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Title
DECLARATION
CERTIFICATE
DEDICATION
ACKNOWLEDGEMENT
CONTENTS
Introduction
I Review of literature
1.1.Chemical carcinogens
1.1.1.Genotoxic carcinogens
1.1.1.1.Direct acting carcinogens (activation -independent)
1.1.1.2.Activation dependent carcinoger~s
a) Polycyclic and heterocyclic aromatic hydrocarbons
b) Carcinogenic nitrosamines and related compounds
c) Aromatic amines, amides and aminoazodyes
d) Nitroaryl compounds
e) Urethan
f) Naturally occurring carcinogens
1.1.1.3. Inorganic carcinogens
1.1.2. Epigenetic carcinogens
1.1.3. Mode of action of chemical carcinogens
1.2.Physical carcinogens
1.2.1. Radiation induced carcinogenesis
1.2.1.1. Ionizing radiations
1.2.1.2. Ultraviolet radiation
1.2.2. Mechanism of radiation carcinogenesis
1.3. Biological carcinogens
1.3.1. Oncogenic DNA virsues
1.3.2. Oncogenic RNA viruses (Retroviruses)
1.3.3. Oncogenes
1.3.4. Tumour suppressor genes
1.4.Cancer Therapy
1.4.1. Surgery
1.4.2.Radiation therapy
1.4.3. Chemotherapy
Table4 Classification of various types cancer chemotherapeutic agents and the mechanism of antitumour agents
1.4.3.1. Toxicity of chemotherapeutic agents
1.5. Hyperthermia
1.6.Combined modalities
1.6.1. Combination of chemotherapy and radiotherapy
1.6.2. Combination of chemotherapy and hyperthermia
1.6.3. Drug combinations
1.6.4. Role of free radicals in radiotherapy and chemotherapy
1.6.5. Radioprotectors and chemoprotectors
1.6.6. Antioxidants
1.7. Plant derived drugs
1.7.1. Colchicine
1.7.2. Vinca alkaloids
1.7.3. Podophyllotoxin
1.7.4. Ellipticine derivatives
1.7.5. Camptothecin
1.7.6. Ergot alkaloids
1.7.7. Tylophora alkaloids
1.7.8. Harringtonine
1.7.9. Benzylisoquinoline and aporphine alkaloids
1.7.10. Isoquinoline alkaloids
1.7.11. Berberis aristata, Dc
1.7.1 2. Berberis asiatica
1.7.13. Hydrastis canedensis (Goldenseal)
1.7.14. Berberine
Scope of the study
II Toxicity studies of Berberine and Coralyne
2.1. Introduction
2.2. Materials
2.3. Methods
2.3.1. Determination of toxicity of berberine through intraperitoneal administration
2.3.2. Determination of acute toxicity of berberine and coralyne given orally
2.3.3. Determination of subacute toxicity of berberine and coralyne given orally
2.3.4. Toxicity studies of berberine at therapeutic concentration
Results
Effect of berberine through intraperitoneal administration
Determination of acute toxicity of berberine and coralyne
Effect of subacute oral administration of berberine
Effect of subacute oral administration of coralyne
Effect of therapeutic concentration of berberine
DISCUSSION
III Cytotoxicity and antitumour activities of berberine and coralyne
3.1. Introduction
3.2. Materials
3.3. Methods
3.3.1. Determination of short term invitro cytotoxicity of berberine
3.3.2. Determination of cytotoxicity of Berberis aristata, berberine and coralyne in tissue culture
3.3.3. Determination of antitumour activity of berberine and its synthetic analoge coralyne
3.3.3.1. Ascites tumour
3.3.3.2. Solid tumour
3.3.4. Determination of antitumour activity of berberine in combination with other modality of treatment
3.3.4.1. Berberine and cyclophosphamide (CTX)
3.3.4.2. Berberine and radiation
3.3.4.3. Berberine and hyperthermia
3.3.5. Effect of berberine on the inhibition of DNA topoisomerases I and II
3.3.6. Determination of cdc 25 tyrosine phosphatase and cdq kinase inhibitory assays
Results
Synergistic effect of berberine along with other modalities
Cyclophosphamide
Radiation
Hyperthermia
Effect of berberine on DNA topoisomerases
DISCUSSION
IV Antioxidant activity of berberine and coralyne and anticarcinogenic activity of berberine
4.1. Introduction
4.2. Materials
4.3. Methods
4.3.1. Determination of antioxidant activities of berberine and coralyne
4.3.1.1. Determination of lipid peroxide formation induced by Fe2+ ascorbate system
4.3.1.2. Determination of hydroxyl radical scavenging activity
4.3.1.3. Determination of superoxide radical scavenging activity
4.3.1.4. Determination of nitric oxide radical scavenging activity
4.4. Determination of the effect of berberine on 20-methylcholanthrene induced sarcoma in mice
4.5. Determination of the effect of berberine on NDEA induced hepatocarcinogenesis
Results
Inhibition of lipid peroxidation by berberine and coralyne
Inhibition of superoxide radical by berberine and coralyne
Hydroxyl radical scavenging activity of berberine and coralyne
Inhibition of nitric oxide radical by berberine
Anticarcinogenic activity of berberine
Fig. 11: Effect of Berberine on 20 - methyl cholanthrene induced sarcoma development
DISCUSSION
Figare 18 (Plate No. 1) Effect of Berberhe on NDEA induced Hepatocarcinogenesis
a) Normal Liver
b) Liver section of normal rates
c) Control (NDEA alone)
d) Liver Section of NDEA alone treated rates
e) NDEA+Bebrine (25mg/kgbwt)
f) Liver Section of NDEA+Be1khe (25mgkgbwt)
g) NDEA+Berberine (5Omg/kgbwt)
h) Liver Section of NDEA+Berberine (50 mg/kgbwt)
V Role of berberine as radio and chemoprotector
5.1. Introduction
5.2. Materials
5.3. Methods
5.3.1. Effect of berberine on haematological parameters in mice after radiation treatment
5.3.2. Effect of berberine on body weights, organ weights and bone marrow cellularity after radiation treatment
5.3.3. Determination of the effect of berberine on radiation induced micronuclei formation
5.3.4. Determination of the effect of berberine on chromosomal aberrations (Bone marrow metaphase analysis)
5.3.5. Effect of berberine on the haematological parameters of mice after cyclophosphamide treatment
5.3.6. Effect of berberine on the bone-marrow cellularity after cyclophosphamide treatment
Results
Effect of berberine on total count (TC) and polymorphonuclear cells (PMN) in irradiated mice
Effect of berberine on Hb levels, body weight and organ weights in irradiated mice
Effect of berberine on bonemarrow cellularity of irradiated mice
Effet of berberine on radiation induced micronuclei formation
Fig. 21: Effect of Berberine on the relative organ weights of irradiated animals
Effect of berberine on radiation induced chromosomal aberrations
Effect of berberine on haematological parameters after cyclophosphamide treatment
Effect of cyclophosphamide administration on bonemarrow cellularity
DISCUSSION
VI Hepatoprotective effect of berberine
6.1. Introduction
6.2. Materials
6.3. Methods
6.3.1. Induction of acute hepatotoxicity by carbon tetrachloride (CCL)
6.3.2. Determination of the effect of bert erine on chronic CC4 induced Liver Fibrosis
6.3.3. Biochemical analysis
Results
Effect of berberine on acute carbontetrachloride (CCb) toxicity
Effect of berberine on chronic CC4 induced toxicity
DISCUSSION
Fig. 24. (Plate No.2) Effect of Berberine on acute and chronic administration of CC4
a) Liver section of normal rats
b) Liver section of control animals (chronic CCL)
c) Chronic administration of CC14 + Berberine (100mglkgbwt)
d) Control animals (acute CCI4)
e) Acute administration of CC14 + Berberine (lOOmg/kgbwt)
VII Summary and conclusion
APPENDIX
BIBILIOGRAPHY
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