anticancer drugs of plant origin

1. “PLANT DERIVED ANTICANCER AGENTS”
Submitted by
Shaikh Asif Jamil
B Pharm VII SEM
Roll No.99
Project Supervisor
Mr. QAZI YASAR QAISER
B. Pharm
Maulana Azad Educational Trust’s
Y. B. Chavan College of Pharmacy
Dr. Rafiq Zakaria Campus,
Aurangabad - 431001 (M.S.) India.
2021-22

2. Dr. Rafiq Zakaria Campus
Maulana Azad Educational Trust’s
Y.B. Chavan College of Pharmacy
Dr. Rafiq Zakaria Marg, Rauza Bagh, Aurangabad
C E R T I F I C A T E
This is to certify that the project entitled “Plant Derived Anticancer Agents”
Represent the bonafide work of Mr. Shaikh Asif Jamil submitted as project work as
requirement for the degree of Bachelor of Pharmacy. This project work has been
carried out in the Y.B. Chavan College of Pharmacy, affiliated to Dr. Babasaheb
Ambedkar Marathwada University, Aurangabad under the guidance of. Mr. Qazi
Yasar Qaiser.
Date: Dr. ABUBAKAR SALAM BAWAZIR
Place: Aurangabad Principal

3. Dr. Rafiq Zakaria Campus
Maulana Azad Educational Trust’s
Y.B. Chavan College of Pharmacy
Dr. Rafiq Zakaria Marg, Rauza Bagh, Aurangabad
C E R T I F I C A T E
This is to certify that the project entitled “Plant Derived Anticancer Agents”
represent the bonafide work of Mr. Shaikh Asif Jamil submitted as project work as
requirement for the Bachelor of Pharmacy. This project work has been carried out
in the Y.B. Chavan College of Pharmacy, affiliated to Dr. Babasaheb Ambedkar
Marathwada University, Aurangabad under my supervision and guidance.
Date: Mr. QAZI YASAR QAISER
Place: Aurangabad M. Pharm

4. DECLARATION
I, the undersigned Mr. Shaikh Asif Jamil student of B. Pharm. VII semester, of Y. B.
Chavan College of Pharmacy, Aurangabad, hereby declare that the project work
entitled “Plant Derived Anticancer Agents” has been carried out by me under the
supervision and guidance of Mr. Qazi Yasar Qaiser faculty of the Y.B. Chavan
College of Pharmacy, affiliated to Dr. Babasaheb Ambedkar Marathwada University,
Aurangabad, during 2016-17. The content presented in the project is the literature
survey and the same is not submitted to any other college or university for award of
any degree.
Date: Mr. SHAIKH ASIF JAMIL
Place: Aurangabad Roll no.99

5. INDEX
Sr. No. Topic Page No.
1. Introduction 6
2. History 9
3. General classification 12
4. Vinca alkaloids 13
5. Taxanes 16
6. Epipodophyllotoxins 19
7. Camptothecins 21
8. References 23

6. Page | 1
INTRODUCTION
CANCER:
Cancer is a disease characterized by uncontrolled multiplication and spread of abnormal
forms of the body’s own cells. It is the second most common cause of death in the
developed nations (cardiovascular disease has the dubious distinction of heading that
table) and one in three people will be diagnosed with cancer during their lifetime. In the
UK, over 365 000 new cases were reported and mortality in 2006 was in excess of 154
000 (Cancer Research UK). Cancer is responsible for approximately one-quarter of all
deaths in the UK, with lung and bowel cancer comprising the largest category, closely
followed by breast and prostate cancer. Statistics from most other countries in the
developed world tell much the same story. At first sight, incidence figures for the past
100 years or so give the impression that the disease is increasing in developed countries,
but cancer is largely a disease of later life, and with advances in public health and
medical science, many more people now live to an age where they are more liable to
contract cancer. The terms cancer, malignant neoplasm (neoplasm simply means ‘new
growth’) and malignant tumor are synonymous. Both benign and malignant tumors
manifest uncontrolled proliferation, but the latter are distinguished by their capacity for
dedifferentiation, their invasiveness and their ability to metastasis (spread to other parts
of the body). we shall be concerned only with the therapy of malignant neoplasia or
cancer. The appearance of these abnormal characteristics reflects altered patterns of gene
expression in the cancer cells, resulting from inherited or acquired genetic mutations. [16]

7. Page | 2

8. Page | 3
TYPES:
 Carcinoma is a cancer that starts in the skin or the tissues that line other organs.
 The majority of breast, colorectal, kidney, liver, lung, oral, pancreatic, and
prostate cancers are carcinoma.
 Sarcoma is a cancer of connective tissues such as bones, muscles, cartilage, and
blood vessels.
 These tumors are most common in the bones, muscles, tendons, cartilage,
nerves, fat, and blood vessels of your arms and legs
 Leukemia is a cancer of the bone marrow, which creates blood cells.
 Leukemia is cancer of the body's blood-forming tissues, including the bone
marrow and the lymphatic system.
 Lymphoma and myeloma are cancers of the immune system.
 Lymphomas can affect any portion of the lymphatic system, including: bone
marrow, thymus, spleen, tonsils, lymph nodes.
CAUSES OF CANCER: [23]
Main causes of cancer, including hazardous circumstances are:
1. Carcinogens
2. Tobacco products
3. Infectious agents
4. Alcohol consumption
5. Sunlight and ultraviolet radiation
6. Ionizing radiation and radiofrequency electromagnetic fields including mobile
phones
7. Diet and nutrition
8. Physical activity, sedentary behavior and obesity
9. Dietary carcinogens
10. Contamination of air, water, soil, and food
11. Occupational exposure

9. Page | 4
12. Pharmaceutical drugs
SYMPTOMS OF CANCER:
Signs and symptoms caused by cancer will vary depending on what part of the body is
affected. Some general signs and symptoms associated with, but not specific to, cancer,
include:
 Fatigue
 Lump or area of thickening that can be felt under the skin
 Weight changes, including unintended loss or gain
 Skin changes, such as yellowing, darkening or redness of the skin, sores that won't
heal, or changes to existing moles
 Changes in bowel or bladder habits
 Persistent cough or trouble breathing
 Difficulty swallowing
 Hoarseness
 Persistent indigestion or discomfort after eating
 Persistent, unexplained muscle or joint pain
 Persistent, unexplained fevers or night sweats
 Unexplained bleeding or bruising
TREATMENT APPROACH:
There are three main approaches to treating established
cancer—surgical excision, irradiation and drug therapy (often called chemotherapy)—
and the relative value of each of these approaches depends on the type of tumor and the
stage of its development. Chemotherapy may be used on its own or as an adjunct to other
forms of therapy.[17]
Biomarker testing is a way to look for genes, proteins, and other substances (called
biomarkers or tumor markers) that can provide information about cancer. [24]
 Chemotherapy

10. Page | 5
 Hormone therapy
 Hyperthermia
 Immunotherapy
 Photodynamic therapy
 Radiation therapy
 Stem cell transplant
 Surgery
 Targeted therapy
Cell cycle specific Cell cycle specific drugs Cell cycle non-specific drugs
G1-S Phase Etoposide camtothecins
G2-M Phase Etoposide
M Phase Vinca alkaloids, Taxanes
History of plant derived antineoplastic [24]
Cancer is becoming a high-profile disease in developed and developing worlds. In 2007
the WHO published that in 2005, 7.6 million people died from cancer related diseases
with the majority of these people living in low-income countries 49
. In the United States
cancer is the cause of 1 in 4 deaths and in 2010 it was estimated there were over 1.5
million new cases of cancer 50
. Cancer Research UK said in 2012 14.1 million adults
were diagnosed with cancer and 8.2 million people were killed by cancer globally 51
.
Therefore, the demand for a cure and the prevention of cancer is extremely high.
Chemically-derived drugs have been developed and other cancer treatments pre-
exist 11
. However, current methods such as chemotherapy have their limitations due to
their toxic effects on non-targeted tissues furthering human health problems 1
. Therefore,
there is a demand for alternative treatments with naturally-derived anticancer agents with
plants being the desired source.

11. Page | 6
The secondary metabolites in the plant kingdom such as polyphenols, flavonoids and
brassinosteroids have been studied for their potential use as anticancer agents.
Collectively they have been shown to possess anticancer activities which include;
antioxidant activity; inhibition of cancer cell growth; induction of apoptosis; target
specificity; cancer cell cytotoxicity 18-19,25,40
. Plant-derived drugs have been developed
from positive results in research and have progressed into clinical trials (below table).
Drugs derived from vinca alkaloids were some of the first compounds to be utilized and
are developing in clinical Phase III trials along with Pacitaxel and other anticancer agents
(below table). These compounds are readily available from the natural environment and
are relatively non-toxic to healthy human cells. Also, there are currently developments
using new technologies such as nanoparticles to be used in administration of anticancer
compounds and therapies. Their development could be applied to control sustained drug
release and help in aims to create drugs that are tissue specific reducing severe side
effects of treatments.
Increasing demand for plant-derived drugs is putting pressure on high-value
medicinal plants and risking their biodiversity 44
. Increasing populations, urbanization
and deforestation are contributing to species endangerment in developing countries. To
aid conservation of these species germplasm conservation, cryopreservation, tissue
cultures and plant part substitution strategies need to be in place 46
. Mass cultivation of
medicinal plant species and utilizing raw by-products in industries may also help with
conservation 32,48
.
Plant-derived anticancer agents are effective inhibitors of cancer cells lines

12. Page | 7
Plant-derived drugs in research and clinical trials
Anticancer agent Isolated or
derived from:
Compound
activity
Research and
clinical
development
Reference
Paclitaxel (Taxol) Taxane; Taxus
brevifolia L
Microtubule
disruptor; block
mitosis; induce
apoptosis;
microtubules
are
polymerized
and stabilized;
disruption of
spindle
formation;
inhibition of
translational
machinery
In clinical use;
Phase I-III
clinical trials;
early treatment
settings; non-
small lung
cancer, breast
cancer, ovarian
cancer, Kaposi
sarcoma.
Research and
development in
alternative drug
administration
using
nanoparticles,
naocochealtes
and
nanoliposomes.
34,39,41,53-
54
Epipodophyllotoxi
n
Podophyllum
peltatum L.;
Podophyllotoxi
n isomer
Pro-apoptotic
effects; cell
cycle
interference
Lymphomas
and testicular
cancer trials
31,36,53
Vincristine Catharanthus
roseus G. Don;
Vinca alkaloids
Anti-mitotic;
microtubule
inhibitor; bind
to β-tubulin;
microtubule
stabilizers or
destabilizers;
pro-apoptotic
properties and
induce cell
cycle arrest;
anti-tumour
Lymphomas,
sarcomas and
leukaemias; in
clinical use;
combination
trials
30,34,36,53,5
5
Vinblastine Testicular
cancer,
Hodgkins
disease and
lymphoma; in
clinical use;
30,34,36,55

13. Page | 8
Anticancer agent Isolated or
derived from:
Compound
activity
Research and
clinical
development
Reference
activity combination
trials
Vinorelbine Non-small cell
lung cancer;
single and
combination
trials; Phase I-III
30,34,36
Vindesine Clinical trials for
acute
lymphocytic
leukaemia
30,36
Vinflunine Clinical trials for
activity against
solid tumors;
Phase III clinical
trials
30-31
,34
Noscapine Opium poppy
(Papaver
somniferum)
Antiproliferativ
e properties;
microtubule
interfering;
inhibits tumour
growth and
progression
Phase I and
Phase II clinical
trials; limited
progression due
to its limited
solubility;
research into
alternative
administration
of drug using
analogues and
nanotechnology
.
42-43
,60
General classification of plant derived antineoplastic agents
Sr. No. Class of Drugs Principle Constituent
1 Vinca alkaloids Vinblastine, vinorelbine, Vincristine

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2 Taxanes Docetaxel, Paclitaxel
3 Epipodophyllotoxins teniposide, Etoposide
4 Camptothecins irinotecan, Topotecan
1. Vinca Alkaloids:
:[6]
The Source:
The vinca alkaloids are derived from the Madagascar periwinkle (Catharanthus
roseus).[1]
The Principle Members:
:[2] The principal members of the Group are vincristine, vinblastine and vindesine [2]
The Mechanism of Action:
:[3] The drugs bind to tubulin and inhibit its polymerisation into microtubules, preventing
spindle formation in dividing cells and causing arrest at metaphase. Their effects become
manifest only during mitosis. They also inhibit other cellular activities that involve the
microtubules, such as leukocyte phagocytosis and chemotaxis, as well as axonal transport
in neurons.

15. Page | 10
Site-1: Tubulin beta chain
Actions: Inhibitor
General Function: Ubiquitin protein ligase binding;
Specific Function: Tubulin is the major constituent of microtubules. It binds two moles
of GTP, one at an exchangeable site on the beta chain and one at a non-exchangeable site
on the alpha chain. [19]
Site -2: Tubulin alpha 4a chain:
Actions: Inhibitor
General Function: Structural constituent of cytoskeleton
Specific Function: Tubulin is the major constituent of microtubules. It binds two moles
of GTP, one at an exchangeable site on the beta chain and one at a non-exchangeable site
on the alpha chain. [20]
T.S. AND MICROSCOPIC CHARECTERSTICS:
The leaves are green ,roots are pale grey,floweres are vioilet pink-white or carmine-redin
color.the order is charecterstic and taste is bitter. Vinca is an erect,pubescent herb, with
branched tap-root . leaves are simple,petiole,ovate or oblong. Unicostate, reticulate,
entire, brittle with acute apex and glossey appearance. Flowers are bractate. [5]
The Dose: [6]
 Vincristine sulphate 10-30µgm/kg of body weight through i.v.
 Vinblastin sulphate 100µgm/kg of body weight through i.v.

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 Vincristine 1.5–2 mg/m2
 Vinblastin 0.1–0.15 mg/kg i.v. weekly × 3 doses. [18]
The Side Effect:
The vinca alkaloids are relatively non-toxic. Vincristine has very mild myelosuppressive
activity but causes paraesthesias (sensory changes), abdominal pain and muscle weakness
fairly frequently. Vinblastine is less neurotoxicbut causes leukopenia, while vindesine has
both moderate myelotoxicity and neurotoxicity. All members of the group can cause
reversible alopecia. [7]
CONCLUSIONS:
Vinca alkaloids have been generally included in combination chemotherapy regimens for
medicinal therapies. They do not have cross-resistance with drugs that alkylate DNA and
have a different mechanism of action. They have been used to treat diabetes, high blood
pressure and have been used as disinfectants and anti-cancer. The vinca alkaloids have
cytotoxic effects that can arrest the division of cells and causes cell death. There are four
major vinca alkaloids in clinical use: VBL, VRL, VCR and VDS. VCR, VBL and VRL
have been approved for use in the United States. Vinflunine is also a new synthetic vinca
alkaloid, which has been approved in Europe for the treatment of second-line TCCU, is
being developed for other malignancies. Overall, vinca alkaloids have the second most-
used class of cancer drugs and will stay among the original cancer therapies. Different
researches and studies for new vinca alkaloid applications will be carried out in this
regard. [10].
MARKET DRUGS:

17. Page | 12
1. TAXANES [6]
The Source:
These taxanes are derived from a naturally occurring compoundound in the bark of the
yew tree (Taxus spp.).
The Principle Members:
:[2] Paclitaxel and docetaxel
The Mechanism of Action:
:[3] They act on microtubules, stabilising them (in effect ‘freezing’ them) in the
polymerised state, achieving a similar effect to that of the vinca alkaloid

18. Page | 13
T.S. and Microscopic Characteristics: [5]
Leaves
Color: dark green
Taste: bitter
Size: 1-3cm ×1-2cm
Shape: lanceolate, flat. Leaves are arranged spirally on the stem; leaf bases are twisted to
align thee leaves in two flat rows on either side of stem except on erect leading shoots
Bark: thin and scaly brown
Seed cones: each contain one seed which is 4-7 mm surrounded by aril get matured after
6-8months
The Dose:
Paclitaxel is given by135–175 mg/m2 by i.v. infusion over 3 hr, repeated every
3 weeks. intravinfusion and docetaxel by mouth. [18]75–100 mg/m2 i.v. over 1 hr; repeat
at 3 weeks. [6][18]
Paclitaxel for breast cancer 175µg/sq.m for lung cancer 135µg/sq.m
The Side Effect:
Unwanted effects, which can be serious, include bone marrow suppression and
cumulative neurotoxicity. Resistant fluid retention (particularly oedema of the legs)
canoccur with docetaxel. Hypersensitivity to both compounds is liable to occur and
requires pretreatment with corticoster and antihistamines. [7]

19. Page | 14
CONCLUSIONS:
Despite giant leaps made in cancer therapy over the last decades, taxanes remain one of
the most clinically used groups of cancer therapeutics. It is due to their unique, strong,
and very specific binding to tubulin, which causes cell cycle arrest and cell death. There
are, however, certain limitations linked to these substances. First, the production of
taxanes is an extreme ecological burden, since 10 tons of yew material are needed for 1
kg of paclitaxel [208]. Unfortunately, in comparison to novel ecologically suitable
methods, such as biotechnological production, isolation from yew is still much more
profitable. Second, there is a rising problem with cancer cells’ chemoresistance to
taxanes. To overcome this problem, drug combinations including taxanes were developed
and registered for cancer treatment, e.g., taxanes plus platinum, sundry low-molecular
inhibitors, siRNAs, other mitotic poisons, or antibodies. Last but not least, taxanes are
limited by their poor water solubility. Therefore, novel delivery systems and taxane
formulations were developed and are already being marketed, mainly liposomal ones. In
addition, other options, such as various nanoparticle-based systems and taxane
derivatives are under development. A significant effort has been devoted to further
tailoring of anticancer properties of taxanes since they are the first-line drugs for cancer
therapy. This review article is proof of unceasing interest in these compounds. It is
certain that among all cancer therapeutics used in clinics, taxanes will remain the leading
compounds and novel approaches for their higher production will emerge. [9]
Market Drugs: [13]

20. Page | 15
3. Epipodophyllotoxins
:[6]
The Source:
Podophyllum is the dried rhizomes and roots of Podophyllum peltatum L.,
Family: Berberidaceae, known as American Podophyllum; and from Podophyllum
hexandrum Royle (Syn. P. emodi Wall. ex Hook. f. & Th.) usually called Indian
Podophyllum.
The Principle Members: [2]
Teniposide, Etoposide
The Mechanism of Action: [3]
Its mode of action is not clearly known, but it may act by inhibiting mitochondrial
function and nucleosidetransport, as well as having an effect on topoisomerase similar to
doxorubicin
Site of action: DNA topoisomerase 2beta
General Function: Protein kinase c binding
Specific Function: Control of topological states of DNA by transient breakage and
subsequent rejoining of DNA strands. Topoisomerase II makes double-strand breaks.

21. Page | 16
Site of action: DNA topoisomerase 2alpha
General Function: Ubiquitin binding
Specific Function: Control of topological states of DNA by transient breakage and
subsequent rejoining of DNA strands. Topoisomerase II makes double-strand breaks.
Essential during mitosis and meiosis for proper segregation [21]
T.S. And Microscopic Charecterstics: [5]
Th Dose:
[18] 50–100 mg/m2/day i.v. for 5 days, 100–200 mg/day oral.
The Side Effect:
[7] Unwanted effects include nausea and vomiting, myelosuppression and hair loss.
Conclusion:
Several investigations have been performed in biosynthesis of PTOX such as cultivation
of these plants, though they were unsuccessful. Thus, it is important to find alternative
sources to satisfy the pharmaceutical demand for PTOX. Moreover, further preclinical
studies are warranted to explore the molecular mechanisms of these agents in treatment
of cancer and their possible potential to overcome chemoresistance of tumor cells.
Podophyllotoxin (PTOX). [8]

22. Page | 17
Market Drugs: [15]
4. CAMPTOTHECINS: [6]
The Source:
The camptothecins isolated from the stem of the tree Camptotheca acuminata
The Principle Members: [2]
Irinotecan ,Topotecan
The Mechanism of Action: [3]
It binds to and inhibit topoisomerase I, high levels of which occur throughout the cell
cycle.
[22] Both irinotecan and topotecan contain lactone structures, which can be hydrolysed
non-enzymatically into the open-ring form. Under acidic conditions, the equilibrium

23. Page | 18
between the biologically active lactone form and the less active carboxylated form is
generally shifted to the lactone form, whereas at physiological or higher values of pH, the
lactone form is unstable, because hydrolysis to the open form is favored. In addition,
owing to preferential binding of the salt form to serum albumin, the affinity of the
carboxylated form for human serum albumin is estimated to be 100 times higher than that
of the lactone form. In consequence, when irinotecan is given intravenously, more than
95% of the dose is bound to serum albumin as inactive drug, and is therefore at least
transiently unavailable to exert its antineoplastic activity [26–29]
T.S. And Microscopic characteristics: [5]
Leaves and dark green in color with radish petiole. leaves are entire, acuminate, ovate
and lanceolate 8-10cm in length and 3-5cm in width. flowers are red in color
The Dose:
Topotecan -1.5 mg/m2 i.v. over 30 min daily for 5 days every 3 weeks, 4 or more cycles.
Irinitecan 125 mg/m2 i.v. over 90 min, weekly for 4 weeks. [18]
The Side Effect:
[7] Diarrhoea and reversible bone marrow depression occur but, in general, these
alkaloids have fewer unwanted effects than most other anticancer agents.
Conclusion:
11] A compilation of the in vivo trials for the small molecule drugs suggest that
irinotecan and exatecan are the most promising derivatives based on half-life and plasma
AUC values. This conclusion may be supported by the number of clinical trials
completed and ongoing using irinotecan (>250 according to clinicaltrials.gov). This
comparison, however, is not as straightforward when evaluating macromolecular
constructs. While each construct has specific half-life and AUC values associated, a
number of variables play a role in the selection of the optimal construct. Synthetic ease,
linker technology, solubility, drug loading, molecular weight, drug accessibility to
esterases and other proteins and polymer degradability must all be taken into account.

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Market Drugs: [12]

25. Page | 20
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