Plants Used In Cancer Treatment

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Plants Used In Cancer Treatment

• Part - II

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Mayapple - Podophyllum peltatum

• Perennial plant in the barberry family
  (Berberidaceae)
• Description
• Distribution
• Well known poisonous plant

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Traditional uses of mayapple

• Rhizomes dried and ground to a powder
• Powerful purgative
• Also used as a poultice to treat warts and
  tumorous growths on the skin

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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

• Podophyllum peltatum rhizome contains high
  concentrations of anticancer lignans and other
  cmpds (16 in all)
• podophyllotoxin
• a and b peltatin
• Another species - Podophyllum emodii
• podophyllotoxin
• a and b peltatin
• berberine an alkaloid which can be used to
  treat fevers (including malaria) and as an
  antibiotic

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Active compound in mayapple

• In the plant podophyllotoxin exists as a
  glycoside
• Active part is the aglycone

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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
• Genital warts caused by HPV (human
  papillomavirus) associated with cancers of the
  genitals (squamous cell carcinomas)

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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

• 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

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Semi-synthetic derivatives of podophyllotoxin
teniposide
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Etoposide

• Marketed as VePesid or VP-16
• Administered intravenously or orally as liquid
  capsules
• Widely used to treat various types of cancer
• 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

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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
• It does not interfere with microtubule assembly,
  surprisingly since podophyllotoxin does
• Antimitotic by inhibiting DNA synthesis

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Inhibition of DNA synthesis

• Acts by inhibition of DNA topoisomerase II
• DNA topoisomerase enzymes catalyse the transient
  breaking and rejoining of DNA strands
• 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

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Pacific Yew Trees and Taxol
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Taxus yew Conifer in the family Taxaceae
Aril
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Poisonous plants

• 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)

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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
• Occurs in old growth forests in British Columbia,
  Alaska, California, Idaho, Montana, Oregon, and
  Washington
• Many populations are in serious decline

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Development of Taxol

• 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

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Interest increases

• 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
• 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

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Phase I trials - 1983

• 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
• 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

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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

• 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

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Supply remains a problem

• Concern there was not enough trees to treat
  patients
• Survey by Forest Service and Bureau of Land
  Management (funded by Bristol-Myers Squibb) found
  gt100 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

• 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

• French scientists found a semi-synthetic method
  of developing taxol from a molecule in needles of
  Taxus baccata
• 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

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Paclitaxel approval

• 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
• 167 clinical trials for Taxol

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Taxol Side Effects

• Administered by IV because it irritates skin and
  mucous membranes on contact
• Allergic reactions as mentioned
• Other side effects
• abnormally low neutrophil, which can leave the
  patient vulnerable to infection
• abnormally low platelet counts, which can cause
  hard-to-control bleeding
• anemia and bone and muscle pain

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Docetaxel - a derivative

• 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

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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
• Phase I and II clinical studies are on-going for
  colorectal, metastatic breast, and non-small cell
  lung cancer
• Excitement because oral administration possible