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– 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

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

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

Pacific Yew Trees and Taxol

Taxus Taxus – yew– yew

Conifer in the Conifer in the

family Taxaceaefamily Taxaceae

Aril

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

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