Plants Used In Cancer Treatment

1. Plants Used In Cancer Treatment Part - III

2. Camptotheca acuminata – the happy tree

3. Camptotheca acuminata – the happy tree • Tree in the Nyssaceae (Liriodendron family) • Distribution • Use in traditional medicine • Late 1950s - NCI screening • 1966 - a quinoline alkaloid camptothecin (CPT) was isolated from bark (and wood)

5. Early clinical trials of CPT • Solubility problems with CPT • Clinical trials were suspended • Sodium salt was problem • 1985 interest renewed when shown CPT topoisomerase I inhibitor • Late 1980s semi-synthetic derivatives developed with fewer side effects

6. Camptothecins status • Camptothecins (CPTs) are becoming the second most important source of anti-cancer drugs • 2 CPT-derivatives already approved • 4 other CPT-derivatives in phase II or phase III clinical trials

7. Topotecan • Marketed as Hycamtin by Smith Kline Beecham • May 1996 FDA approved topotecan for advanced ovarian cancers that have resisted other drugs • Clinical trials on-going for other cancers

8. Irinotecan • June 1996 - irinotecan approved for metastatic cancer of the colon or rectum • Marketed as Camptosar by Pharmacia & Upjohn • Clinical trials on-going for other cancers

9. Other CPTs • Other CPTs undergoing clinical trials for various forms of cancer • 9-nitrocamptothecin • BAY-38-3441 • Exatecan • 9-aminocamptothecin • CPTs also being investigated as anti-viral drugs, esp anti-HIV

10. Side effects of CPT derivatives • Major side effects of camptothecin drugs • severe diarrhea • nausea • lowered leukocyte counts • possible bone marrow damage

11. Source of CPTs • Population decline of Camptotheca acuminata trees in China • Plantations in US • Found in leaves • Laboratory synthesis • New source of CPTs - Camptotheca lowreyana

12. Lapacho

13. Lapacho • Tabebuia impetiginosa - tree in the family Bignoniaceae (catalpa family) • Distribution • Traditional uses in South America • Available as a dietary supplement

14. Medical Uses • As early as 1873, physicians were aware of the healing action of lapacho bark • Prescribed as a fever-reducer • Used for ulcers, for venereal and rheumatic disorders, skin disorders, especially eczema, herpes • Eliminated pain caused by cancer • Increased production of red blood cells

15. Early work • Active constituent, lapachol, was first isolated in 1884 • In 1896 chemical structure of lapachol was determined • In 1927 lapachol was synthesized • Many other compounds in lapacho • Lapachol and Beta-lapachone have anti-cancer properties

16. Lapachol and Beta-lapachone • Both are simple phenolic compounds • Lapachol is a napthaquinone • Beta-lapachone is a quinone • Both have anti-cancer properties but are both highly toxic

17. Clinical Studies • Clinical studies of lapacho largely carried out in South America by several scientists in Brazil and Argentina • Studies show that extracts of lapacho effective for several different types of cancer • These studies were somewhat primitive by US standards and lacked adequate controls

18. Further Evaluation • NCI did evaluate lapachol • Found to be effective but side effects were too great so dropped further investigation • Some scientists critical of this study because animal testing done in other labs showed much greater potential

19. Current investigations • Number of on-going pre-clinical studies using beta-lapachone • Most are still in animal testing phase • Results look very promising

20. Beta-lapachone activity • Beta-lapachone inhibits DNA Topomerase-I; BUT, cell death occurs at concentrations lower than required for Topo-I inhibition • In tissue culture studies seems to selectively kill cancer cells while leaving normal cells unharmed!!! • Exact mechanism not known but it does activate check-point mediated apoptosis

21. Other on-going studies • Derivative: 3-allyl-beta-lapachone has lower toxicity in cell culture tests and may prove to be more useful • Great deal of interest in anti-viral effects of beta-lapachone

22. Concerns about lapacho teas • Lapacho teas promoted as effective for many different diseases • Because of the availability of lapacho teas as dietary supplements, some concern in the medical community about self-medication • putting off chemotherapy • interactions with current chemotherapy

23. Fumagillin – an angiogenesis inhibitor

24. Aspergillus • Morphological characteristics of the genus Aspergillus • Habitat and distribution • Health effects of the Aspergillus • Allergic diseases • Infections • Toxins • Medicinal compounds

25. Aspergillus fumigatus • Environmental sources • Thermophilic • Human pathogen

26. Fumagillin • Antibiotic from Aspergillus fumigatus • Discovered in 1953 – not widely used for human infections – used for animals • Recent interest as anti-malarial and other protozoan • Accidental discovery led to observation of death of endothelial cell cultures

27. Fumagillin derivative • Animal studies showed fumagillin inhibited vascularization of tumors in mice but quite toxic • Semisynthetic derivatives of fumagillin developed • TNP-470 now in Phase I, II, and III clinical trials for various types of cancer • Inhibits vascularization of tumors by arresting endothelial cell cycle in late G1 stage

28. Other sources • Many other plants, fungi, and bacteria have anti-cancer properties • Some are used in chemotherapy • Others in clinical trials • Others not developed • Many others not investigated yet