Advanced study of natural sources of anti-cancer

ADVANCED STUDY OF NATURAL SOURCES OF ANTI-CANCER AGENTS
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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

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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.
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).
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

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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

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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.
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.

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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).
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)

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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

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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

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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

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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

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(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

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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.

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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.

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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:

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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:

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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

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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

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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

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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
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
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
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
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
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
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
(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
-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
-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
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
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
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
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
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
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
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
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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