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CA Br. Protocol Version 1.1 Confidential

Effect of A Herbomineral Preparation in Women with Non-Metastatic Breast Cancer: A randomized controlled

comparative study

Acharya Balkrishna, ChairmanAvnish K. Upadhyay Research Consultant

Subhas C Nayak, Scientist

Department of Ayurved Research & DevelopmentDivya Yog Mandir Trust, Patanjali Yog Peeth , Haridwar

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TABLE OF CONTENTS

1. INTRODUCTION

1.1. Background1.2. Hypothesis

2. STUDY OBJECTIVES

3. STUDY DESIGN

3.1. Study population3.1.1. Inclusion Criteria3.1.2. Exclusion Criteria

3.2. Study Observations3.2.1. Screening Visit3.2.2. Visit One3.2.3. Subsequent three monthly visits

4. PATIENT WITHDRAWAL

5. TREATMENT ADMINISTERED

5.1. Randomization of Subjects5.2. Dosage and Administration

5.2.1. Conventional Regime5.2.2. An Ayurvedic Preparation by Divya Pharmacy.

6. EFFICACY VARIABLES

6.1. Primary Endpoints6.2. Secondary Endpoints

7. DATA ANALYSIS METHODS

7.1. Sample Size7.2. Randomization7.3. General Consideration7.4. Statistical Methods

8. DATA COLLECTION

8.1 Demographics

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9. CLINICAL AND LAB PROCEDURES

9.1. Acuity Ductoscopy9.2 AMAS Test9.3 CA15.3, CA 1259.4 DR-709.5 Thermography9.6 Clinical Laboratory Assesments

10. REFERENCES

11. TABLE. TIME AND EVENT SCHEDULE

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1. INTRODUCTION

1.1. Background

Breast cancer is a cancer of the glandular breast tissue. Worldwide, breast cancer is the fifth most common cause of cancer death (after lung cancer, stomach cancer, liver cancer, and colon cancer). In 2005, breast cancer caused 502,000 deaths (7% of cancer deaths; almost 1% of all deaths) worldwide. Among women worldwide, breast cancer is the most common cancer and the most common cause of cancer death.[1]

In the United States, breast cancer is the third most common cause of cancer death (after lung cancer and colon cancer). In 2007, breast cancer is expected to cause 40,910 deaths (7% of cancer deaths; almost 2% of all deaths) in the U.S.[2] Among women in the U.S., breast cancer is the most common cancer and the second most common cause of cancer death (after lung cancer). Women in the U.S. have a 1 in 8 lifetime chance of developing invasive breast cancer and a 1 in 33 chance of breast cancer causing their death.[3]

The number of cases has significantly increased since the 1970s, a phenomenon partly blamed on modern lifestyles in the Western world.[4][5]

Because the breast is composed of identical tissues in males and females, breast cancer also occurs in males, though it is less common.[6]

There are numerous ways breast cancer is classified. Like most cancers, breast cancer can be divided into groups based on the tissue of origin, e.g. epithelial (carcinoma) versus stromal (sarcoma). The vast majority of breast cancers arise from epithelial tissue, i.e. they are carcinomas, which can divided further into subclassifications (e.g. DCIS versus LCIS versus papillary carcinoma).

Other pathologically based classifications:

Location of the tumour origin - breast duct (i.e. ductal) versus breast lobule (i.e. lobular).

Histology - see Histologic types section. Grade of tumour - well-differentiated (looks almost like normal tissue) versus

poorly differentiated (does not look like any normal tissue/mass of proliferating cells) versus moderately differentiated (somewhere between poorly differentiated and well-differentiated).

Stage of the tumour.

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Immunohistochemical marker status - (ER positive versus ER negative versus HER2/neu positive versus HER2/neu negative), e.g. triple negative breast cancer which is ER negative, PR negative and HER2/neu negative.

TNM classification - o Tumour size/invasiveness - presence of invasion (poorer prognosis) versus

in situ (better prognosis).o Nodal status.o Presence/absence of metastases.

An integrated approach is needed to manage cancer using the growing body of knowledge gained through scientific developments. Thousands of herbal and traditional compounds are being screened worldwide to validate their use as anti-cancerous drugs. The science of Ayurveda is supposed to add a step on to the curative aspects of cancers that have resemblance with clinical entities of arbuda and granthi mentioned in Sushrutha samhita. Hence, an attempt is made in this review to discuss about the pathology and therapeutic management of various cancers described in Ayurveda. Review of literature on anticancer drugs of plant origin revealed identification of newer ayurvedic drugs that are not mentioned in the ancient texts. These new findings add up to ayurvedic science that has been developed through ages. In addition, details of experimental and clinical studies conducted on single and compound ayurvedic preparations for their anticancer efficacy strongly emphasize ayurvedic therapy as a scientifically driven one and not simply unconventional.(7)

CAM is a growing field in health care and particularly among breast and other cancer patients. Knowledge of CAM by physicians, especially oncologists, is necessary. Oncologists should be willing to discuss the role of CAM with their patients and encourage patients to participate in well-organized research about CAM.(8)

Metal therapy, according to Ayurvedic texts which are thousands of years old, is based on the premise that human body tissues contain different metals in various degrees. Any imbalance in the content of these metals, caused by natural or self-inflicted methods such as substance abuse, disturbs the body and triggers ailments. The patients can be treated with metal-based drugs that replace the balance. Metal therapy rests on the belief that all ailments can be treated with metal-based drugs if they are diagnosed correctly and in time. All metals including gold, silver, mercury, arsenic, iron, copper, lead, tin and zinc and their alloys and some wastes are used to make the drugs. Metals (ionised form which can be absorbed by the human body) have a very important role to play in the prevention and cure of cancer.

"The same metal can be mixed with different herbs and processed to treat different diseases," Dr R M Anand, an assistant director at state-run Central Council for Research in Ayurveda and Siddha (CCRAS), told Reuters. He said metals are first purified in herbal decoctions, oxidized, subjected to heat and crushed several hundred times till they are converted into a non-metallic, non-toxic form that can be absorbed by the body. The drugs are either in the form of tablets or powders.(9)

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Traditional knowledge will serve as a powerful search engine and most importantly, will greatly facilitate intentional, focused and safe natural products research to rediscover the drug discovery process. Benefits in health care and improvement of quality of life.Natural harmaceuticals (Naturaceuticals), nutraceuticals and cosmeceuticals are of great importance as a reservoir of chemical diversity aimed at new drug discovery and are explored for antimicrobial, cardiovascular, immunosuppressive and anticancer drugs . US FDA has granted approvals to many biotechnology-based products, including Novartis: Gleevec – for treatment of CML; Genezyme: Carticel – cartilage regeneration; Immunex: Enbrel – for RA; Genentech: Herceptin – for Breast cancer; CDR Therap: Integrilin – for heart diseases; Organogenesis: Apligraft – a skin substitute. Over 300 drugs are in Phase III and over 200 are expected to be in the market by 2007.(10,11)

In a study arsenic compounds are effective agents in the treatment of APL and their activity against other types of cancer requires further investigation. Treatment of newly diagnosed and relapsed patients with acute promyelocytic leukemia (APL) with arsenic trioxide (As2O3) has been found to result in complete remission (CR) rates of 85-93% when given by intravenous infusion for 2-3 h at a dose of 10 mg/day diluted in 5% glucose saline solution.(12)

Extract of Tinospora cordifolia has been shown to inhibit the lipid peroxidation and superoxide and hydroxyl radicals in vitro. Concentration needed for 50% inhibition was 6 mg and 12.5 mg/ml, respectively. The extract was also found to reduce the toxic side effects of cyclophosphamide administration (25 mg/kg b.wt, 10 days) in mice hematological system by the free radical formation as seen from total white blood cell count, bone marrow cellularity and alpha-esterase positive cells.(13)

Exposure of HeLa cells to 0, 5, 10, 25, 50 and 100 microg/ml of guduchi extracts (methanol, aqueous and methylene chloride) resulted in a dose-dependent but significant increase in cell killing, when compared to non-drug-treated controls.(14)

The metal based formulations have been found to be effective in the successful treatment of leukaemia. In 1996, Ministry of Health and Family Welfare again reviewed my results and a pilot project entitled ‘Effect of metal based formulation in the treatment of 30 patients of Acute Promyelocytic Leukemia (APML)’ was sanctioned by CCRAS under the supervision of Cancer Research Committee headed by Dr Dinesh Chandra, Professor and Head, Department of Pharmacology, Maulana Azad Medical College, Delhi. The other members of the committee were Haematologist and Oncologist from AIIMS andexperts from ICMR and CCRAS.(15)

Although there is no certain treatment for cancer in ayurveda, it can help in restoring the normal functioning of organs and enable the body to fight disease to a certain extent. It does not have specific medicines to kill cancer cells, but works more as a supplemental therapy towards overall management of the disease. Some ayurvedic physicians claim having achieved positive results in treatment with heerak bhasma (a medicine prepared from diamonds).(16)

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Tamra bhasma purifies the blood. It has the qualities of Swarna Bhasma. Tamra Bhasma (Cupric oxide) is Useful in leprosy, asthma, bronchitis, cough, consumption, anaemia, piles, liver trouble etc.(17)

Involving 400 cancer patients, the Ayurvedic formulation containing herbal drugs bhallatak (Semecarpus anacardium), rohitak (Amoora rohitaka), madhuyasti (Glycyrrhiza glabra), and tamra bhasma was evaluated alone or in combination with other treatment modalities, chemotherapy, and radiotherapy.The patients were monitored for 10 years(18)

In 400 BC, Ayurvedic surgeon Sushrut described various cancers (called arbud) and their surgical and holistic therapy in his textbook of surgery. In addition to surgical treatment, Ayurvedic physicians observed and documented the effects of various natural therapies, spiritual practices, yoga, meditation and herbal and mineral preparations on cancer.(19,20,21)

Various medicinal plants and Herbomineral preparations described in Ayurveda like Amla(Emblica officinalis), Giloy (Tinospora cordifolia), Kutki (Picrirhiza kurroa), Bahera(Terminalia chebula), Haldi(Curcuma longa), Khair(Acacia catechu), Nimb(Azadirachta indica), Bhuiamla (Phyllanthus urinaria), Sadampushpa(Lochnera rosea), pomegranate(Punica granatum Linn), Ashwagandha(Withania somnifera), Heerak Bhasma, Kanchanar Guggul etc. found effective in various types of cancer.(22-63)

1.2. Hypothesis

Many ayurvedic formulations and Herbs given in traditional texts used by ayurvedic practitioners for long times like Heerak Bhasma, Ras Manikya, Swarn Basant Malti, Tal Sindur, Amrita sat etc. are looking very much useful in different types of carcinomas, may be due to lekhan properties of these drugs and pranayama.

2. STUDY OBJECTIVES

The assessment of relative importance of Herbomineral Preparation by Divya Pharmacy in Womens with Non-Metastatic Breast patients especially pathological and symptomatic changes. The result of this study will decide long term study on different type of carcinoma patients.

3. STUDY DESIGN Sixty newly diagnosed Non- Metastatic Breast Cancer Patients patients will be recruited and randomized in a 1 (Conventional regime) : 1 (ayurvedic regimefashion and followed for at least two years.

Treatment failure:

- Negative changes in parameters

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- If patients condition not improving in sense of QoL etc.

Outcomes:

- Mortality

- Treatment failure

3.1. Study population

3.1.1. Inclusion Criteria

A subject will be included in the study only if all the following criteria apply:

1. Non-Metastatic or locally advanced breast cancer not amenable to curative surgery

2. Life expectance of greater than 12 months

3. Pre- and postmenopausal

4. Performance status 0-1

5. Patient who have given written informed consent. 3.1.2. Exclusion Criteria

A subject will not be eligible for inclusion in the study if any of the following criteria apply:

1. Active brain metastases

2. Uncontrolled cardiac disease

3. Patients who have participated in a study within the previous 3 months.

4. They have clinically significant diagnosis of other life threatening disorders.

5. Patients with life expectancy less than 24 months ( According to Oncologist’s/ Physician’s opinion)

6. Patients with significant psychiatric disorder or mental disability. 3.2. Study Observations

3.2.1. Screening Visit

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A maximum of 7-8 days elapse between screening and the start of treatment. Patients will be randomized and assigned an identification number during the screening visit.

The following procedure will be performed:

1. Patient must sign informed consent form.

2. Physical examination.

3. Collection of blood for cytochemistry, biochemistry and haematology analysis.

4. Record of Vital signs

The following information will be recorded:

1. Demographics including – Date of birth, Gender and race.

2. Height, Weight

3. Primary disease.

3.2.2. Visit One

Visit one will take place around 45 days after treatment starts.

The following procedure will be performed:

1. Physical examination.

2. Collection of blood for cytochemistry, biochemistry and haematology analysis.

3. Record of Vital signs

The following information will be recorded:

1. Date treatment started

2. Weight

3.2.3. Subsequent three monthly visits

Treatment period continues for twelve months. Patients will be with drawn from the study if they have life threatening problem.

The following procedure will be performed:

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1. Physical examination.

2. Collection of blood for cytochemistry, biochemistry and haematology analysis.

3. Record of Vital signs

The following information will be recorded:

1. Treatment regime

2. Weight

4. PATIENT WITHDRAWAL

Patients are withdrawn from the study for any of the following reasons:

1. Completion of study

2. Patient preference

3. Death

4. Physician discretion

5. TREATMENT ADMINISTERED

5.1. Randomization of Subjects

Patients will be randomized 1:1

1 Anti Cancer Drug (Mixture of certain drugs of Ayurveda widely used for different treatments)1 Conventional solution (Chemo/Radiotherapy)

5.2. Dosage and Administration

5.2.1. Conventional Regime

The conventional regime i.e. chemotherapy given by premier hospital or institution will be selected for the study.

5.2.2. (Ayurvedic Preparation)

Each 750 mg Capsule or Tablet containsName Botanical/English Name Qty. (mg.)

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Extract ofPanwar Cassia tora 100Daruhaldi Barberis aristata 100Karanj Pongamia pinnata 100Amla Emblica officinalis 100Giloy Tinospora cordifolia 100Kutki Picrirhiza kurroa 100Bakuchi Phal Psoralia corylifolia 100Bahera Terminalia chebula 100Kali Jeeri Centratherum anthelminticum 100Choti Kateli Solanum surattense 100Haldi Curcuma longa 100Khair Acacia catechu 100Nimb Azadirachta indica 100Manjeeth Rubia cordifolia 100Chirayita Swertia chirayita 100Dronpushpi Leucas cephalotes 100Harad Termenalia bellerica 100Indrayanmool Cirullus colocynthis 100Devdaru Cedrus deodara 100Usba Smilex arnata 100Punarnavamool Boerhavia diffusa 100Bhuiamla Phyllanthus urinaria 100Makoy Solanum nigrum 100Sadampushpa Lochnera rosea 100Ashwagandha Withania somnifera 100Powders of

Heerak Bhasma 5

Sila Sindur 80

Tamra Bhasm 8.3

Swarn Basant Malti 25

Amrita Sat 80

Mukta Pishti 41.5

Praval Panchamrit 41.5

Kanchanar Guggul 330

Vrddhivadhika Vati 165

1 tab. Or capsule of Karkatnashini will be given to patients with 50ml. fresh juices of wheat grass and guduchi - Tinosporsa cordifolia (25 ml. each) twice in a day half n hour before breakfast and dinner.

6. EFFICACY VARIABLES

6.1. Primary Endpoints

The primary measure of efficacy will be a significant difference in AMAS - Anti-malignin antibody screen test, Acueity ductoscopy, Biological Terraine Assessment (BTA) , Cancer

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Marker Tests (CA 15.3, CA125), DR-70, Thermography, Ductal levage T/Tn Antigen Test, between the treatment and control groups.

6.2. Secondary Endpoints

1. The secondary outcome will be significant changes in Hb %, WBC (White blood cells) count, Platelets counts etc.

2. Psychological measures of mood, stress and QOL using: POMS, PSS-10, Cook-Medley and SF-36 questionnaires.

3. Physiologic markers of stress using 24 hour urinary cortisol and catecholamines

7. DATA ANALYSIS METHODS

7.1. Sample Size

A minimum of **********patients will be recruited to commence the study in order to detect the minimum relevant clinical difference at a statistical power of 80 % and p=0.05. 7.2. Randomization

Twenty patients will be recruited from ******and randomized in a 1 Control (Conventional regime): 1 (ayurvedic regime) fashion and followed for at least two years.

7.3. General Consideration

As this is a randomized controlled trial, the primary analysis will be an intend-to-treat (ITT) analysis whereby all comparisons will be made on the basis of the treatment group to which patients are initially randomized.

A secondary as-treated analysis will also be performed based solely on those patients deemed to be evaluable throughout the study. This as-treated analysis will directly access the effectiveness of treatment regime with respect to the primary and secondary outcome variables.

7.4. Statistical Methods

Student‘t’ test and repeated measure ANOVA.

8. DATA COLLECTION

8.1. Demographics

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Demographic measure includes age, gender and race.

9. CLINICAL AND LAB PROCEDURES

9.1. Acueity ductoscopy is a patented optical system and ductoscope, about the size of a pencil tip, enable physicians to look through the nipple directly into the milk ducts -- areas previously inaccessible to medical intervention -- where 85% of breast cancer develops.  Their  system of microendoscopes, coupled with patented OptiCueTM optical technology results in large, clear and sharp video images of the mammary duct system, with unprecedented depth of field perception and detects lesions as small as 0.2 mm in diameter (50 times more sensitive than a standard mammogram)

9.2. Amas test :  This test can be the first choice to check for breast cancer. The AMAS test detects malignant growth only (not benign tumors) and is more sensitive than mammograms. If the AMAS is positive, further tests are warranted as the AMAS doesn't indicate Where the cancer is located, only that there is cancer within the body.   In addition, the AMAS test can be used to follow breast cancer patients who are in remission, since the AMAS returns to normal within 3 months after the breast tumor (and metastases, if present) are removed or eradicated.

9.3. CA 15.3 values are often elevated in patients with breast cancers. When there is a history of cancer among family members, patients may be advised to also do a breast mammogram. Besides breast cancer, other non-malignant conditions (eg. cirrhosis, benign diseases of ovaries & breast) have also been known to cause elevated CA 15.3 levels.

CA125 has become a widely used tumor marker which is measured most often in women with cancers of the reproductive system including the uterus, fallopian tubes and ovaries. Other cancers that may cause abnormal CA125 levels include cancer of the pancreas, lungs, breast and colon. However, CA125/CA125-II can be elevated during menstruation, pregnancy or in individuals with ovarian cysts, pericarditis, hepatitis, cirrhosis of the liver or peritonitis, an infection of the lining of the abdomen, and even in 1-2% of healthy individuals. Once a cancer is diagnosed, CA125/CA125-II levels may prove to be an effective indicator of the effectiveness of cancer treatment. A declining CA125/CA125-II value may indicate a good response to treatment and a favorable prognosis. Persistently rising CA125/CA125-II levels may be associated with a growing tumor, presence of tumor on the peritoneum that lines the abdomen or a recurrence of a previously treated tumor. Additional evaluation is necessary to make such determinations. CA 125-II, an improved version of the original CA 125 assay, is now commercially available.

9.4. DR-70 is a simple blood test that screens for 13 different cancers at the same time. It

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is highly specific and catches cancer long before you would suspect anything was amiss. Cancers that can be detected by the test are of the lung, colon, breast, stomach, liver, rectum, ovary, cervix, esophagus, thyroid, and pancreas, and trophoblast and malignant lymphoma. AMDL has also received clearance from the FDA to market the PyloriProbe™ test, which can detect the presence of Helicobacter Pylori in the stomach, the primary cause of ulcers and a potential cause of stomach cancer.

9.5. Thermography  uses thermal imaging which detects new blood vessels and chemical changes associated with a tumor’s genesis and growth. Thermography measures the radiation of infrared heat from our body and translates this information into anatomical images.  Thermography offers a very early warning system, often able to pinpoint a cancer process years before it would be detectable by mammography. This approach can detect cancer when they are at a minute physical stage of development, when it is still relatively easy to halt and reverse the progression of the cancer.  Most breast tumors have been growing slowly for up to 20 years before they are found by typical diagnostic techniques. When used as part of a multi-modal approach (clinical examination + mammography + thermography) 95% of early stage cancers can be detected.

9.5. T/Tn Antigen Test developed by Dr. Georg Springer can detect the majority of cancers before any biopsy can pick up the presence of cancer.  The T and Tn antigens are proteins on the surface of blood and skin cells and can be identified by the immune system antibodies. The concentration of these antigens vary depending on the cancer type and stage.  A skin prick can predict or indicate the likely development of cancers, even 6-10 years in advance of other tests. The test appears to successfully diagnosis about 94% of lung cancers and 80% of breast cancers. More information about the test can be obtained by calling the Chicago Medical School at (847) 578-3435.

9.6. Clinical Laboratory Assesments

1. Haematology

5ml blood in to EDTA will be screened for

RBC count

Hb%

WBC count

TLC

DLC

MCV

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MCH

MCHC

Platelet count

2. Biochemistry

10ml blood in to heparinised tubes to screen for:

Serum uric acid

Glucose

Albumin

Total protein

Total bilirubin

Urea

Creatinine

Total cholesterol

HDL

LDL

Triglyceride

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4. Laurance, Jeremy. "Breast cancer cases rise 80% since Seventies", The Independent, 2006-09-29. Retrieved on 2006-10-09.  5. Breast Cancer: Statistics on Incidence, Survival, and Screening. Imaginis Corporation (2006). Retrieved on 2006-10-09.

6. Male Breast Cancer Treatment - National Cancer Institute. National Cancer Institute (2006). Retrieved on 2006-10-16.

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40. Chauhan, K. (1995) - Successful treatment of throat cancer with Ayurvedic drugs, Sachitra Ayurved 47, 11, 840-842.

41. Chauhan, Kashinath R. (1998) - Clinical study and research on phupphus arbud, Sachitra Ayurved 51, 2, 129-130.

42. Chen, S., X.Z. Sun, Y.C. Kao, A. Kwon, D. Zhou and E. Eng (1998) - Suppression of breast cancer cell growth with grape juice, Pharmaceutical Biology 36 (Suppl.), 53-61. Chen, S.J., B.N. Wu, J.L. Yeh, Y.C. Lo, I.S. Chen and I.J. Chen (1995) - C-fiber-evoked autonomic cardiovascular effects after injection of Piper betle inflorescence extracts, Journal of Ethnopharmacology 45, 183-188.

43. Cragg, Gordon M. and David J. Newman (2005) - Plants as a source of anti-cancer agents, Journal of Ethnopharmacology 100, 1/2, 72-79.

44. Davis, L. and G. Kuttan (2000a) - Effect of Withania somnifera on 20-methylcholanthrene induced fibrosarcoma, Journal of Experimental Clinical Cancer Research 19, 2, 165-167.

45. Davis, Leemol and Girija Kuttan (2000b) - Effect of Withania somnifera on cyclophosphamide-nduced urotoxicity, Cancer Letters 148, 1, 9-17.

46. Dhokte, R.L. (1997) - Ranvila plant - an effective Ayurvedic therapy on cancer, Sachitra Ayurved 50, 6, 448-450.

47. Gupta, M., U.K. Mazumder, S. Chakrabarti, S. Bhattacharya, N. Rath and S.R. Bhawal (1997) - Anti-epileptic and anti-cancer activity of some indigenous plants, Indian Journal of Physiology and Allied Sciences 51, 53-56.

48. Jagetia, Ganesh Chandra, Vijayashree Nayak and M.S. Vidyasagar (1998) - Evaluation of the antineoplastic activity of guduchi (Tinospora cordifolia) in cultured HeLa cells, Cancer Letters 122, 1/2, 71-82.

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Anti Cancer Drug

49. Jeena, K. Jose, K.L. Joy and Ramadasan Kuttan (1999) - Effect of Emblica officinalis, Phyllanthus amarus and Picrorrhiza kurroa on N-nitrosodiethylamine induced hepatocarcinogenesis, Cancer Letters 136, 1, 11-16.

50. Jeune, M.A. Louis, J. Kumi-Diaka and J. Brown (2005) - Anticancer activities of pomegranate extracts and genistein in human breast cancer cells, Journal of Medicinal Food 8, 4, 469-475.

51. Kuttan, Ramadasan, P. Bhanumathy, K. Nirmala and M.C. George (1985) - Potential anticancer activity of turmeric (Curcuma longa), Cancer Letters 29, 2, 197-202.

52. Kuttan, R., P.C. Sudheeran and C.D. Joseph (1987) - Turmeric and curcumin as topical agents in cancer therapy, Tumori 73, 1, 29-31.

53. Lintrakul, P., S. Lipigorngoson, O. Namwong, A. Apisariyakul and F.W. Dunn (1997) - Inhibitory effect of dietary curcumin on skin carcinogenesis in mice, Cancer Letters 116, 2, 197-203.

54. Mathew, S., and G. Kuttan (1996) - Antioxidant activity of Tinospora cordifolia and its usefulness in the amelioration of cyclophosphamide induced toxicity, Amala Research Bulletin 16, 113-121; also in: Journal of Experimental and Clinical Cancer Research 16, 4, 1997, 407-411.

55. Menon, L.G., R. Kuttan and G. Kuttan (1996) - Inhibition of chemically induced carcinogenesis by rasayanas, an indigenous herbal preparation, Journal of Experimental and Clinical Cancer Research 15, 241-243.

56. Menon, L.G., R. Kuttan and G. Kuttan (1997) - Effect of rasayanas in the inhibition of lung metastasis induced by B16F-10 melanoma cells, Journal of Experimental and Clinical Cancer Research 16, 4, 365-368.

57. Mohanty, K.R. (1991) - Study in immunological alteration in cancer under the influence of indigenous drugs, M.D. thesis, B.H.U., Varanasi.

58. Saleem, Ammar, Michael Husheem, Pirkko Härkönen and Kalevi Pihlaja (2002) - Inhibition of cancer cell growth by crude extract and the phenolics of Termnalia chebula Retz. fruit, Journal of Ethnopharmacology 81, 3, 327-336.

59. Siddiqui, M. Badruzzaman (2003) - Anti-cancer drugs from traditional plants of Sitapur district (Uttar Pradesh), Ancient Science of Life 22, 3, 95-97. [plants mentioned: Azadirachta indica A.Juss., Cataranthus roseus (Linn.) G.Don, Delonix elata (Linn.) Gamble = D. regia (Bojer) Rafin., Euphorbia neriifolia Linn., Glycyrrhiza glabra Linn., Hydrolea zeylanica Vahl, Lygodium flexuosum (Linn.) Sw., Ocimum sanctum Linn., Papaver somniferum Linn., Polygonum barbatum Linn.]

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Anti Cancer Drug

60. Stich, H.F., H. Ohshima, B. Pignatelli, J. Michelon and H. Bartsch (1983) - Inhibitory effect of betel nut extracts on endogenous nitrosation in humans, Journal of the National Cancer Institute 70, 6, 1047-1050.

61. Subapriya, R. and S. Nagini (2003) - Ethanolic neem leaf extract protects against N-methyl-N-nitro-N-nitrosoguanidine induced gastric carcinogenesis, Asian Pacific Journal of Cancer Prevention 4, 215-223. [on nimba, Azadirachta indica A.Juss.]

62. Acharya, Durgesh Kumar (1994) - Herbomineral preparations as adjuvants to chemotherapy in breast cancer, The Antiseptic 91, 2, 67-70.

63. Acharya, Durgesh Kumar (2002) - Supportive treatment with herbal remedies along with external irradiation in cancer cervix patients (a review of 108 cancer cervix patients), The Antiseptic 99, 8, 299-301.

64. Agarwal, K.C. and R. Parks Jr. (1983) - Forskolin: a potential antinetastatic agent, Intern. J. Cancer 32, 801.

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