Post on 25-Dec-2015
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– 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
Active Compounds in Rhizome
Podophyllum peltatum rhizome contains high concentrations of anticancer lignans and other cmpds (16 in all) podophyllotoxin and peltatin
Another species - Podophyllum emodii podophyllotoxin and peltatin berberine – an alkaloid which can be used to treat
fevers (including malaria) and as an antibiotic
Active compound in mayapple
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 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.
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
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
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
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
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
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)
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
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
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
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
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
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 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
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
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
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
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
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