Plants Used In Cancer Treatment Part - II

Mayapple - Podophyllum peltatum n Perennial plant in the barberry family (Berberidaceae) n Description n Distribution n Well known poisonous plant

Traditional uses of mayapple n 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 n Resin from mayapple rhizomes used in cream to treat cancerous tumors, polyps and granulations in traditional medicine n Podophyllin (resin from rhizome) was used by physicians in Missouri, Mississippi, and Louisiana by 1897 for treatment of genital warts

Active Compounds in Rhizome n Podophyllum peltatum rhizome contains high concentrations of anticancer lignans and other cmpds (16 in all)  podophyllotoxin   and  peltatin n 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 n In the plant podophyllotoxin exists as a glycoside n Active part is the aglycone

Mode of action of podophyllotoxin n Podophyllotoxin acts as a cell poison for cells undergoing mitosis n Too toxic for chemotherapy use n 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 n Adverse reactions to topical applications include burning, inflammation n 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 n Etoposide and teniposide are derivatives of phyllotoxin that are much less toxic and are safely used in chemotherapy n Etoposide is much more widely used n Both compounds block the cell cycle in at least two specific places n 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 n Marketed as VePesid or VP-16 n Administered intravenously or orally as liquid capsules n 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 n Major side effects include hair loss, nausea, anorexia, diarrhea, and low leukocyte and platelet counts n Some people have severe allergic reactions to the drug n Can cause genetic damage and may increase a patient's risk of developing leukemia n Causes fetal damage and birth defects

Mode of action of etoposide n Blocks cell division possibly by two or more different actions n At high concentrations etoposide causes lysis of cells entering mitosis n 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 n Acts by inhibition of DNA topoisomerase II n 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 – yew Conifer in the family Taxaceae Aril

Poisonous plants n Arils are the only part of the plant that is not poisonous n All other parts (especially leaves and seeds) contain taxine alkaloids that are deadly to humans or other animals. n 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 n Nevertheless, widely used in traditional medicine (and as poisons)

Yews n Widely used as ornamentals - the commonly planted yew is the English yew - Taxus baccata n 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 n Taxol ( paclitaxel ) is produced from the bark of Taxus brevifolia n Taxol is probably the most significant drug developed through the NCI-USDA program n Bark extract only showed moderate activity in the early screening program against mouse leukemia so only slight interest initially n Wall and Wani at RTI - Paclitaxel was first chemically isolated in 1969 and structure determined in 1971 – a diterpene but complex

Interest increases n In mid to late 70s - paclitaxel shown effect against several human tumor lines n 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 n Almost ended testing on Taxol n Serious problems of toxicity and strong allergic reactions including anaphalaxis n 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 n Problems alleviated by longer infusion times and also by premedication with corticosteroids and antihistamines

Problems n Slow progress in Phase I trials n Supply became more of an issue when Phase II trials showed activity against ovarian cancer in % positive response in refractory cases n This greatly increased the demand for bark

Bark supply n Yield of Taxol was about 0.5 gram per 30 pounds of bark n Average Pacific yew tree that was 100 yrs old yielded 20 lb of bark (3 trees/g) n Usual treatment 2 g/patient (6 trees) n 12,000 women dying yearly from ovarian cancer - 24,000 g of taxol - 72,000 trees n Meanwhile significant activity shown in metastatic breast cancer - 40,000 deaths per year

Supply remains a problem n Concern there was not enough trees to treat patients n Survey by Forest Service and Bureau of Land Management (funded by Bristol- Myers Squibb) found >100 million trees n Over 1.6 million pounds of bark harvested in 1991 and again in 1992 n Need for alternative sources soon realized

New Sources Identified n Other species of Taxus contain taxol even in needles  Although yield much lower it is a renewable resource n Tissue cultures of bark cells promising n Semi-synthesis in the laboratory from precursors in needles n Fungal pathogen on yews also synthesizes taxol

Taxus baccata - English yew n 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) n In 1992 – Holton, FSU scientist, found an easier semi-synthesis method – this became the method for commercial development of Taxol n Dec 1993 – Holton achieved total synthesis

Paclitaxel approval n Paclitaxel is a complex diterpene marketed by Bristol Myers Squibb as Taxol n 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 n Since then approved for other forms of cancer  167 clinical trials for Taxol

Taxol – Side Effects n Administered by IV because it irritates skin and mucous membranes on contact n Allergic reactions as mentioned n 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 n Marketed as Taxotere by Rhone-Poulenc Rorer n Initially approved by FDA in 1996 for localized breast cancer and in 1998 for metastatic breast cancer n Like paclitaxel, it prevents the mitotic spindle from being broken down but mode of action is slightly different - stabilizes microtubule bundles n Clinical trials indicate it may be about twice as effective as paclitaxel n Also tested on carcinomas of the bladder, cervix, lung, and ovaries; on malignant melanoma; and on non-Hodgkin's lymphoma

Side effects of Taxotere n Also given intravenously n Allergic reactions n Skin rashes n Edema n Abnormally low neutrophil counts n Peripheral nervous system disorders

Dozens of New Derivatives n Whole family of taxol derivatives (taxanes) produced by Holton and other FSU scientists n 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