DRUG
 A substance used in the diagnosis, treatment, or
prevention of a disease or as a component of a medication
recognized or defined by the U.S. Food, Drug, and
Cosmetic Act.
 A drug is any chemical or biological substance, synthetic
or non-synthetic
The New Drug Development Process
(Steps from Test Tube to New Drug Application Review)
Four categories of drugs used for the treatment of cancers
during the past 50 years. Cytotoxic natural products played a
major role in conventional chemotherapy until the late 1990s
with the advent of molecular targeted therapies using
monoclonal antibodies and small molecule kinase inhibitors
Natural products in 2007 make
a comeback in oncology
Drugs recently approved by FDA for the treatment of
cancers by category of origin
Plant-derived
anticancer agents
Vinca Alkaloids
The first agents to advance into clinical use were the so-called
vinca alkaloids are vinblastine and vincristine
These Alkaloids were isolated from the Madagascar periwinkle,
Catharanthus roseus G. Don. belong to Apocynaceae family.
Traditionally the plant was used for the treatment of diabetes.
These drugs were first discovered during an investigation of the
plant as a source of potential oral hypoglycemic agents.
But, while research investigators could not confirm this activity, it
was noted that extracts reduced white blood cell counts and
caused bone marrow depression in rats, and subsequently it
was found that the treatment of mice bearing a transplantable
lymphocytic leukemia caused significant life extension.
Cont’d
Based on the ‘lead compound’ vincristin and vinblastin, researchers
synthesized their semi-synthetic analogues, vinorelbine and
vindesine
These agents are primarily used in combination with other cancer
chemotherapeutic drugs for the treatment of a variety of cancers.
vinblastine used for the treatment of leukemias, lymphomas,
advanced testicular cancer, breast and lung cancers, and Kaposi’s
sarcoma, and vincristine, in addition to the treatment of
lymphomas, also shows efficacy against leukemias, particularly
acute lymphocytic leukemia in childhood.
Vinorelbine has shown activity against non-small-cell lung cancer and
advanced breast cancer.
Cont’d
The semi-synthetic vinca
alkaloid
vinorelbine,
synthesized from the leaves
of Catharanthus roseus,
was first approved in 1989
in Europe for the i.v.
treatment of non-small cell
lung cancer. In 2001, the
drug was approved as soft
gelatin capsules for oral
treatments of NSCLC
Structures
Taxol
Taxol is known by the generic name Paclitaxel
This compound is a complex polyoxygenated diterpenoid
isolated from the pacific yew, Taxus brevifolia
It was discovered during extensive screening of different
plant materials for antineoplastic agents in the late 1960s
by a systematic research approach
Stages in development paclitaxel as
anticancer drug
1962-68
NCI screening of cytotoxic agents from natural products
1967
Antitumor activity detected
1969
Pure paclitaxel isolated
1971
Structure elucidated
1983
Phase I studies initiated
1986
Hypersensitive reaction observed
1988
NCI suggests premedication regimen
1989
Proved effective against ovarian cancer
1991
Proved effective against non-small cell lung cancer
1992
Approved by US FDA for ovarian cancer
1992
Approved by US FDA for breast cancer
Total synthesis by Nicolaou and Holton, Independently
1994
Approved in India for ovarian cancer
1995
Approved in India for breast cancer
Paclitaxel (Taxol) and Docetaxel
(Taxotere)
O
R2O
R1
NH
O
O
Ph
O
OH
HO
Taxol
OH
R1= C6H5; R2= Ac
Toxotere R1= O
R2= H
H
AcO
BzO
O
Brief Description of Structure and
activity relationship of Taxol
Structure and activity relationship
(SAR) of Taxol
 The removal of C-1-hydroxyl reduces the activity
 The C-2-benzoyloxy is essential for activity. However, some
substituted benzoyloxy groups are also acceptable. Removal of
the 4-acetyl group reduces the activity. The 4,5,20-oxetane
ring is essential for activity
 The derivatization of the C-7-hydroxyl or change of its
stereochemistry has no significant effect on anticancer activity
of the molecule.
 Reduction of 9-ketone slightly increases the activity
 The 10-acetate has better activity in the case of taxol but in
some analogues 10-hydroxyls have better activity
Development of Taxol
 Taxol has poor bioavailability due to its poor solubility in
water
 The widely used technique to solubilize taxol is in a
vehicle cremophore EL (polyethoxylated castor
oil/ethanol)
 Nanoparticle taxol in the form of a drug-eluting stent is
likely to gain FDA approval
Conversion of isotaxel to taxol
under physiological conditions
Isotaxel is nearly 1800-fold
more soluble than taxol
Isotaxel itself is an inactive
molecule, but, at physiological
pH, O–N intramolecular acyl
migration takes place and
within 12 min it converts into
taxol, the active molecule
Problems
 The availability of paclitaxel was a problem due to its poor




abundance in the plant.
Several research groups now have devised the total
synthesis of taxol, but being a complex molecule it is not
economic
T. brevifolia is a slow-growing plant
At age 100 years old, 6-9 m high and have trunk diameter
about 25 cm, provide 1 g taxol
Demand 100-200 kg per annum (2001)
Taxol in Taxus sumatrana (Cemara
Sumatra)
 new source of taxol
 In screening of plants for
source of taxol production,
Lince Yarni, 2007 have isolated
taxol from Taxus sumatrana
(bhs. Cemara Sumatra)
Camptothecin
In the early sixties, the discovery
of camptothecin
as an anticancer drug.
This naturally occurring alkaloid
was first extracted from the
stem wood of the Chinese
ornamental
tree
Camptotheca
acuminata during the screening of
thousands of plants in a search for
steroids
.
Camptothecin
Presently, the first generation analogues of
Camptotechin, hycamtin (Topotecan) and camptosar
(Irinotecan), marketed by Glaxo-SmithKline and
Pfizer, respectively, are used for the treatment of
ovarian and colon cancers
Camptotechin has also been isolated from Ophiorrhiza
pumila and Mapia foetida
.
CPT and its analog
Camptotechin is a member of the quinolinoalkaloid group. It
consists of a pentacyclic ring structure that includes a
pyrrole) quinoline moiety and one asymmetric centre within
the a-hydroxy lactone ring with 20(S) configuration
Structure and activity relationship
O
of CPT
B
A
C N
The planar pentacyclic ring structure
(rings A–E) was suggested to be one of
the most important structural features.
Earlier, it was reported that the complete
pentacyclic ring system is essential for
its activity, but recently reported results
show that the E-ring lactone is not
essential for its activity. However, this
ring in the present lactone form with
specific C-20 configuration is required
for better activity
N
D
E
O
OH
O
Camptothecin analogues
on A and B ring modifications
R3
R4
R2
O
A
R1
B
N
C N
D
E
O
OH
O
Future prospects of CPT
CPT and its analogues exhibit a broad spectrum of
antitumour activity and represent a very promising class
of agents
The discovery of topoisomerases as new targets for cancer
chemotherapy and the mechanism of action of
camptothecin put camptothecin back on the frontlines of
anticancer drug development
Two of the successful drugs, topotecan and irinotecan,
have achieved nearly $750 million in annual sales
Combestratin A-4
Combretastatins are mitotic agents
isolated from the bark of the South
African tree Combretum caffrum
Combretastatin A-4 is a simple stilbene
that has been shown to compete with colchicines for binding sites on
tubulin
It has been found to be a potent cytotoxic agent which strongly inhibits
the polymerization of brain tubulin by binding to the colchicine site
CA-4 shows potent cytotoxicity against a wide variety of human
cancer cell lines
CA-4 is thus an attractive ‘lead molecule’ for the development of
anticancer drugs
Chemical Structure
H3CO
OH
H3CO
OCH3
OCH3
SAR of Combestatin
H CO
3
A
H3CO
OH
B
OCH3
OCH3
•For a minimal cytotoxic activity, a diaryl system should
be separated through a double bond along with a
trimethoxy system in one of the rings
•Trimethoxy benzene moiety is essential for its activity
•The two aryl groups should be separated through a
double bond and the cis (Z) isomer is preferred over the
trans (E) as cis is much more active than trans
Synthetic Analog of Combestatin
Future prospects
A large number of combretastatins has been synthesized and
evaluated, but the main problem associated with this class of
compounds is their poor water solubility
Therefore, the main emphasis on combretastatins research has
been diverted towards watersoluble prodrug
One of the prodrugs, that is CA-4 phosphate, is currently in
phase II clinical trial in the UK and the USA
Podophyllotoxin
Podophyllotoxin and
deoxypodophyllotoxin are two
well-known naturally occurring aryltetralin lignans
Podophyllotoxin, a bioactive lignan, was first isolated in 1880 from the
North American plant Podophyllum peltatum L
Podophyllotoxin was also isolated from several other species like P.
emodi Wall (Indian) and P. pleianthum (Taiwan)
Other than these, 4-deoxypodophyllotoxin has also been isolated from
Anthriscus sylvestris and Pulsatilla koreana
It is a potent cytotoxic agent, two of the semisynthetic derivatives of
PDT, etoposide and teniposide, are currently used in frontline cancer
chemotherapy against various cancers
SAR of PDT
• Only the A and E rings are
essential for its activity
• D-ring in lactone form is
preferred for better activity.
• Modifications at the C-4
position in ring C are mostly
acceptable and bulky groups at
this position enhance both
anticancer and topoisomerase
activities
OH
O
O
O
O
H3CO
OCH3
OCH3
Podophyllotoxin and analogues
Cytotoxicity and DNA topo II inhibition
by ananlogous of podophyllotoxin
Problems in Cancer therapy
Over the years, a number of approaches have been
developed for clinical use and a number of anticancer
drugs have come out of these as a result.
The main problem with these agents is the toxicity
associated with them due to their lack of specificity, as
these agents also kill healthy cells
Other than this, drug resistance is another problem which
arises after some time
Nowadays, combination therapy is used to combat this
problem
Dietary chemopreventive compounds in
active clinical trials
Chemoprotective products found in plant extracts
causing molecular changes
Chemoprotective products found in plant
extracts causing molecular changes ..Cont’d
Herbs and spices can modify microorganism which can stimulate growth within
organisms that protect against cancer as well as within microrganisms that may serve to
increase cancer risk. Culinary herbs and spices generally serve as antioxidants.
Inflammation, tumorigenesis, and carcinogen bioactivation influence cancer risk and
tumor behavior, but interventions which inhibit these processes can contribute to
cancer prevention.
Anticancer activity in vitro and Carcinogenesis
inhibition effect of Red Fruit extract (Pandanus
conoideus Lam) on 7,12-deimethylbenz(a) anthracene
(DMBA)-induced rat cancer
Mun’im et al. 2006, and 2007
Pandanus
Red fruit is a kind of traditional
pieces from Papua. By society
Wamena, Papua, this fruit is
used for seasoning Pandanus
conoideus Lam scientific name
For Red fruit including plant
Families Pandananaceae with pandan-like
pandanus trees, but plant height can reach 16 meters
with its own branch-free stem height as high as 5-8
m, which strengthened the aerial roots of on the
lower trunk
Nutritional composition
It was the intention of the Red Fruit juices contain lots of
antioxidants :
• Carotene (12,000 ppm)
• Beta-carotene (700 ppm)
• Tocopherol (11,000 ppm)
In addition to several other substances that increase
endurance, among others: oleic acid, linoleic acid,
linolenic acid, dekanoat, Omega 3 and Omega 9 which are
all active compounds antidote to the formation of free
radicals in the body
Results
Red fruit extractshows anticancer activity in vitro to HeLa
cell. That results suggested that the extract has strong
anticancer activity ( LC50 = 23.38 μg/ml ) to Leukimia L
1210 cell and low anticancer activity to HeLa cell ( LC50 =
240 μg/ml )
Observed Tumor Incidence on
Organ after incision
Histology of lungs tissue with normal alveolus cell,
thickness in alveolus cell, cancer cell proliferation, and
cancer
Conclusions
 Red fruit extract demonstrated strong anticancer activity
in vitro to Leukemia L 1210 cell, but showed weak activity
to HeLa cell
 Based on lung histology examination shows that the
extract statistically does not cause significance effect, but
at dose 0,21 ml/200g bw can inhibit lungs cancer
carcinogenesis DMBA -induced rats
Antitumor Effects of Pandanus conoideus in in vitro and in vivo Studies
Toshiaki NISHIGAKI1,2, Kunitaka HIROSE3 and Hidekazu SHIGEMATSU1,2
1 Department of Histopathology, School of Medicine, Shinshu University (3-3-1 Asahi, Matsumoto,
Nagano 390-8621 Japan)
2 Research Association of Tropical Medicinal Plants (1286-18 Yamato, Azusagawa, Matsumoto,
Nagano 390-1701 Japan)
3 Effector Cell Institute (4-7-7 Aobadai, Meguro, Tokyo 153-0042 Japan)
Pandanus conoideus (Buah Merah) is exclusively grown in Papua
island and its neighbor areas and the inhabitants have been utilizing
its extract oil (SBM) as functional food for tens thousands years. The
extract found relatively higher quantity of carotenoids which consists
of a- and b-carotene as well as a- and b-cryptoxanthin in SBM. bcryptoxanthin is a novel micronutrient to associate with reduced risk
of some types of cancers. The researcher evaluated antitumor
potentials of SBM in the in vitro and in vivo studies. In the in vitro
study, human non-small lung cancer cells, A549 were inhibited on
cell proliferation at more than 500 μg/mL of SBM in MTT assay. The
in vivo antitumor activity of SBM was evaluated using mouse
Sarcoma180, mouse Lewis lung cancer and A549 models. In any
animal model assays, SBM demonstrated significant antitumor
effects in either tumor volumes or tumor weights. From the
experiment using nude mice in A549 assay, antitumor effect of SBM
may not be associated with immunological involvement. Buah Merah
has higher potentials in prevention of cancers, especially lung cancer
Other research
 Inhibition carcinogenesis combination of Neem
(Azadirachta indica) leaves and Curcuma zedoaria
Rhizoma extracts on 7,12-DMBA-induced rat
cancer(Mun’im et al, 2009)
 Inhibition carcinogenesis of Brucea javanica leaves
extracts on 7,12-DMBA-induced rat cancer (Marisa
et al, 2010)
Natural products potentiates
anticancer activity of conventional
anticancer
 Lev-Ari et al. 2005. Curcumin synergistically potentiates the growth
inhibitory and pro-apoptotic effects of celecoxib in pancreatic
adenocarcinoma cells. Biomed Pharmacother 59(2): S276-S280.
 Zhao et al. 2010. Wogonin potentiates the antitumor effects of low dose 5fluorouracil against gastric cancer through induction of apoptosis by downregulation of NF-kappaB and regulation of its metabolism. Toxicol Lett,
197(3): 201-21
 Carnesecchi et al. 2004. Geraniol, a component of plant essential oils,
modulates DNA synthesis and potentiates 5-fluorouracil efficacy on human
colon tumor xenografts. Cancer Lett, 215(1): 53-59.
Combination chemoprevention by tomato
and garlic in the hamster buccal pouch
carcinogenesis model
 We evaluated the combined chemopreventive effect of tomato paste and aqueous
garlic extract against DMBA-induced hamster buccal pouch (HBP) carcinogenesis.
Hamsters were divided into 8 groups. Animals in group 1 served as control. Groups
2 through 4 were given tomato, garlic and mixture of tomato and garlic
respectively. The right BP of animals in group 5 were painted with 0.5% DMBA
three times a week. ipid peroxidation, GSH, GPx, GST, GR and GGT as well as
GSH/GSSG ratio were measured in the buccal pouch, liver and erythrocytes at the
end of 14 weeks. Diminished lipid peroxidation in the HBP tumours was associated
with enhanced levels of GSH and GSH-dependent enzymes. In contrast to the
buccal pouch, the liver and erythrocytes of tumour-bearing hamsters exhibited
elevated lipid peroxidation accompanied by compromised antioxidant status.
Although administration of tomato paste and garlic alone significantly reduced the
tumour incidence and tumour burden, combined administration of tomato and
garlic was more effective in inhibiting the development of HBP carcinomas as
revealed by modulation of the cellular redox status. From these results, we suggest
that broader spectrum of chemoprevention with less adverse effects can be
attained through effective combination of functional foods
Chemoprevention of oral cancer in animal models, and
effect on leukoplakias in human patients with
ZengShengPing, a mixture of medicinal herbs
ZSP, a mixture of six medicinal herbs, has been reported to prevent esophageal
squamous cell carcinoma (SCC) in human patients with dysplasia. This study was
designed to investigate the chemopreventive effects of ZSP on oral cancer in animal
models and human patients. In DMBA-induced hamster cheek pouch model, ZSP (6
g/kg BW/day by gavage for 10 weeks) significantly reduced the number of visible
tumor, the tumor volume, and the incidence of SCC. Two biomarkers associated
with cell proliferation, silver stained nucleolar organizer region (AgNOR) and
proliferating cell nuclear antigen (PCNA)-labeling index, were also significantly
suppressed by ZSP treatment (P < 0.01). In the 4-nitroquinoline 1-oxide-induced
oro-esophageal cancer model in mice, ZSP (10% in diet) also significantly reduced
the incidence of tongue SCC from 55.2% to 22.2%, and slightly reduced the
incidence of esophageal SCC from 34.5% to 22.2% . Furthermore, in a RCT on
patients with oral leukoplakia, ZSP (4 x 3 /day for 8–12 months) reduced the size of
oral lesion in 67.8% patients, whereas the placebo was effective in 17% patients .
Such an effect was associated with significant decrease of AgNOR and PCNAlabeling index. In summary, our studies have demonstrated the chemopreventive
effects of ZSP on two animal models of oral cancer, and human patients with oral
A systematic review of the effectiveness of Chinese herbal
medication in symptom management and improvement of quality
of life in adult cancer patients
Molassiotis et al. 2009. Comp Ther Med
The aim of this systematic review was to assess the effectiveness of
Chinese medicinal herbs used concurrently with cancer treatments
in terms primarily of toxicity management but also quality of life and
survival in adult cancer patients. Forty-nine trials met the inclusion
criteria and were reviewed according to standard processes of
systematic reviews. These trials included 3992 patients. All studies
with the exception of one were of low methodological quality. The
vast majority of the studies have shown that Chinese medicinal
herbs improved treatment side effects, quality of life, and
performance status, and some have provided evidence of tumour
regression and increased survival. While no clinical
recommendations can derive from such low quality studies, the
number of studies reporting positive results is high enough to
suggest that Chinese medicinal herbs may have a role in cancer care.
However, more methodologically rigorous studies need to be
developed as a priority before any firm conclusions can be drawn.
Formularium Herbal Indonesia
2011
To promote the use herbal medicinal product in health care
center, Ministry of Health publish some regulations,
among them are:
- Saintifikasi Jamu (Permenkes 003/2010)
- Formularium Herbal Indonesia 2011
This formulary is guidance of the use of herbal therapy for
physician in Formal Health Care Center
Pilot project 2012: 200 Hospitals and Community Health
Centers (Puskesmas ) in Indonesia
Herbal for Cancer in FHI 2011
Current status
Vinca rosea L/ Cataranthus roseus G. Don  data
requested
2. Annona muricata L  data requested
3. Andrographis paniculata (Burm) F. Nees  OK
4. Garcinia mangostana L  data requested
5. Typhonium flagiforme Lodd  data requested
6. Kaemferae rotunda L  OK
1.
Herbal Potency in Cancer Therapy
1. Antineoplastic
Provide anticancer and lead compound
2. Adjuvant/ complement
Synergistic effect with conventional anticancer
3. Reduce side effect from chemotherapy or Radiotherapy
4. Reduce cancer symptoms (Palliative)
5. Cancer prevention
References
Bailly C. 2009. Ready for a comeback of natural products in oncology. Biochem Pharmacol,77: 1447–1457
Fouche et al. 2008. In vitro anticancer screening of South African plants. J Ethnopharmacol, 119: 455–461.
Goswami SK, and Das DK, 2009. Resveratrol and chemoprevention . Cancer Lett, 284: 1–6.
Hail Jr et al. 2008. Cancer chemoprevention: A radical perspective. Free Rad Biol Med, 45: 97–110.
Kaefer CM and Milner JA. 2005. The role of herbs and spices in cancer prevention. Bioorg Med Chem, 13 : 5892–
5908
Li et al. 2011. Implications of cancer stem cell theory for cancer chemoprevention by natural dietary compounds . J
Nutrit Biochem, 22: 799–806
Mun'im A, et al. 2006. Uji hambatan tumorigenesis sari buah merah (Pandanus conoideus Lam.) merek M
terhadap tukis putih betina yang diinduksi dengan 7,12-dimetilbenz(a)antrasen (DMBA). Majalah Ilmu
Kefarmasian, 3(3)
Mun'im et al. 2007. Uji Hambatan Karsinogenesis sari buah merah (Pandanus conoideus Lam) dari perdagangan
terhadap tikus putih betina yang diinduksi DMBA. Acta Pharmaceutica Indonesia , I, 28-33
Neergheen et al. 2010. Targeting specific cell signaling transduction pathways by dietary and medicinal
phytochemicals in cancer chemoprevention. Toxicol, 278 : 229–241
Reddy et al. 2003. Natural products for cancer prevention: a global perspective. Pharmacol Therapeut, 99: 1– 13
Rocha et al. 2001. Natural products in anticancer therapy. Current Opin Pharmacol, 1:364–369.
Russo GL. 2007. Ins and outs of dietary phytochemicals in cancer chemoprevention. Biochem Pharmacol, 74:
533–544.
Srivastava et al. 2005. Plant-based anticancer molecules: A chemical and biological profile of some important
leads. Bioorg Med Chem, 13: 5892–5908