down regulate expression of mutant p53 protein to nearly undetectable levels in human breast cancer cell lines. Lower concentrations gave less reduction [34-37].

 

1.)    G1 phase arrest:
The G1 checkpoint controlled by the p53 gene is a major site for the control of cellular proliferation. Quercetin has been found to arrest human leukemic T-cells in the late G1 phaseof the cell cycle.[38]

This G1 arrest was also seen in gastric cancer cells treated with Quercetin.

2.)    Tyrosine Kinase Inhibition:
Tyrosine kinases are a family of proteins located in or near the cell membrane and involved in transduction ofgrowth factor signal to nucleus. lymphocyte tyrosine kinase can be inhibited by the Quercetin on I.V. administration at a one hour time.[39-41].

3.)    Estrogen receptor binding capacity: 
Quercetin has been shown to induce ER II expression in both type I estrogen receptor positive (ER+) and type I estrogen receptor negative (ER-) human breast cancer cells. induction of ER II allows for greater growth inhibition of ER- cells with quercetin treatment. In cultured human melanoma cells, quercetin was found to bind ER II sites with an affinity similar to tamoxifen and diethylstilbestrol. ER II sites are found in normal tissue and on many different human tumor types, including breast, ovarian, colorectal, meningeal, leukemic, and melanoma.[42-44].

Use of Quercetin with Standard Oncologic Therapeutics:
1.) topical and oral administration of quercetin to reduce skin damage during radiotherapy in patients with head and neck cancers[45]

2.) Quercetin has been shown to increase the therapeutic efficacy of cisplatin both in vivo and in vitro.[46]

3.) An absence of potentiation of the effect of adriamycin or etoposide due to quercetin administration was noted.[47]

4.) Quercetin (10-100 microM) has also been shown in vitro to protect normal renal tubular cells from cisplatin toxicity.[48]

5.) Quercetin has also been shown in vitro to increase the cytotoxic effect of cyclophosphamide.[49]

6.) Decrease the resistance to gemcitabine and topotecan. [50]

2.)  SELENIUM:
Selenium is a chemical element with symbol Se and atomic number 34. Selenium is found in cereals, meat, poultry, seafood, and eggs. Cereals may provide about 50% of  dietary selenium, however data on the selenium content of Australian foods is limited. The selenium  content of plant foods varies with the selenium content of the soil. Selenium acts as an antioxidant and helps protect the body against the damaging effects of free radicals. Selenium is essential for the activity of glutathione peroxidase, an enzyme that protects against reactive  oxygen species and subsequent cell membrane damage.[51]

Selenium exists in many forms. The most well studied include selenomethionine (SeMet), sodium selenite, selenium methylselenocysteine (SeMeSC), 1,4,-phenylenebis (methylene) selenocyanate (p-XSC), and methylseleninic acid (MSA).[52]

Selenium is acomponent   of the antioxidant.the average daily dietary selenium (Se) intake in the United States is consistently above the adult RDA of 55 μg Se/day, supranutritional supplements of 200 μg Se/day have been shown to provide chemopreventive benefits against several cancers, particularly prostate cancer. selenium compounds contents  the greatest anticarcinogenic potency are likely to be sodium selenite with Se in the +4 oxidation state and methylseleninic acid. These compounds exert their cancer chemopreventive effects by directly oxidizing critical thiol-containing cellular substrates, and are more effective than the more frequently preferred (used) supplements of selenomethionine and Se–methylselenocysteine that lack oxidation capability. Selenate (+6 Se) the immediate precursor of selenite (+4 Se) can be metabolically reduced, and although less potent than the +4 Se compounds cited above, appears to be a more effective anticarcinogen than organic forms of dietary selenium.

It is a potent modulator of eukaryotic cell growth with strictly concentration-dependant effects. Lower concentrations are necessary for cell survival and growth, whereas higher concentrations inhibit growth and induce cell death.[53]

The protective effect of this mineral is especially associated with its presence in glutathione peroxidase and thioredoxin reductase, enzymes that protect the DNA and other cellular components against oxidative damage caused by ROS. Several studies have demonstrated reduced expression of these enzymes in various types of cancer, especially when associated with a low intake of selenium, which may exacerbate the damage.[54]

Selenium increased the activity of cisplatin in mice, and decreased its toxicity in humans.

In recent years, selenium has become controversial following results from the large Selenium and Vitamin E Cancer Prevention Trial (SELECT), which was prematurely terminated after demonstrating no effect on prostate cancer risk [55]

MECHANISM OF ACTION OF SELENIUM:
A number of mechanisms have been suggested to explain the anti-cancer effects of Se. Although there is fairly general acceptance that methyl selenol (CH3SeH) is involved in the anti-cancer effects of Se at supra-nutritional doses.

Anti-cancer processes or pathways	Selected evidence for Se involvement	Reference
Seleno-enzyme mechanisms Reduction of DNA damage	Se intake or status affects DNA damage in both human and animal studies	[56-58]
Induction of phase II conjugating enzymes: detoxifycarcinogens and reduce DNA adduct formation	Some selenocompounds e.g. methyl selenol (CH3SeH), can up regulate phase II conjugating enzymes such as glutathione-S-transferase, increasing detoxification of carcinogens	[59]
Increase in tumour suppressor protein p53: inhibits proliferation, stimulates DNA repair and promotes apoptotic death by acting as a transcription factor	SeMet can activate p53 through redox regulation of key p53 cysteine residues. Methyl seleninic acid (CH3SeO2H) and Na2SeO3 modulate p53 activity by Phosphorylation	[60]

Use of Selenium with Standard Oncologic Therapeutics:
1) selenium depletion reduces the lethal dose of radiation [61]

2) selenium decreased nephrotoxicity of cisplatin, while simultaneously increasing its anti   tumor activity. [62].

3) seleniumcontaining antioxidant compound called Ebselen (2-phenyl-1,3-benzisoselenazol  3(2H)one) has a mild inhibitory effect on the anti-tumor effect of bleomycin. [63]

3. VITAMIN E:
Scientific/medical name(s)of vitamins E are  alpha-tocopherol, tocopherols, tocotrienols,

Vitamin E is an essential fat-soluble nutrient that serves as an antioxidant and is also used in cell signaling, regulating gene expression and immune function. (Antioxidants block the action of free radicals, which are activated molecules that can damage cells.)

Vitamin E comprises a group of compounds possessing vitamin E activity. alpha- Tocopherol is the compound demonstrating the highest vitamin E activity, which is available both in its natural form as RRR-alpha-tocopherol isolated from plant sources, but more common as synthetically manufactured all-rac-alpha-tocopherol. Synthetic all-racalpha-tocopherol consists of a racemic mixture of all eight possible stereoisomers.[ 64]

The SELECT (Selenium and Vitamin E Cancer Prevention Trial) looked at the effect of vitamin E alone or in combination with selenium (an antioxidant mineral) on prostate cancer risk.

The ability of the vitamin E (RRR--tocopherol) derivatives -tocopheryl succinate (-TOS) and -tocopheryloxyacetic acid (-TEA) to suppress tumor growth.[65].

Vitamin E succinate (VES, alpha tocopherol succinate),has generated some interest as an adjunctive cancer therapy recently. VES demonstrated growth inhibition of human B-cell lymphoma. [66] With aim to evaluate the neuroprotective effect of antioxidant supplementation with vitamin E in patients treated with cisplatin chemotherapy. [67]

Research on human oral squamous carcinoma cells suggests the VES effect is biphasic; growth stimulatory at  physiological concentrations, while pharmacological concentrations are inhibitory. [68]

Phase I clinical trials are being planned or are underway in patients with breast and prostate cancers.[69]Vitamin E and its derivatives are particularly attractive therapeutic agents due to their remarkable lack of toxicity in vivo. [70]

Vitamin E induces apoptosis in experimental tumor lines.Vitamin E with omega-3 fatty acids increased survival time in terminal cancer patients.Vitamin E in doses below 500 mg/kg (approximately 35,000 IU human dose) may increase the effect of radiotherapy in mice. Vitamin E increases the activity of 5- fluorouracil, doxorubicin, and cisplatin in vivo.No evidence exists that vitamin E reduces the effect of chemotherapy in vivo.

Use of Vitamin E with Standard Oncologic Therapeutics:
1) Vitamin E(750mg/kg)  have a greater anti- tumor activity with administration of  5- fluorouracil in mice bearing human colon cancer lines than either agent alone. Addition of vitamin E to either 5-fluorouracil or doxorubicin enhances the effect of these agents on human colon cancer cells. [72]

2) The tumor-bearing mice pretreated with vitamin E lived longer on average than those treated with doxorubicin alone the vitamin E blocked lipid peroxidation-mediated toxicity, while not impairing the anti-tumor property of doxorubicin. [73]

3) mice treated with 1 g/kg of vitamin E had an increased in the lethal radiation dose (LD50). [74]

4. Curcumin:
Curcumin is obtained from the Turmeric. Turmeric comes from the root of the Curcuma longa plant and has a tough brown skin and a deep orange flesh. Turmeric has long been used as a powerful anti-inflammatory in both the Chinese and Indian systems of medicine.

Curcumin have a strong antioxidant.

Antioxidant actions of Curcumin' enable it to protect the colon cells from free radicals that can damage cellular DNAâ?"a significant benefit particularly in the colon where cell turnover is quite rapid, occuring approximately every three days. Because of their frequent replication, mutations in the DNA of colon cells can result in the formation of cancerous cells much more quickly. Curcumin also helps the body to destroy mutated cancer cells, and prevent the spreading of mutated cancer cell in  the body. A primary way in which curcumin does so is by enhancing liver function. Additionally, other suggested mechanisms by which it may protect against cancer development include inhibiting the synthesis of a protein thought to be instrumental in tumor formation and preventing the development of additional blood supply necessary for cancer cell growth.[75-76]

Curcumin suppresses the growth of several tumor cell lines, including drug-resistant lines.

It suppresses the expression of cyclin D1, which is deregulated in a wide variety of tumors. Cyclin D1 is a component  subunit of cyclin-dependent kinases (CDK) 4 (Cdk4) and 6 (Cdk6), which are rate limiting in progression of cells through the cell cycle. [77]

Curcumin also suppresses the activation of several transcription factors that are implicated in carcinogenesis.58 It suppresses the activation of nuclear factor kappa B (NF-_B). [78]

Curcumin suppresses the expression of TNF (TNF has been shown to mediate tumor initiation, promotion, and metastasis.) at both the transcriptional and posttranscriptional levels. Studies in our laboratory have shown that both TNF mRNA and protein are constitutively expressed in mantle cell lymphoma cell lines. [79-80]

Nagabhushan has shown that the curcumin in turmeric can: [81-85]

• inhibit the mutagenicity of polycyclic aromatic hydrocarbons (PAHs) (carcinogenic chemicals created by the burning of carbon based fuels including cigarette smoke)
• inhibit radiation-induced chromosome damage
• prevent the formation of harmful heterocyclic amines and nitroso compounds, which may result in the body when certain processed foods, such as processed meat products that contain nitrosamines, are eaten
• irreversibly inhibit the multiplication of leukemia cells in a cell culture

Use of Curcumin with Standard Oncologic Therapeutics:
1) Curcumin has been shown to augment the cytotoxic effects of chemotherapeutic drugs, including doxorubicin,tamoxifen. [86-87]
2) the combination of curcumin with cisplatin resulted in synergistic antitumor activity in the hepatic cancer HA22T/VGH cell line. [88]

LACK OF ANTIOXIDANT THERAPY:
The role and quantified level of consumed dietary antioxidants by individual patients as contained in fruits, vegetables, and grains, have not been viewed as an issue with respect to a patient’s response to anticancer drugs. [89-90]

Conclusions:
There is a concern that antioxidants might reduce oxidizing free radicals created by radiotherapy and some forms of chemotherapy, and thereby decrease the effectiveness of the therapy. animal and human studies demonstrate no reduction of efficacy of chemotherapy or radiation when given with antioxidants. In fact, considerable data exists showing increased effectiveness of many cancer therapeutic agents, as well as a decrease in adverse effects, when given concurrently with antioxidants.

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