Transcript Plants Used In Cancer Treatment

Plants Used In Cancer Treatment
Part - II
Mayapple - Podophyllum peltatum
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Perennial plant in the
barberry family
(Berberidaceae)
Description
Distribution
Well known poisonous
plant
Traditional uses of mayapple
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Rhizomes dried and ground to a powder
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Powerful purgative
Also used as a poultice to treat warts and
tumorous growths on the skin
Use in cancer chemotherapy
Resin from mayapple rhizomes used in
cream to treat cancerous tumors, polyps and
granulations in traditional medicine
 Podophyllin (resin from rhizome) was used
by physicians in Missouri, Mississippi, and
Louisiana by 1897 for treatment of genital
warts
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Active Compounds in Rhizome
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Podophyllum peltatum rhizome contains high
concentrations of anticancer lignans and other
cmpds (16 in all)
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podophyllotoxin
a and b peltatin
Another species - Podophyllum emodii
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podophyllotoxin
a and b peltatin
berberine – an alkaloid which can be used to treat
fevers (including malaria) and as an antibiotic
Active compound in mayapple
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In the plant
podophyllotoxin exists
as a glycoside
Active part is the
aglycone
Mode of action of podophyllotoxin
Podophyllotoxin acts as a cell poison for
cells undergoing mitosis
 Too toxic for chemotherapy use
 Used in creams as treatment for genital
warts
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 Genital
warts caused by HPV (human
papillomavirus) associated with cancers of the
genitals (squamous cell carcinomas)
Side effects of podophyllotoxin
Adverse reactions to topical applications
include burning, inflammation
 When the drug was being investigated as a
chemotherapy agent, it caused nausea,
vomiting, fever, mouth ulcers, diarrhea,
nervous system problems, seizures, kidney
damage, etc.
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Semi-synthetic derivatives
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Etoposide and teniposide are derivatives of
phyllotoxin that are much less toxic and are safely
used in chemotherapy
Etoposide is much more widely used
Both compounds block the cell cycle in at least
two specific places
Today these are produced from the Podophyllum
emodii from SE Asia but supply is dwindling and
USDA scientists are trying to develop mayapple
Semi-synthetic derivatives of
podophyllotoxin
teniposide
Etoposide
Marketed as VePesid or VP-16
 Administered intravenously or orally as
liquid capsules
 Widely used to treat various types of cancer
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 Testicular
cancer which hasn't responded to
other treatment
 First-line treatment for small-cell lung cancers
 Used for chorionic carcinomas, Kaposi's
sarcoma, lymphomas and malignant melanomas
Side effects of etoposide
Major side effects include hair loss, nausea,
anorexia, diarrhea, and low leukocyte and
platelet counts
 Some people have severe allergic reactions
to the drug
 Can cause genetic damage and may increase
a patient's risk of developing leukemia
 Causes fetal damage and birth defects
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Mode of action of etoposide
Blocks cell division possibly by two or
more different actions
 At high concentrations etoposide causes
lysis of cells entering mitosis
 At low concentrations cells are inhibited
from entering prophase
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 It
does not interfere with microtubule assembly,
surprisingly since podophyllotoxin does
 Antimitotic by inhibiting DNA synthesis
Inhibition of DNA synthesis
Acts by inhibition of DNA topoisomerase II
 DNA topoisomerase enzymes catalyse the
transient breaking and rejoining of DNA
strands
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 The
type I cleaves only one of two stands
 Type II cleaves both strands at the same time,
allowing one DNA duplex to pass through
another
Pacific Yew Trees and Taxol
Taxus – yew
Conifer in the family
Taxaceae
Aril
Poisonous plants
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Arils are the only part of the plant that is not
poisonous
All other parts (especially leaves and seeds)
contain taxine alkaloids that are deadly to humans
or other animals.
Alkaloid is a nervous system depressant that
causes the heart rate to slow or stop - often
remarkably quick - death often in minutes. Horses
or cattle die within 5 minutes are ingesting
Nevertheless, widely used in traditional medicine
(and as poisons)
Yews
Widely used as ornamentals - the commonly
planted yew is the English yew - Taxus
baccata
 The source of taxol is the Pacific yew Taxus brevifolia
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 Occurs
in old growth forests in British
Columbia, Alaska, California, Idaho, Montana,
Oregon, and Washington
 Many populations are in serious decline
Development of Taxol
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Taxol (paclitaxel) is produced from the bark of
Taxus brevifolia
Taxol is probably the most significant drug
developed through the NCI-USDA program
Bark extract only showed moderate activity in the
early screening program against mouse leukemia
so only slight interest initially
1963-1971 Wall and Wani at RTI - Paclitaxel was
first chemically isolated in 1969 and structure
determined in 1971 – a diterpene but complex
Interest increases
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In mid to late 70s - paclitaxel shown effect against
several human tumor lines
Susan Horowitz at Albert Einstein College of
Medicine - paclitaxel had a unique mode of action
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Binds to microtubules and inhibits their
depolymerization into tubulin
This blocks a cell's ability to break down the spindle
during mitosis
With the spindle still in place the cell can't divide into
daughter cells - opposite vinca alkaloids
Phase I trials - 1983
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Almost ended testing on Taxol
Serious problems of toxicity and strong allergic
reactions including anaphalaxis
Toxicity traced back to poor solubility of
paclitaxel in aqueous systems
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This required use of an emulsifying agent called
Cremophore EL (castor oil derivative)
Cremophore EL is known to cause hypersensitivity
Problems alleviated by longer infusion times and
also by premedication with corticosteroids and
antihistamines
Problems
Slow progress in Phase I trials
 Supply became more of an issue when
Phase II trials showed activity against
ovarian cancer in 1987 - 30% positive
response in refractory cases
 This greatly increased the demand for bark
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Bark supply
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Yield of Taxol was about 0.5 gram per 30 pounds
of bark
Average Pacific yew tree that was 100 yrs old
yielded 20 lb of bark (3 trees/g)
Usual treatment 2 g/patient (6 trees)
12,000 women dying yearly from ovarian cancer 24,000 g of taxol - 72,000 trees
Meanwhile significant activity shown in metastatic
breast cancer - 40,000 deaths per year
Supply remains a problem
Concern there was not enough trees to treat
patients
 Survey by Forest Service and Bureau of
Land Management (funded by BristolMyers Squibb) found >100 million trees
 Over 1.6 million pounds of bark harvested
in 1991 and again in 1992
 Need for alternative sources soon realized
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New Sources Identified
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Other species of Taxus contain taxol even in
needles
 Although
yield much lower it is a renewable
resource
Tissue cultures of bark cells promising
 Semi-synthesis in the laboratory from
precursors in needles
 Fungal pathogen on yews also synthesizes
taxol
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Taxus baccata - English yew
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French scientists found a semi-synthetic method of
developing taxol from a molecule in needles of
Taxus baccata
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Also led to the development of a second anti-cancer
compound - docetaxel (Taxotere)
In 1992 – Holton, FSU scientist, found an easier
semi-synthesis method – this became the method
for commercial development of Taxol
Dec 1993 – Holton achieved total synthesis
Paclitaxel approval
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Paclitaxel is a complex diterpene marketed by
Bristol Myers Squibb as Taxol
Approved by FDA in 1992 for ovarian cancer and
in 1994 for breast cancer - first unmodified
secondary plant product approved by FDA in 30
yrs
Since then approved for other forms of cancer
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167 clinical trials for Taxol
Taxol – Side Effects
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Administered by IV because it irritates skin and
mucous membranes on contact
Allergic reactions as mentioned
Other side effects
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abnormally low neutrophil, which can leave the patient
vulnerable to infection
abnormally low platelet counts, which can cause hardto-control bleeding
anemia and bone and muscle pain
Docetaxel - a derivative
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Marketed as Taxotere by Rhone-Poulenc Rorer
Initially approved by FDA in 1996 for localized breast
cancer and in 1998 for metastatic breast cancer
Like paclitaxel, it prevents the mitotic spindle from being
broken down but mode of action is slightly different stabilizes microtubule bundles
Clinical trials indicate it may be about twice as effective as
paclitaxel
Also tested on carcinomas of the bladder, cervix, lung, and
ovaries; on malignant melanoma; and on non-Hodgkin's
lymphoma
Side effects of Taxotere
Also given intravenously
 Allergic reactions
 Skin rashes
 Edema
 Abnormally low neutrophil counts
 Peripheral nervous system disorders
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Dozens of New Derivatives
Whole family of taxol derivatives (taxanes)
produced by Holton and other FSU
scientists
 MAC-321
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 Phase
I and II clinical studies are on-going for
colorectal, metastatic breast, and non-small cell
lung cancer
 Excitement because oral administration
possible