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Plants Used In Cancer Treatment. Part - II. Mayapple - Podophyllum peltatum. Perennial plant in the barberry family (Berberidaceae) Description Distribution Well known poisonous plant. Traditional uses of mayapple. Rhizomes dried and ground to a powder Powerful purgative

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mayapple podophyllum peltatum
Mayapple - Podophyllumpeltatum
  • Perennial plant in the barberry family (Berberidaceae)
  • Description
  • Distribution
  • Well known poisonous plant
traditional uses of mayapple
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
use in cancer chemotherapy
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
active compounds in rhizome
Active Compounds in Rhizome
  • Podophyllumpeltatum 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
active compound in mayapple
Active compound in mayapple
  • In the plant podophyllotoxin exists as a glycoside
  • Active part is the aglycone
mode of action of podophyllotoxin
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)
side effects of podophyllotoxin
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.
semi synthetic derivatives
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 Podophyllumemodii from SE Asia but supply is dwindling and USDA scientists are trying to develop mayapple
etoposide
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
side effects of etoposide
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
mode of action of etoposide
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
inhibition of 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
    • 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
slide18

Taxus – yew

Conifer in the family Taxaceae

Aril

poisonous plants
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)
slide20
Yews
  • Widely used as ornamentals - the commonly planted yew is the English yew - Taxus baccata
  • The source of taxol is the Pacific yew - Taxusbrevifolia
    • Occurs in old growth forests in British Columbia, Alaska, California, Idaho, Montana, Oregon, and Washington
    • Many populations are in serious decline
development of taxol
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
interest increases
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
phase i trials 1983
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
problems
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
bark supply
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
supply remains a problem
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 >100 million trees
  • Over 1.6 million pounds of bark harvested in 1991 and again in 1992
  • Need for alternative sources soon realized
new sources identified
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
taxus baccata english yew
Taxus baccata - English yew
  • French scientists found a semi-synthetic method of developing taxol from a molecule in needles of Taxusbaccata
    • 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
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
taxol side effects
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
docetaxel a derivative
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
side effects of taxotere
Side effects of Taxotere
  • Also given intravenously
  • Allergic reactions
  • Skin rashes
  • Edema
  • Abnormally low neutrophil counts
  • Peripheral nervous system disorders
dozens of new derivatives
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