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
Slide 3
The New Drug Development Process (Steps from Test Tube to New
Drug Application Review)
Slide 4
Slide 5
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
Slide 6
Natural products in 2007 make a comeback in oncology Drugs
recently approved by FDA for the treatment of cancers by category
of origin
Slide 7
Plant-derived anticancer agents
Slide 8
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.
Slide 9
Contd 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
Kaposis 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.
Slide 10
Contd 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
Slide 11
Structures
Slide 12
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
Slide 13
Stages in development paclitaxel as anticancer drug 1962-68NCI
screening of cytotoxic agents from natural products 1967Antitumor
activity detected 1969Pure paclitaxel isolated 1971Structure
elucidated 1983Phase I studies initiated 1986Hypersensitive
reaction observed 1988NCI suggests premedication regimen 1989Proved
effective against ovarian cancer 1991Proved effective against
non-small cell lung cancer 1992Approved by US FDA for ovarian
cancer 1992Approved by US FDA for breast cancer Total synthesis by
Nicolaou and Holton, Independently 1994Approved in India for
ovarian cancer 1995Approved in India for breast cancer
Slide 14
Paclitaxel (Taxol) and Docetaxel (Taxotere)
Slide 15
Brief Description of Structure and activity relationship of
Taxol
Slide 16
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
Slide 17
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
Slide 18
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, ON
intramolecular acyl migration takes place and within 12 min it
converts into taxol, the active molecule
Slide 19
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)
Slide 20
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)
Slide 21
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.
Slide 22
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.
Slide 23
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
Slide 24
Structure and activity relationship of CPT The planar
pentacyclic ring structure (rings AE) 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
Slide 25
Camptothecin analogues on A and B ring modifications
Slide 26
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
Slide 27
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
Slide 28
Chemical Structure
Slide 29
SAR of Combestatin 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
Slide 30
Synthetic Analog of Combestatin
Slide 31
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
Slide 32
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
Slide 33
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
Slide 34
Podophyllotoxin and analogues
Slide 35
Cytotoxicity and DNA topo II inhibition by ananlogous of
podophyllotoxin
Slide 36
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
Slide 37
Slide 38
Dietary chemopreventive compounds in active clinical
trials
Slide 39
Chemoprotective products found in plant extracts causing
molecular changes
Slide 40
Chemoprotective products found in plant extracts causing
molecular changes..Contd
Slide 41
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.
Slide 42
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 Munim et
al. 2006, and 2007
Slide 43
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
Slide 44
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
Slide 45
Results Red fruit extractshows anticancer activity in vitro to
HeLa cell. That results suggested that the extract has strong
anticancer activity ( LC 50 = 23.38 g/ml ) to Leukimia L 1210 cell
and low anticancer activity to HeLa cell ( LC 50 = 240 g/ml )
Slide 46
Observed Tumor Incidence on Organ after incision
Slide 47
Histology of lungs tissue with normal alveolus cell, thickness
in alveolus cell, cancer cell proliferation, and cancer
Slide 48
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
Slide 49
Antitumor Effects of Pandanus conoideus in in vitro and in vivo
Studies Toshiaki NISHIGAKI 1,2, Kunitaka HIROSE 3 and Hidekazu
SHIGEMATSU 1,2 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 - and -carotene as well as - and
-cryptoxanthin in SBM. - cryptoxanthin 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 g/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
Slide 50
Slide 51
Other research Inhibition carcinogenesis combination of Neem
(Azadirachta indica) leaves and Curcuma zedoaria Rhizoma extracts
on 7,12-DMBA-induced rat cancer(Munim et al, 2009) Inhibition
carcinogenesis of Brucea javanica leaves extracts on
7,12-DMBA-induced rat cancer (Marisa et al, 2010)
Slide 52
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 5- fluorouracil
against gastric cancer through induction of apoptosis by down-
regulation 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.
Slide 53
Slide 54
Slide 55
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
Slide 56
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 812 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
PCNA- labeling index. In summary, our studies have demonstrated the
chemopreventive effects of ZSP on two animal models of oral cancer,
and human patients with oral leukoplakia
Slide 57
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.
Slide 58
Formularium Herbal Indonesia 2011
Slide 59
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
Slide 60
Herbal for Cancer in FHI 2011
Slide 61
Current status 1. 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
Slide 62
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
Slide 63
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