Plants Used In Cancer Treatment

1. Plants Used In Cancer Treatment Part - II

2. Mayapple - Podophyllumpeltatum • Perennial plant in the barberry family (Berberidaceae) • Description • Distribution • Well known poisonous plant

5. 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

6. 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

7. 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

8. Active compound in mayapple • In the plant podophyllotoxin exists as a glycoside • Active part is the aglycone

9. 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)

10. 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.

11. 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

12. Semi-synthetic derivatives of podophyllotoxin teniposide

13. 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

14. 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

15. 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

16. 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

17. Pacific Yew Trees and Taxol

18. Taxus – yew Conifer in the family Taxaceae Aril

19. 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)

20. 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

21. 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

23. 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

24. 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

25. 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

26. 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

27. 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

28. 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

29. 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

30. 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

31. 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

32. 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

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

35. 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