Advanced study of natural sources of anti-cancer

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Advanced study of natural sources of anti-cancer

  1. 1. ADVANCED STUDY OF NATURAL SOURCES OF ANTI-CANCER AGENTS 1 RGR.SIDDHANTHI COLLEGE OF PHARMACY Tivoli gardens, Patny, Secunderabad. Abstract Natural products remain an important source of new drugs, new drug leads and new chemical entities. The plant based drug discovery resulted mainly in the development of anticancer agents including plants (vincristine, vinblastine, etoposide, paclitaxel, camptothecin, topotecan and irinotecan), marine organisms (citarabine, aplidine and dolastatin 10) and micro-organisms (dactinomycin, bleomycin and doxorubicin). Beside this there is numerous agents identified from fruits and vegetables can used in anticancer therapy. The agents include curcumin (turmeric), resveratrol (red grapes, peanuts and berries), genistein (soybean), diallyl sulfide (allium), S-allyl cysteine (allium), allicin (garlic), lycopene (tomato), capsaicin (red chilli), diosgenin (fenugreek), 6-gingerol (ginger), ellagic acid (pomegranate), ursolic acid (apple, pears, prunes), silymarin (milk thistle), anethol (anise, camphor, and fennel), catechins (green tea), eugenol (cloves), indole-3-carbinol (cruciferous vegetables), limonene (citrus fruits), beta carotene (carrots), and dietary fiber. In this review active principle derived from natural products are offering a great opportunity to evaluate not only totally new chemical classes of anticancer agents, but also novel lead compound and potentially relevant mechanisms of action. (bhanot, (2011) 09-26) Definition of Cancer There are many different forms of cancer. Their manifestation is a growth of cells and tissues, which differ in various aspects from the surrounding tissue. Cancers occur in all living things. All lifeforms share similar DNA and RNA blueprints and cell physiology. Therefore, the mechanisms for cancer development and methods for cancer treatment are similar. (http:/www.digital-recordings.com) How is Cancer formed? Cancer cells are formed from normal cells due to a modification / mutation of DNA and/or RNA. These modifications / mutations can occur spontaneously(II Law of Thermodynamics - increase of entropy) or they may be induced by other factors such as: nuclear radiation, electromagnetic
  2. 2. ADVANCED STUDY OF NATURAL SOURCES OF ANTI-CANCER AGENTS 2 RGR.SIDDHANTHI COLLEGE OF PHARMACY Tivoli gardens, Patny, Secunderabad. radiation (microwaves, X-rays, Gamma-rays, Ultraviolet-rays, etc.), viruses, bacteria and fungi, parasites (due to tissue inflamation/irritation), heat, chemicals in the air, water and food, mechanical cell-level injury, free radicals, evolution and ageing of DNA and RNA, etc. All these can produce mutations that may start cancer. Cancer can be called therefore "Entropic Disease" since it is associated with the increase of entropy of the organism to the point where the organism cannot correct this itself. External intervention is required to allow the organism to return to a stable entropic state. (http:/www.digital-recordings.com) Cancer cells are formed continuously in the organism (it is estimated that there are about 10,000 cancer cells at any given time in a healthy person). The question is why some of these result in macroscopic-level cancers and some don't. First, not all damaged cells can multiply and many of them die quickly. Those which have the potential to divide and form cancer are effectively destroyed by the various mechanisms available to the immune system. This process takes place continuously. Therefore cancer develops if the immune system is not working properly and/or the amount of cells produced is too great for the immune system to eliminate. The rate of DNA and RNA mutations can be too high under some conditions such as: unhealthy environment (due to radiation, chemicals, etc.), poor diet (unhealthy cell environment), people with genetic predispositions to mutations and people of advanced age (above 80). (http:/www.digital-recordings.com) Precursors of Cancer and Cancer Prevention A weak or non-functioning immune system, poor health, an unhealthy environment and advanced age (over 80) can contribute to cancer. In the majority of people cancer can be prevented with proper lifestyle which consists of a low-entropy diet, exercise, sleep, stress reduction, etc. In most cases cancer develops slowly over many years. With a positive change of lifestyle and healthy environment this trend can be reversed in the majority of cases (probably in 90% -> 95%) - the cancer will shrink and eventually disappear
  3. 3. ADVANCED STUDY OF NATURAL SOURCES OF ANTI-CANCER AGENTS 3 RGR.SIDDHANTHI COLLEGE OF PHARMACY Tivoli gardens, Patny, Secunderabad. (http:/www.digital-recordings.com) Mechanisms responsible for Cancer development Factors which produce cancer cells are: radiation (such as X-rays, nuclear, microwaves, cosmic, ultrasound, etc.), toxic cell environment, chemicals in the air, water and food, bacteria, viruses and fungi. Factors which suppress immune functions are the same factors as above plus poor diet, stress, lack of proper exercise and lack of sufficient rest and sleep. Traditional Treatment of Cancer Cancer can be a very scary thing. The survival rates of some cancers is very low and treatments are not very effective, if one uses traditional medicine (one estimate puts it at 3%). On top of that, cancer is demonized as this scary thing which is growing in you and is going to kill you. Many people feel helpless and put blind trust in traditional medicine for treatment. Traditional medicine is very good in detecting and monitoring cancer but it is very poor and ineffective in the treatment of cancer. Detection is good and aided by imaging techniques such as NMR, CT- scan, ultrasound, PET, etc. and many other chemical, genetic, tissue, etc. tests. Below a few conventional medical treatments techniques are mentioned: Radiation Therapy Attempts to locally destroy cancer cells with the various types of radiation such as X-ray, Gamma-ray, particle beams, isotopes, ultrasound, etc. Beams of radiation are focused mainly on the cancer growth and doses are calculated to minimize the collateral damage to surrounding tissues, which nevertheless occurs. This kind of treatment increases the entropy of the organism, suppresses the immune system, destroys healthy cells and potentially forms new mutated cells some of which could become cancerous (and possibly more dangerous than original cancer cells). Chemotherapy
  4. 4. ADVANCED STUDY OF NATURAL SOURCES OF ANTI-CANCER AGENTS 4 RGR.SIDDHANTHI COLLEGE OF PHARMACY Tivoli gardens, Patny, Secunderabad. This aims to destroy the cancer cells with various types of chemicals. The substances used are supposed to target mainly the cancer cells (sometimes via direct injection to cancer tissue) and doses are calculated to minimize the collateral damage to surrounding tissues, which nevertheless occurs. This kind of treatment increases the entropy of the organism, suppresses the immune system, forms a toxic cell environment, destroys healthy cells and potentially forms new mutated cells some of which could become cancerous (and more dangerous than original cancer cells). Surgery This is another very invasive technique. Underlying logistics is to locally remove cancer cells with as few healthy cells as possible. This in turn should stop any further growth, since there are no cancer cells left in the body. This is a wrong assumption, since it is very difficult to find the exact boundaries of the cancer growth and remove all cells. Besides that, cancer cells can enter the blood stream and lymphatic fluid during an operation and spread to other parts of the body. This kind of treatment also increases the entropy of the organism, suppresses the immune system and destroys healthy cells and organs. (http:/www.digital-recordings.com) All mentioned above methods are very invasive, destroy healthy cells and suppress the immune system. This approach leads to an increase of entropy of the organism and lowers the chances of recovery from cancer. All these methods are designed to treat symptoms (cancerous growth), not the cause of cancer (non-functioning immune system and factors contributing to cancer cells formation). Since the cause of cancer is not addressed and treatment is not provided, cancer will, in the majority of cases, spread and recur (the 5-year survival rate for conventional treatments quoted by The American Cancer Society is 63% and it is much lower for longer periods of time - one estimate puts it at 3%). Very often cancer patients in hospitals are consuming poor quality food with hydrogenated fats, which are very unhealthy and dangerous. This only illustrates that a holistic approach is not considered or followed. Cancer treatment is a very good money-making machine/system and the patients' welfare is largely ignored.
  5. 5. ADVANCED STUDY OF NATURAL SOURCES OF ANTI-CANCER AGENTS 5 RGR.SIDDHANTHI COLLEGE OF PHARMACY Tivoli gardens, Patny, Secunderabad. The described above methods are primitive and barbaric. As a result, millions of people die prematurely while suffering (according to WHO, the World Health Organization, 7.6 million people died of cancer in the year 2005). There is also a great effort, burden and expense which is put on the families and society at large. The only explanation for this state of affairs is total scientific incompetence, greed and lack of integrity and moral standards on the part of the majority of cancer researchers and people and organizations who deliver cancer treatments (and consume billions of dollars in public funding in the process). (http:/www.digital-recordings.com) What are Anti-Cancer agents? Anti-cancer agents are the drugs which are used in the treatment of cancer; "anticancer drug"; "an antineoplastic effect" Plants as source of anti-cancer agents: The history of plant as source of anti-cancer agents started in earnest in the 1950s with the discovery and development of the vinca alkaloids (vinblastine and vincristine) and the isolation of the cytotoxic podophyllotoxins. Vinca alkaloid was responsible for an increase in the cure rates for Hodgkin’s disease and some forms of leukemia. Vincristine inhibits microtubule assembly, inducing tubulin self-association into coiled spiral aggregates. Etoposide is a epipodophyllotoxin, derived from the mandrake plant Podophyllum peltatum andthe wild chervil Podophyllum emodi. It has also significant activity against small-cell lung carcinoma. Etoposide is a topoisomerase II inhibitor, stabilizing enzyme–DNA cleavable complexes leading to DNA breaks. The taxanes paclitaxel and docetaxel has been show antitumor activity against breast, ovarian and other tumor types in the clinic trial. Paclitaxel stabilizes microtubules and leading to mitotic arrest. In addition, the camptothecin derivatives irinotecan and topotecan, have shown significant antitumor activity against colorectal and ovarian cancer respectively. These compounds were initially obtained from the bark and wood of Nyssacea Camptotheca accuminata and act by inhibiting topoisomerase I. The taxanes and the camptothecins are presently approved for human use in various countries (Table 1). (avidon, 1974)
  6. 6. ADVANCED STUDY OF NATURAL SOURCES OF ANTI-CANCER AGENTS 6 RGR.SIDDHANTHI COLLEGE OF PHARMACY Tivoli gardens, Patny, Secunderabad. Table 1: Plant based anticancer agents in clinical practice. S.No. Compound Uses Status 1. Vincristine Leukemia, lymphoma, Phase breast, lung, pediatric III/IV solid cancers and others 2. Vinblastine Breast, lymphoma, Phase germ-cell and renal III/IV cancer 3. Paclitaxel Ovary, breast, lung, Phase bladder and head and III/IV neck cancer 4. Docetaxel Breast and lung cancer Phase III 5. Topotecan Ovarian, lung and Phase pediatric cancer II/III 6. Irinotecan Colorectal and lung Phase cancer. II/III Rohitukine the plant alkaloid, isolated from the leaves and stems of Dysoxylum binectariferum (Maliaceae). Synthetic flavone derived from rohitukine, Flavopiridol representing the first cyclin-dependent kinase inhibitor to enter the clinical trial. The mechanism of action involves interfering with the phosphorylation of cyclin-dependent kinases and arrest cell-cycle progression at growth phase G1 or G2. (avidon, 1974) Homoharringtonine an alkaloid isolated from the Chinese tree Cephalotaxus harringtonia (Cephalotaxacea). The mechanism of action is the inhibition of protein synthesis and blocking
  7. 7. ADVANCED STUDY OF NATURAL SOURCES OF ANTI-CANCER AGENTS 7 RGR.SIDDHANTHI COLLEGE OF PHARMACY Tivoli gardens, Patny, Secunderabad. cell-cycle progression. It has shown efficacy against various leukemias. A lung-cancer-specific antineoplastic agent 4-Ipomeanol is isolated from the sweet potato Ipomoea batata (Convolvulaceae). The mechanism of action is converted into DNA-binding metabolites upon metabolic activation by cytochrome P450 enzymes that are present in cells of the lung. DNA topoisomerase I inhibitor β-lapachone, that induces cell-cycle delay at G1 or S (synthesis) phase before inducing either apoptotic or necrotic cell death in a variety of human carcinoma cells, including ovary, colon, lung, prostate and breast. Beside this there are so many plants which are used in cancer; following enlist the plant which prevent and target for future studies as potential anticancer agent (Table 2): Plants used as anti-cancer: S.No Plant Species Family Plant Part 1. Salvia officinalis Labiatae Leaves 2. Viscum album Loranthaceae Leaves 3. Combretum caffrum Combretaceae Bark 4. Melaleuca alternifolia Myrtaceae Leaves 5. Lavandula angustifolia Labiatae Leaves 6. Aglaia foveolata Meliaceae Fruit 7. Maytenus serrata Celastraceae Seed 8. Tabebuia impetiginosa Bignoniaceae Stem bark and trunk wood 9. Tabebuia rosea Bignoniaceae Stem bark and trunk wood 10. Tabebuia serratifolia Bignoniaceae Stem bark and trunk wood 11. Dipteryx odorata Fabaceae Seed 12. Thapsia garganica Apiaceae Fruit 13. Indigofera tinctoria Leguminosae Aerial part 14. Matricaria chamomilla Asteraceae Flower 15. Erythroxylum pervillei Erythroxylaceae Root 16. Broussonetia papyrifera Urticaceae Entire 17. Cyclopia intermedia Fabaceae Leaves 18. Scutellariae radix, Scutellariae Labiatae Root
  8. 8. ADVANCED STUDY OF NATURAL SOURCES OF ANTI-CANCER AGENTS 8 RGR.SIDDHANTHI COLLEGE OF PHARMACY Tivoli gardens, Patny, Secunderabad. indica 19. Physalis philadelphica Solanaceae Seed 20. Dysoxylum binectariferum Meliaceae Stem bark 21. Aristotelia chilensis Elaeocarpaceae Leaf and Stem 22. Cyathostemma argentium Annonaceae Root 23. Epimedium hunanense Berberidaceae Aerial parts 24. Croton urucurama Euphorbiacaeae Bark 25. Epilobium hirsutum Onagraceae Entire 26. Pleione bulbocodioides Orchidaceae Tuber 27. Cassia quinquangulata Caesalpiniaceae Root 28. Begonia glabra Begoniaceae Entire 29. Celastrus orbiculatus Celastraceae Entire 30. Croton draco Euphorbiacaeae Aerial parts 31. Smilax sieboldii Liliaceae Entire 32. Ximenia Americana Olacaceae Root 33 Maytenus emarginata Celastraceae Entire 34 Sarcandra glabra Choranthaceae Entire 35 Salvia plebeian Labiatae Aerial 36 Scutellaria barbata Labiatae Entire 37 Ocotea caparrapi Lauraceae Essential oil 38 Caragana cuneata Leguminosae Leaf 39 Croton flavens Euphorbiacaeae Leaf 40 Euphorbia heterophylla Euphorbiacaeae Stem 41 Echites vucatanensis Apocynaceae Latex 42 Thevetia ahouia Apocynaceae Leaf and Stem 43 Thevetia gaumeri Apocynaceae Leaf and Stem 44 Thevetia peruciana Apocynaceae Leaf and Stem 45 Euphorbia ebracteolata Euphorbiacaeae Aerial parts
  9. 9. ADVANCED STUDY OF NATURAL SOURCES OF ANTI-CANCER AGENTS 9 RGR.SIDDHANTHI COLLEGE OF PHARMACY Tivoli gardens, Patny, Secunderabad. 46 Dioscorea collettii Dioscoreaceae Rhizome 47 Juglans mandshurica Juglandaceae Root 48 Maackia tenuifolia Leguminosae Root 49 Juncus acutus Juncaceae Leaf 50 Hedyotis chrysotricha Rubiaceae Entire 51 Arisaema erubescens Araceae Root 52 Leptadenia hastate Asclepiadaceae Bark 53 Viscum calcaratum Loranthaceae Entire 54 Aphanamixis polystachya Meliaceae Stembark 55 Pratia nummularia Campanulaceae Entire 56 Aeonium arboretum Crassulaceae Leaf 57 Ocotea foetens Lauraceae Branchlets 58 Maytenus canariensis Celastraceae Fruit juice 59 Sedum alboroseum Crassulaceae Entire 60 Euphorbia micractina Euphorbiacaeae Entire 61 Euphorbia prolifera Euphorbiacaeae Latex 62 Scirpus holoschoenus Cyperaceae Inflorescence 63 Dillenia suffruticosa Dilleniaceae Fruit 64 Hypoxis rooperii Hypoxiaceae Tuber 65 Inula linariaefolia Compositae Flowers 66 Ziziphus mauritiana Rhamnaceae Stem bark and Fruit 67 Adiantum macrophyllum Pteridaceae Entire 68 Thalictrum fabri Ranunculaceae Root 69 Scutellaria indica Labiatae Root 70 Hypericum japonicum Guttiferae Entire 71 Cyathea fauriei Cyatheaceae Shoot 72 Fissistigma oldhamii Annonaceae Stem 73 Monnina obtusifolia Polygalaceae Aerial parts 74 Coriolus versicolor Polyporaceae Fruitbody
  10. 10. ADVANCED STUDY OF NATURAL SOURCES OF ANTI-CANCER AGENTS 10 RGR.SIDDHANTHI COLLEGE OF PHARMACY Tivoli gardens, Patny, Secunderabad. (http:/www.arjournals.org/index.php/ijpm/index) PLANT DESCRIPTION: The following chemical compounds were selected for the study, the predicted structures are obtained from the Pub-Chem. database of National Centre for Biotechnology I information. (burov, V.V, & korolchenko, 1990) 1. Taxol Belongs to the family of drugs called mitotic inhibitors. It is obtained via a semi-synthetic process from Taxusbaccata and other species of Taxus (Yew trees). It is approved for treating certain cancers like breast cancer, ovarian Cancer and lung cancer. 4. Topotecan (a camptothecin derivative) Belongs to the family of drugs called topoisomerase inhibitors. It is also called Hycamtin. Camptothecin, a quinoline-based alkaloid is isolated from Nothapodytesfoetida. It has been approved for ovarian cancer therapy. 5. Irinotecan Belongs to a family of drugs called topoisomerase inhibitors. It is a camptothecinanalog and isolated from Nothapodytesfoetida. Also called CPT 11. It is approved for metastatic colorectal cancers. 7. Teniposide 75 Melastoma malabathricum Melatomataceae Flower 76 Carapa guianensis Meliaceae Seed oil 77 Swietenia humilis Meliaceae Seed 78 Ficus pretoiae Moraceae Sap
  11. 11. ADVANCED STUDY OF NATURAL SOURCES OF ANTI-CANCER AGENTS 11 RGR.SIDDHANTHI COLLEGE OF PHARMACY Tivoli gardens, Patny, Secunderabad. Belongs to the family of drugs called mitotic inhibitors.Teniposide is a semisynthetic podophyllotoxin derived from the root of Podophyllumpeltatum (the May apple or mandrake). It is used for treating Acute lymphocytic leukemia and neuroblastoma. Vinca alkaloids: Vinca minor (common names lesser periwinkle or dwarf periwinkle) is a species offlowering plant native to central and southern Europe, from Portugal and France north to the Netherlands and the Baltic States, east to the Caucasus, and also south western Asia in Turkey. Other vernacular names used in cultivation include small periwinkle, common periwinkle, and sometimes in the United States, myrtle or creeping myrtle,although this is misleading, as the name myrtle normally refers to the Myrtus species. (Farnsworth, Draus, R.W., & Bianculli) Chemical constituents: Vinca minor contains more than 50 alkaloids, and vincamine is the molecule responsible for Vinca's nootropic activity.Otheralkaloidsinclude reserpine, reserpinine,akuammicine, majdine , vinerine, ervine, vineridine, tombozine, vincamajine, vincanine,vincanidine,vincamone, apovin camine, vincaminol, desoxyvincaminol,[10] vincorine[11] and perivincine. Vinpocetine (brand names: Cavinton, Intelectol; chemical name: ethyl apovincaminate) is a semisynthetic derivative alkaloid of vincamine. Vinblastine Belongs to the family of plant drugs called vinca alkaloids. It is a mitotic inhibitor. Vinblastine alkaloid is extracted from Catharanthusroseus. It is used in the treatment for some types of cancer including leukaemia, lymphoma, breast and lung cancer.
  12. 12. ADVANCED STUDY OF NATURAL SOURCES OF ANTI-CANCER AGENTS 12 RGR.SIDDHANTHI COLLEGE OF PHARMACY Tivoli gardens, Patny, Secunderabad. Chemical structure: Vincristine: TradeNames: Oncovin ® , Vincasar,Pfs ® Other Names: Vincristine Sulfate, LCR, VCR Belongs to the family of plant drugs called vinca alkaloids. Vincristine alkaloid is extracted from Catharanthus roseus, belonging to the family Apocynaceae. This species is also known as Vincarosea and has the alternative common name of Vinca. Vincristine is an alkaloid derived from flowering periwinkle. Vincristine is used as a chemotherapeutic agent for some types of cancers including leukaemia, lymphoma, breast and lung cancer.
  13. 13. ADVANCED STUDY OF NATURAL SOURCES OF ANTI-CANCER AGENTS 13 RGR.SIDDHANTHI COLLEGE OF PHARMACY Tivoli gardens, Patny, Secunderabad. Drug Type: Vincristine is an anti-cancer ("antineoplastic" or "cytotoxic") chemotherapy drug. Vincristine is classified as a plant alkaloid. For more detail, see "How Vincristine Works" section below. What Vincristine Is Used For: Cancers treated with Vincristine include: acute leukemia, Hodgkin's and non- Hodgkin's lymphoma, neuroblastoma, rhabdomyosarcoma, Ewing's sarcoma, Wilms' tumor, multiple myeloma, chronic leukemias, thyroid cancer, brain tumors. It is also used to treat some blood disorders. Note: If a drug has been approved for one use, physicians sometimes elect to use this same drug for other problems if they believe it might be helpful. (chemocare) How Vincristine Is Given: Vincristine is given through a vein by intravenous injection (IV push) or infusion (IV). There is no pill form. Vincristine is a vesicant. A vesicant is a chemical that causes extensive tissue damage and blistering if it escapes from the vein. The nurse or doctor who gives Vincristine must be carefully trained. If you notice pain, redness or swelling at the IV site while you are receiving Vincristine sulfate, alert your health care professional immediately. The amount of Vincristine you will receive depends on many factors, including your height and weight, your general health or other health problems, and the type of cancer you have. Your doctor will determine your dose and schedule. Vincristine Side Effects: Important things to remember about the side effects of Vincristine:
  14. 14. ADVANCED STUDY OF NATURAL SOURCES OF ANTI-CANCER AGENTS 14 RGR.SIDDHANTHI COLLEGE OF PHARMACY Tivoli gardens, Patny, Secunderabad. Most people do not experience all of the side effects listed. Side effects are often predictable in terms of their onset and duration. Side effects are almost always reversible and will go away after treatment is complete. There are many options to help minimize or prevent side effects. There is no relationship between the presence or severity of side effects and the effectiveness of Vincristine. The following side effects are common (occurring in greater than 30%) for patients taking Vincristine: Hair loss (in 20-70% of patients) may be partial or complete hair loss Constipation Low blood counts. Your white and red blood cells and platelets may temporarily decrease. This can put you at increased risk for infection, anaemia and/or bleeding. Nadir: Meaning low point, nadir is the point in time between chemotherapy cycles in which you experience low blood counts. Onset: 7 days Nadir: 7-10 days Recovery: 21 days Abdominal cramps Weight loss Nausea and vomiting Mouth sores Diarrhea Loss of appetite Taste changes (chemocare) Chemical structure:
  15. 15. ADVANCED STUDY OF NATURAL SOURCES OF ANTI-CANCER AGENTS 15 RGR.SIDDHANTHI COLLEGE OF PHARMACY Tivoli gardens, Patny, Secunderabad. Color: The color name periwinkle is derived from the flower. EXTRACTION PROCEDURES: Vincristine and vinblastine: A sensitive and selective high-performance liquid chromatographic (HPLC) method for the determination of vinblastine and vincristine in plasma and urine is described. The drugs are isolated from 1.0 ml of the biological fluid with a solid-phase extraction column (Bond- ElutDiol® ). The HPLC method was combined with electrochemical detection at +850 mV versus an Ag/AgCl reference electrode. The detection limit is 100 pg for vinblastine and 250 pg for vincristine with a signal-to-noise ratio of 3, which permits the determination of these compounds in biological fluids at the nanogram level. Evaluation of the isolation method revealed that the drug recoveries and the reproducibility of the extraction procedure depend on the batch number of the solid-phase extraction column used. Pharmacology: The vinca alkaloid vincristine induces cytotoxicity by interacting with and disrupting microtubules, especially those comprising the mitotic spindle apparatus (Rowinsky&Donehower, 1996). Vincristine may bind at low-density high-affinity sites at the ends of the microtubule, with the effect of inhibiting microtubule assembly, and at low-affinity high-density sites along the wall of the microtubule, causing disruption of microtubule architecture. For human leukaemia
  16. 16. ADVANCED STUDY OF NATURAL SOURCES OF ANTI-CANCER AGENTS 16 RGR.SIDDHANTHI COLLEGE OF PHARMACY Tivoli gardens, Patny, Secunderabad. cell lines, vincristine causes apoptotic cell death in a manner which relates to the concentration and time of exposure to the drug (da Silva et al, 1996). For CCRF-CEM and Jurkat cells, maximum cytotoxicity was found when cells were exposed to 3 µM and 0·1 µM of vincristine for 72 h respectively. However, the cytotoxicity of vincristine is subject to the inoculum effect, in which an increase in cell density causes a reduction in the intracellular levels and therefore cytotoxicity of a given dose of the drug (Kobayashi et al, 1992). For Molt-3 cells, maximum cell kill is associated with 25% saturation of the cellular vincristine binding sites, and the lesser effect of the drug at high cell density could be explained by the lack of drug molecules to saturate cellular binding sites sufficiently (Kobayashi et al, 1998). In most experimental models, resistance to vincristine is associated with decreased drug accumulation and retention, a phenomenon which is usually associated with the cellular expression of P-glycoprotein and the MDR phenotype (Rowinsky&Donehower, 1996). Single-agent studies of vincristine in the therapy of childhood ALL were performed in the 1960s, mainly in children with disease which had relapsed after therapy with methotrexate and 6- mercaptopurine. With doses of 0·06 mg/kg/week (Heyn et al, 1966) or 2 mg/m2 /week (Karon et al, 1966), complete remission (CR) rates of 50–60% were obtained, although the study of Karon et al (1966) suggested that vincristine had no advantage over a placebo in remission maintenance. However, monthly pulses of vincristine, in association with prednisolone, have been shown to improve the disease-free survival of children with ALL (Bleyer et al, 1991; Childhood ALL Collaborative Group, 1996). In modern protocols for the therapy of childhood ALL, vincristine forms one of the mainstays of remission induction therapy. In most protocols, vincristine is administered during remission induction as a weekly intravenous bolus at a dose of 1·5 mg/m2 (Chessells et al, 1995; Evans et al, 1998) or 2·0 mg/m2 (Veerman et al, 1996), and the maximum dose is conventionally capped at 2–2·5 mg in view of the risk of toxicity (Rowinsky&Donehower, 1996). Vincristine also plays a role in the intensification/consolidation therapy (Chessells et al, 1995; Nachman et al, 1998) and maintenance therapy (Chessells et al, 1995; Veerman et al, 1996) of ALL in many protocols. The clinical pharmacology of vincristine has been investigated for children with ALL. After bolus intravenous administration, the pharmacokinetics of vincristine are characterized by large inter- and intrapatient variations in parameters such as clearance, volume of distribution and
  17. 17. ADVANCED STUDY OF NATURAL SOURCES OF ANTI-CANCER AGENTS 17 RGR.SIDDHANTHI COLLEGE OF PHARMACY Tivoli gardens, Patny, Secunderabad. elimination half-life (Gidding et al, 1999). Peak plasma concentrations of 100–400 nM are only briefly achieved after an intravenous bolus of vincristine; the t1/2α (initial or elimination half-life) of approximately 8 min reflecting the rapid cellular uptake and extensive tissue binding of the drug. Indeed, in the majority of children, plasma levels fall to below 5 nm by 60 min (de Graaf et al, 1995), and the long t1/2β (half-life of the terminal phase of elimination) of approximately 14 h means that plasma levels of 1–2 nM are maintained for relatively long periods of time. Although the clearance values for children are generally greater than those for infants and adults (Gidding et al, 1999), it is not certain whether vincristine clearance decreases with age during childhood (Crom et al, 1994; Gidding et al, 1999). In addition, there is no clear relationship between vincristine neurotoxicity and systemic exposure (Crom et al, 1994). When administered as a continuous infusion of 0·5 mg/m2 /24 h for 5 d after a 1·5-mg/m2 intravenous loading dose, mean steady-state plasma vincristine concentrations of 1·7 nM are maintained with acceptable toxicity (Pinkerton et al, 1988). Although the cerebrospinal fluid (CSF) penetration of vincristine has not been determined in children, adult studies have shown vincristine levels in the CSF to be 20- to 30-fold lower than concurrent plasma concentrations (Rowinsky&Donehower, 1996). Vincristine is rapidly taken up by cells, and the ratio of intracellular to extracellular concentrations ranges from 150- to 500-fold for various human haemopoietic cell lines (Rowinsky&Donehower, 1996). For mice bearing human rhabdomyosarcomaxenografts, sensitivity to vincristine was associated with prolonged retention of the drug after a single intraperitoneal injection (Horton et al, 1988). The only studies of vincristine in relation to leukaemic blasts from children with ALL have related to in vitro drug sensitivity testing by means of the MTT assay (Klumper et al, 1995), in which a mean IC50of 0·71 µM (range <  0·05 to >  50) was demonstrated. In summary, although vincristine has an established role in the therapy of ALL, little is known of the relationship between the clinical and cellular pharmacology of the drug in vivo for childhood ALL. In vitro studies have highlighted the importance of the degree of saturation of vincristine binding sites and time of exposure for vincristine cytotoxicity in human leukaemia cell lines. Therefore, studies are needed to determine the relationship between systemic exposure to vincristine, as determined by pharmacokinetic measurements, and intracellular levels, binding site saturation and retention in leukaemic blasts. In this respect, a loading dose of vincristine
  18. 18. ADVANCED STUDY OF NATURAL SOURCES OF ANTI-CANCER AGENTS 18 RGR.SIDDHANTHI COLLEGE OF PHARMACY Tivoli gardens, Patny, Secunderabad. followed by a prolonged infusion (Pinkerton et al, 1988) may optimize therapy with this agent, especially in the initial stages of remission induction therapy when a high leukaemic burden could potentially generate a positive inoculum effect (Kobayashi et al, 1998). SCREENING METHOD: It has been claimed that the micronucleus test (MNT) is a simple and practical in vivo cytogenetic screening method for mutagens. To evaluate the MNT as an initial screening method, mice and Chinese hamsters were treated in vivo with triethylene melamine (0.016, 0.032, 0.062, 0.125, or 0.25 mg/kg), azathioprine (50, 200, or 500 mg/kg), colchicine (0.625, 1.25, or 2.5 mg/kg) or caffeine (100, 200, or 250 mg/kg). The treated animals were examined by means of the MNT, chromosome analysis (CA) and sister chromatid exchange (SCE) scoring. For the MNT and CA, each dose level was applied twice to 3–4 animals with an interval of 24 h. For the SCE test, the animals received a treatment with 5-bromodeoxyuridine (BUDR) and 5- fluorodeoxyuridine (FUDR), during which time the test compounds were administered once. Triethylene melamine was clearly positive in all three tests, whereas azathioprine was positive in the MNT and CA, but negative in the SCE. Colchicine was positive in the MNT, but negative in the other two tests. Caffeine gave negative results in all three tests. The results indicate that the MNT can detect not only chromosome-breaking agents but also spindle poisons. This is a great advantage over other cytogenetic methods as far as screening is concerned, as is the technical simplicity with which the test can be performed. Furthermore, the basic treatment for the in vivo SCE method using BUDR and FUDR was shown to be positive in the MNT and CA. A review of the literature dealing with the MNT in which the results of testing 150 agents are reported confirms the present findings, i.e., the usefulness of the MNT for screening clastogens and spindle poisons. We conclude that, among the various in vivo cytogenetic methods using mammalian somatic cells, the MNT is the most practical when applied as an initial screening test in laboratories in which a large number of compounds are to be tested
  19. 19. ADVANCED STUDY OF NATURAL SOURCES OF ANTI-CANCER AGENTS 19 RGR.SIDDHANTHI COLLEGE OF PHARMACY Tivoli gardens, Patny, Secunderabad. Etoposide : Belongs to the families of drugs called podophyllotoxin derivatives and topoisomerase inhibitors. Etoposide is a semisynthetic derivative of the podophyllotoxins, an epipodophyllotoxin. It is used in treating various types of cancers including bladder cancer, brain tumours, cervical cancer, ependyoma, germ cell tumor and gestationaltrophoblasticneoplasia. Trade names: Toposar® , VePesid® , Etopophos® Other name: VP-16, Etoposide phosphate EXTRACION PROCEDURE: Etoposide was extracted from 100 µL aliquots of plasma treated with deuteratedetoposide as the internal standard using an ether based liquid-liquid extraction (LLE). Following evaporation and reconstitution of the organic supernatant, HPLC separation was achieved on an Agilent Zorbax SB-C18 Chemocare.com uses generic names in all descriptions of drugs. VP-16 is the trade name for etoposide. VePesid and etopophos and toposar or etoposide phosphate are other names for etoposide. In some cases, health care professionals may use the trade name VP-16 or other names VePesid or etopophos or toposar or etoposide phosphate when referring to the generic drug name etoposide. (O'Dwyer PJ, 1985) Drug type: Etoposide is an anti-cancer ("antineoplastic" or "cytotoxic") chemotherapy drug. This medication is classified as a "plant alkaloid" and "topoisomerase II inhibitor." (For more detail, see "How this drug works" section below). What this drug is used for: Testicular, bladder, prostate, lung, stomach, and uterine, cancers. Hodgkin's and non-Hodgkin's lymphoma, mycosis fungoides, Kaposi's sarcoma, Wilm's tumor, rhabdomyosarcoma, Ewing's sarcoma, neuroblastoma, brain tumors. It also may be given as high-dose therapy in bone marrow transplant setting.
  20. 20. ADVANCED STUDY OF NATURAL SOURCES OF ANTI-CANCER AGENTS 20 RGR.SIDDHANTHI COLLEGE OF PHARMACY Tivoli gardens, Patny, Secunderabad. Note: If a drug has been approved for one use, physicians may elect to use this same drug for other problems if they believe it may be helpful. How this drug is given? In tablet form by mouth. As an infusion into the vein (intravenous, IV), as a short infusion or as a continuous infusion over 24 hours. Etoposide is considered an irritant. An irritant is a chemical that can cause inflammation of the vein through which it is given. If the medication escapes from the vein it can cause tissue damage. The nurse or doctor who gives this medication must be carefully trained. If you experience pain or notice redness or swelling at the IV site while you are receiving etoposide, alert your health care professional immediately. The amount of etoposide that you will receive and the method it is given depends on many factors, including your height and weight, your general health or other health problems, and the type of cancer or condition being treated. Your doctor will determine your dose, schedule and how it will be given. (chemocare, http://chemocare.com/chemotherapy/drug-info/etoposide.aspx#.ukK3-dKBk5E) chemical structure:
  21. 21. ADVANCED STUDY OF NATURAL SOURCES OF ANTI-CANCER AGENTS 21 RGR.SIDDHANTHI COLLEGE OF PHARMACY Tivoli gardens, Patny, Secunderabad. Pharmacology: Etoposide is a potent cytostatic. It seems to be more effective when administered in multiple than as a single dose. Its mode of action differs from that of mitosis inhibitors such as colchicine and the vinca alkaloids. It produces a therapeutic synergism with a number of drugs and this promises a considerable broadening of the range of indications for etoposide SCREENING METHOD: BMY-40481-30 is a new, water-soluble derivative and probable prodrug of etoposide characterized by the presence of a phosphate group in position 4′ of the E ring of the etoposide molecule. The compound was only weakly cytotoxic in vitro and, consequently, an investigation of its antitumor activity was conducted in several murine and human tumor (xenograft) models. Etoposide was administered ip or po whereas BMY-40481-30 was given ip, po or iv. The potency of the derivative, when administered parenterally, as defined on the basis of maximum tolerated dose (MTD), was less than the parent compound on a weight (mg/kg) basis in some experiments but comparable to etoposide in other instances. Comparison at the MTD of the two compounds showed that BMY-40481-30 administered ip was as active as etoposide against ip P388 leukemia. BMY-40481-30 given iv was more active than etoposide given ip in two of five experiments versus iv P388 leukemia, but the two compounds were comparably active in the other three studies. Of particular interest was the finding that the derivative was more active than the parent compound at many of the comparable (on a mg/kg basis) dose levels of both evaluated po versus iv P388 leukemia; MTD levels were not achieved, and hence not compared, for either compound using the po route of administration. Both etoposide and BMY-40481-30 yielded
  22. 22. ADVANCED STUDY OF NATURAL SOURCES OF ANTI-CANCER AGENTS 22 RGR.SIDDHANTHI COLLEGE OF PHARMACY Tivoli gardens, Patny, Secunderabad. comparable maximum effects against ic P388 leukemia, ic L1210 leukemia, and sc B16 melanoma, but etoposide was more efficacious versus sc M5076 sarcoma. In addition to murine tumors, the HCT-116 human colon carcinoma was tested in a subrenal capsule model in athymic (nude) mice; both compounds demonstrated similar tumor inhibitory effects. Lastly, the human lung carcinomas, LX-1 and H2981, implanted sc into nude mice, showed either equivalent sensitivity to etoposide and BMY-40481-30, or a slightly enhanced sensitivity to the parent compound, in several experiments performed. BMY-40481-30 is a novel derivative and probable prodrug of etoposide with excellent solubility in water and antitumor activity generally comparable to that of the parent compound as demonstrated in several preclinical models. CHEMICAL STRUCTURE OF ANTICANCER DRUGS Taxol: Biological activity is the result of chemical compound's interaction with biological entity. In clinical study biological entity is represented by human organism. In preclinical testing it is the experimental animals (in vivo) and experimental models (in vitro). Biological activity depends on peculiarities of compound (structure and physico-chemical properties), biological entity (species, sex, age, etc.), mode of treatment (dose, route, etc.). Any biologically active compound reveals wide spectrum of different effects. Some of them are useful in treatment of definite diseases but the others cause various side and toxic effects. Total complex of activities caused by the compound in biological entities is called the "biological activity spectrum of the substance".Biological activity spectrum of a compound presents every its activity despite of the difference in essential conditions of its experimental determination. Then the results are
  23. 23. ADVANCED STUDY OF NATURAL SOURCES OF ANTI-CANCER AGENTS 23 RGR.SIDDHANTHI COLLEGE OF PHARMACY Tivoli gardens, Patny, Secunderabad. validated and predicted., In case when the probabilities for more than 400 different activities are estimated simultaneously, and the ideal training set should include all referenced biologically active compounds from literature, the best estimate of prediction's quality can be calculated by leave one out cross validation. Each of the compounds is subsequently removed from the training set and the prediction of its activity spectrum is carried out on the basis of the remaining part of the training set. The result is compared to the known activity of a compound, and the maximal error of prediction (MEP) is calculated through the all compounds and activities. Etaposide and Irinotecan are DNA intercalators. Now a bandwith of drugs for the cancer treatment is analysed,it must be improved and lot of studies have to be continued to ensure its activity invitro and invivo. (50 x 2.1mm, 5 micron) column. A mobile phase gradient operating at a flow of 300 µL/min increased from 25 to 90 %B over 2 minutes where mobile phase A was 10 mM ammonium acetate (aq) acidified with 0.1% formic acid and mobile phase B was acetonitrile:methanol:formic acid (50:50:0.1, v:v:v). An LLOQ of 1.00 ng/mL was achieved using multiple reaction monitoring of the etoposide-ammonium adduct ion on an AB Sciex API 4000™ operating in positive ESI. Paclitaxel: An isocratic high-performance liquid chromatographic method has been developed and validated for the quantitative determination of paclitaxel (Taxol® ), a novel antimitotic, anticancer agent, in human plasma. The analysis required 0.5 ml of plasma, and was accomplished by detection of the UV absorbance of paclitaxel at 227 nm following extraction and concentration. The method involved extraction of paclitaxel from plasma, buffered with 0.5 ml of 0.2 M ammonium acetate (pH 5.0), onto 1-ml cyano Bond Elut columns. The eluent was evaporated under nitrogen and low heat, and reconstituted with the mobile phase, acetonitrile-methanol-water (4:1:5, v/v/v) containing 0.01 M ammonium acetate (pH 5.0). The samples were chromatographed on a reversed-phase octyl 5 μm column. The retention time of paclitaxel was 10 min. The validated quantitation range of the method was 10–1000 ng/ml (0.012–1.17 μM) of paclitaxel in plasma. Standard curve correlation coefficients of 0.995 or greater were obtained during validation experiments and analysis of clinical study samples. The observed recovery for paclitaxel was 83%. Epitaxol, a biologically active stereoisomer, and baccatin III, a degradation product, were also chromatographically separated from taxol by this assay. The method was applied to samples
  24. 24. ADVANCED STUDY OF NATURAL SOURCES OF ANTI-CANCER AGENTS 24 RGR.SIDDHANTHI COLLEGE OF PHARMACY Tivoli gardens, Patny, Secunderabad. from a clinical study of paclitaxel in cancer patients, providing a pharmacokinetic profiling of paclitaxel. Combinations of the herbal drugs to be given to anti-cancer patient: (1) Drugs and Herbs of Ayurveda used according to specific system location (a) Brain Cancer - Ayurvedic Herbs –Mandukaparni (Bacopa monerea) -Kastoori Bhairav Rasa with combination of divya herbs. (b) Oropharyngeal Cancers - Ayurveda Herbs – Kasamarda (cassia oxidentalis) -Mahalaxmi vilas Rasa (c) Lung Cancers - Ayurveda Herbs - Pippali (Piper longum) -Hirak Rasayan (d) Stomach Cancers - Ayurveda Herbs – Shatavari (Asparagus resimosus) -Amlaki (Philanthus amblica) -Banga Bhasma -Aloe-Vera -Amaltas (Casia fistula) -Bhoy-Amli (Philanthus nurare) -Sarphunkha (Tephrosia purpura) (e) Intestinal Cancers - Ayurveda Herbs -Shigru (Moringa olifera) -Panchamrut purpti
  25. 25. ADVANCED STUDY OF NATURAL SOURCES OF ANTI-CANCER AGENTS 25 RGR.SIDDHANTHI COLLEGE OF PHARMACY Tivoli gardens, Patny, Secunderabad. (f) Female Genital Cancers - Ayurvedic Herbs -Ashoka (Seraka Ashoka) -Vaikranta Bhasma (g) Mail Genital Cancers - Ayurveda herbs -Triphala (Three myrobelans) -Makardhvaja (h) Liver Cancers - Ayurveda Herbs -Bhumvamalaki -Arogyavardhini (i) Blood Cancer - Ayurveda Herbs -Anantmula (Hermidesmus indicus) -Suvarna Vasant Malti Rasa (j) Bone Cancers - Ayurveda Herbs -Aabha Gugglu -Madhu Malini Vasant Rasa (k) Breast Cancers - Ayurvedic Herbs -Gojivha -Chinchabhallataka (l) Skin Cancers - Ayurveda Herbs -Manjishtha (Rubia cordifolia) -Samira Panaga Rasa -Kaishore Gugglu -Gandhak Rasayan (2) Drugs of Ayurveda According to the general condition of the patient
  26. 26. ADVANCED STUDY OF NATURAL SOURCES OF ANTI-CANCER AGENTS 26 RGR.SIDDHANTHI COLLEGE OF PHARMACY Tivoli gardens, Patny, Secunderabad. -Sutashekhar rasa -Punarnava Mandura -Aarogya Vardhini -Avipattikar Churna -Kamadhugdha Rasa -Swarna Gairika -Laghu Vasant Malti -Hirak Bhasma (3) Drugs pf Ayurveda according to the Agni of the patient -Drakshasava -Swarna Makshika Bhasma -Shivakshara Pachan Churna -Chitrakadi Vati -Trifala Churna -Panchskhar Churna (4) Drugs of Ayurveda used in all cancers -Kanchnara Gugglu -Kaishore Gugglu -Bhallatak Phalmajja Churna -Trifala Gugglu -Tribang Bhasma -Shilajatu Vati -Aabha Gugglu -Laksha Gugglu (5) Drugs of Ayurveda according to Nadi
  27. 27. ADVANCED STUDY OF NATURAL SOURCES OF ANTI-CANCER AGENTS 27 RGR.SIDDHANTHI COLLEGE OF PHARMACY Tivoli gardens, Patny, Secunderabad. -Vishtinduka for Vatta Nadi -Katuki for Pitta Nadi -Bhallatak for Kapha Nadi -Combination of above for dvidosha Nadi -All three for Tridosh Nadi (6) Decoctions of Ayurveda for purification of body cells Prescribed to all patients. One, two or more from the following -Varunadi Kwath -Panchvalkal Kwath -Manjishthadi Kwath -Dashmula Kwath -Varunadi Kwath -Kanchnar Kwath (7) Drugs of Ayurveda for symptomatic relief -All Gugglu preparations for pain relief, and tumor reducing. -Gandhak Rasayan for infections -Bilva, Mayurpichha, Tankan, sphatika for loose motions and vomiting -Shigru, Chitrakadi vati for pain in the abdomen -Rohitaka, Shamaka yoga for pain in pancreas and renal colic. -Shirashooladi vajra rasa, for headaches -Beejapuraka and trikatu in jaundice -Vasa+Goat milk in bleeding -Aabha+Madhumandura in bone pain (8) DARF methodology to reduce the side effects of chemotherapy
  28. 28. ADVANCED STUDY OF NATURAL SOURCES OF ANTI-CANCER AGENTS 28 RGR.SIDDHANTHI COLLEGE OF PHARMACY Tivoli gardens, Patny, Secunderabad. Some of the most common side effects of chemotherapy -Mucositis- in the form of mouth ulcers, vomiting, loose motions etc. -Phlebitis-In the form of skin discolouration with veins paining -Leukopenia-In the form of low w.b.c. counts with increased chances of infection. -Hair loss Therapies three days prior to chemotherapy- -Sadhya Snehan-One teaspoon cow ghee+one teaspoon salt, mixed and consumed at morning, empty stomach with hot water. -Manjishthadi Kwath and Kanchnar Gugglu. During chemotherapy, coriander leaves juice frshly prepared about 20 to 30 gms, twice a day. Treatment during Radiotherapy -Sadhya snehan + Matra basti for three days -A piece of tamarind to be kept in mouth during R.T. is advised in mouth and throat cancers. -A vaginal tampon of Erand oil is applied daily in vaginal cervical and rectal cancers. -A mrudu virechan –Mild laxative is always advised during R.T, except in vaginal and cervical cancers. -Symptomatic treatment as per the situation is offered. (ayurveda-cancer.org) Present regimens: Why Are Our Anticancer Herbal Remedies Potent? The herbal remedies used at HCC are produced using high-techniques rather than traditional methods. We identified, analyzed and refined 16 new anticancer herbal remedies from >200 sorts of anticancer herbs. The active ingredients of our anticancer herbal remedies are extracted and concentrated using pharmaceutical industry processes of investigating western medicine.
  29. 29. ADVANCED STUDY OF NATURAL SOURCES OF ANTI-CANCER AGENTS 29 RGR.SIDDHANTHI COLLEGE OF PHARMACY Tivoli gardens, Patny, Secunderabad. To qualify and quantify the products the effective dose of anticancer herbal remedies has been examined at levels of microgram /ml by cancer killing tests in vitro, animal tumor models in vivo, and cancer patients in clinical studies at university hospitals. The anticancer herbal remedies are manufactured in GMP workshops and they are made in capsule forms. This is convenient to oral administration by patients. All anticancer herbal remedies meet with the US-FDA regulations and they are effective, safe, and only have slight side effects. There is no conflict in the treatment results between western medicine and herbal remedies. Both anticancer western medicine and anticancer herbal remedies can be used at the same time to attain synergetic effects. Clinical studies of CT scan and MRI imaging have shown regression and shrinking of cancer lesions in patients who received the standard anticancer herbal therapy at HCC. Why Are Anticancer Herbal Treatments Effective? Doctors at HCC are experienced herbal specialists. They have studied, trained and practiced western medicine and herbal medicine at Tongji Medical University in China, Hanover Medical School in Germany, and Harvard Medical School in the USA. By applying the principle of cell cycle in light of design of cancer treatment, they have developed 5 herbal treatment regimens, which exerts 1+1>3 therapeutic result. Therefore, their clients are more effectively treated compared to traditional and conventional herbal therapeutics.
  30. 30. ADVANCED STUDY OF NATURAL SOURCES OF ANTI-CANCER AGENTS 30 RGR.SIDDHANTHI COLLEGE OF PHARMACY Tivoli gardens, Patny, Secunderabad. Cocktail Herbal Therapy is to use the triple-anticancer herbal remedies plus a cocktail anticancer herbal extract liquid for treatment of conditions of cancer. Patients take 2 to 3 different hi-tech anticancer herbal capsules plus a cocktail herbal extract liquid at the same time to combat a cancer condition. One of the herbal remedies blocks mitosis of cancer cells in phase M, and 2 others attack cancer cells in phases G1, S and G2 by destroying the membranes of cancer cells, damaging mitochondria in the cytoplasm and microtubules in cytoskeleton, and splitting DNA in the nucleus. The cocktail herbal extract liquid is an anticancer enhancer that uplifts the therapeutic effect. Each of the anticancer herbal components in this regimen hits a key point of cancer cell cycle. The cocktail herbal therapy is usually used as an intensive cancer therapy for patients with critical cancer conditions. Intensive Herbal Therapy is administered in the case of critical cancer conditions that are life- threatening and require emergency treatment. The purpose of this treatment is to quickly control the growth of primary tumor and metastatic lesions. Patients from out of Massachusetts are admitted to HCC for a week to receive a high-dose of intensive herbal therapy which consists of 3 to 4 different anticancer herbal remedies. Generally, patients take about 15 capsules per medication, every 6 hours. The dose is dependent upon patient’s body weight and physical condition.
  31. 31. ADVANCED STUDY OF NATURAL SOURCES OF ANTI-CANCER AGENTS 31 RGR.SIDDHANTHI COLLEGE OF PHARMACY Tivoli gardens, Patny, Secunderabad. Maintenance Herbal Therapy is indicated for patients who have finished the intensive anticancer herbal therapy and whose cancer conditions are stable. The goal of this treatment is to attain a healing, complete remission, partial remission or extension of life-span. Generally, this treatment is done at home. Patients in Massachusetts should visit HCC weekly or biweekly. Patients from out of Massachusetts should visit HCC monthly or bimonthly, and patients from out of the USA should visit HCC every 2 to 3 months to evaluate the treatment effect. Targeting Herbal Therapy is to use our specific anticancer herbal remedies to target tumors in certain organs or tissues, such as the LDL-110 herbal remedy targets human breast cancer, liver cancer, lung cancer and prostate cancer. It also has high concentration in lymphatic tissue that targets lymphoma and metastases in lymph nodes. Anticancer-2 selectively accumulates in large bowel that targets colorectal carcinoma. Carcinoma of the esophagus and stomach is sensitive to ingredient rabdosia. Anticancer-1 and Anticancer-3 can pass the brain blood barrier (BBB) to target brain tumors and metastases in bony tissue. Combination Herbal Therapy: The anticancer herbal therapies can be used as the first-chosen treatment of conditions of cancer patients. They can also be used in combination with western medicine and radiotherapy for synergetic results. Cancer patients who have failed to chemotherapy or other treatments can still use the hi-tech herbal therapy, which provide a possible chance of healing, complete remission, partial remission or extension of life-span. HCC cooperates with patients’ primary care physicians and oncologists to provide top quality service to clients and protect patients from clinical complications and sideeffects. Side Effects of the hi-tech anticancer herbal remedies are mild, including multiple bowel movements and slight decrease in white blood cell count in approximately 7% of individuals who have had previous medical histories of dysfunction of the digestive system and hemapoietic system. Expected Results: Generally, as demonstrated by CT scan and MRI imaging, patients suffering from malignant tumor or cancer, who have received standard anticancer herbal therapy at HCC, may see a stable cancer condition by 2 months, approximately 20-30% regression of primary tumor and metastatic lesions by 3 months; 30-40% regression of primary tumor and metastatic
  32. 32. ADVANCED STUDY OF NATURAL SOURCES OF ANTI-CANCER AGENTS 32 RGR.SIDDHANTHI COLLEGE OF PHARMACY Tivoli gardens, Patny, Secunderabad. lesions by 6 months; 40-60% regression of primary tumor and metastatic lesions by 9 to 12 months; and further regression of primary tumor and metastatic lesions by continuation treatments. Then, a maintenance anticancer therapy is required to protect the patient from recurrence of cancer condition. One should understand that each patient’s genetics is different from another, each patient’s physical condition is different from another, each patient’s cancer condition is also different from others, and various cancer types have different responses to herbal therapy. Therefore, some of the cancer patients may be healed, and some of them may reach complete remission, while others may obtain partial remission or even no response to the herbal therapy at all. Candidate.Physical.Conditions: * Patients should be positive and confident in fighting against cancer with the hi-tech anticancer herbal therapies. Patients who have enrolled in the herbal therapy program should not give up or discontinue their treatment. * Patients should have good general health, normal meals, no major dysfunction of the heart, lung, liver and kidney, and be able to walk. * Normal appetite and meals are important because the hi-tech anticancer herbal remedies are made in capsule forms that are administered by mouth. * The expected patient’s life-span in pretreatment should be longer than 3 months because we usually see remarkable regression of cancer lesion(s) by 2 to 3 months after starting treatment. * Bring past medical records, pathology diagnosis, recent CT scan and/or MRI image disks (also written reports) when patient visits HCC. These data are available from your primary care physicians and oncologists. (hmcboston.com)
  33. 33. ADVANCED STUDY OF NATURAL SOURCES OF ANTI-CANCER AGENTS 33 RGR.SIDDHANTHI COLLEGE OF PHARMACY Tivoli gardens, Patny, Secunderabad. DISCUSSION: Planning experiments and choosing the activities on which the compound has to be tested, one should have in mind the necessity of balancing between the novelty of pharmacological action and the risk to obtain negative result in experimental testing. Certainly, one will also take into account the particular interest in some kinds of activity, experimental facilities, etc. The accuracy of prediction is about 90%. CONCLUSION:
  34. 34. ADVANCED STUDY OF NATURAL SOURCES OF ANTI-CANCER AGENTS 34 RGR.SIDDHANTHI COLLEGE OF PHARMACY Tivoli gardens, Patny, Secunderabad. All the drugs estimated show a good tendency to fight against the neoplastic cancer, also the drug Irinotecan is against Alzimers disease. Teniposide is not as worthy as others as it is a cardiotoxic and It is suggested that health care professionals and consumers should be aware of the potential for adverse interactions with these herbs, question their patients on their use of them, especially among patients whose disease is not responding to treatments as expected, and urge patients to avoid herbs that could confound their cancer care. BIBLIOGRAPHY: al., b. e. ((2011) 09-26). international journal of phytomedicine 3 . avidon. (1974). chim-pharm.j.(Rus). ayurveda-cancer.org. http://www.ayurveda-cancer.org/cancerdrugs.htm. bhanot. ((2011) 09-26). international journal of phytomedicine . burov, V.V, & korolchenko. (1990). bull. natl. center for biological active compounds(Rus).
  35. 35. ADVANCED STUDY OF NATURAL SOURCES OF ANTI-CANCER AGENTS 35 RGR.SIDDHANTHI COLLEGE OF PHARMACY Tivoli gardens, Patny, Secunderabad. chemocare. (n.d.). http://chemocare.com/chemotherapy/drug- info/vincristine.aspx#.ukK3VdKBk5F . chemocare. http://chemocare.com/chemotherapy/drug-info/etoposide.aspx#.ukK3-dKBk5E. Farnsworth, N., Draus, F., R.W., & Bianculli, J. (n.d.). "studies on vinca major L. (Apocynaceae) I. Isolation of perivicine". Journal of the American pharmaceutical Association 49 (9):589.doi:10.1002/jps.3030490908 . hmcboston.com. http://www.hmcboston.com/HCC/. http:/www.arjournals.org/index.php/ijpm/index. (n.d.). http:/www.digital-recordings.com. http:/www.digital-recordings.com/publ/cancer.html. O'Dwyer PJ, L.-j. B. (1985). current status of an active anticancer drug. New England J Med 312.

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