Plants Used In Cancer Treatment

1
Plants Used In Cancer Treatment

• Part - III

2
Camptotheca acuminata

• Camptotheca acuminata is a deciduous tree in the
  family Nyssaceae (tupelo family)
• Tree is native to southern China and Tibet, where
  it is known as xi shu -Chinese happy tree
• Medications prepared from Camptotheca have been
  used in China for centuries to treat cancer,
  especially cancers of the stomach, liver, and
  leukemia

3
(No Transcript)
4
Camptothecin

• In the late '50s, screening program conducted by
  NCI confirmed that a compound from the tree had
  anticancer properties
• In 1966 a quinoline alkaloid camptothecin (CPT)
  was isolated from bark (and wood)
• Animal studies confirmed anti-cancer properties

5
(No Transcript)
6
Early clinical trials of CPT

• CPT is very insoluble in water so first clinical
  trials used a sodium salt of camptothecin that
  was water soluble
• Clinical trials were suspended because of high
  toxicity and severe side effects
• What was not known at the time was that the
  sodium salt was only 1/10 as active as the
  camptothecin but had all the toxicity

7
Renewed interest

• In 1985 it was discovered that camptothecin
  inhibited topoisomerase I and therefore
  inhibiting DNA replication
• This renewed interest in developing CPT as an
  anticancer drug
• CPT itself too toxicity but researchers developed
  several semi-synthetic derivatives had fewer side
  effects in late 80s

8
Camptothecins

• Camptothecins (CPTs) are the second most
  important source of anti-cancer drugs
• It is expected that CPTs will soon surpass taxol
  as the number one source of natural anti-cancer
  drugs
• 3 semi-synthetic drugs from CPT have already been
  approved by the FDA for the treatment of ovarian,
  colorectal and pancreatic cancer

9
Topotecan

• May 1996 FDA approved topotecan as a treatment
  for advanced ovarian cancers that have resisted
  other chemotherapy drugs
• Topotecan worked as well as or better than Taxol
  in clinical trials
• Manufactured by Smith Kline Beecham
  Pharmeceuticals and is sold under the trade name
  Hycamtin

10
Irinotecan

• June 1996 - injectable irinotecan HCl was
  approved as a treatment for metastatic cancer of
  the colon or rectum
• Marketed by Pharmacia Upjohn under the trade
  name Camptosar.
• Prescribed for colorectal cancer cases that
  haven't responded to standard chemotherapy
  treatment

11
9-Nitro-Camptothecin

• Given provisional approval by FDA for treating
  pancreatic cancer following remarkable success in
  early clinical trials
• Marketed as Rubitecan
• Other CPT derivatives are in clinical trials to
  treat breast cancer, colon cancers, malignant
  melanoma, small-cell lung cancer, and leukemia
• Also testing for anti-viral (anti-HIV) uses

12
Side effects of CPT derivatives

• Major side effects of camptothecin drugs are
  potentially severe diarrhea, nausea, and lowered
  leukocyte counts
• The drugs may also damage bone marrow

13
Source of Camptothecin

• Medicinal harvesting of Camptotheca acuminata has
  resulted in a severe decline of the species in
  China where it is now on the protected species
  list and export of seeds is prohibited
• Fortunately plantings had already been started in
  several US states - unfortunately the yields of
  CPT levels seem to be lower in trees growing in US

14
Camptothecin distribution

• Initially isolated from bark and wood
• Later found to occur in leaves, especially young
  leaves
• Lots of research has been done trying to figure
  out conditions to optimize the synthesis of CPT -
  what conditions stimulate CPT production

15
Lab Synthesis

• Lab synthesis of CPT has been achieved
• However the complete chemical synthesis is not
  cost effective so production of CPT and
  derivatives are still dependent on a natural
  supplies

16
New source of camptothecin

• Scientists in Texas recently developed a new
  source of CPT have now patented
• New variety of species Camptotheca lowreyana
• New cultivar a shrub
• CPT can be extracted from the leaves in 6 months
• Also drought and cold temperature tolerant
• Contains a much higher concentration of CPT
• If developed into a crop, it can easily be
  harvested with machinery rather than by hand,
  thus lowering the production cost

17
Lapacho
18
Lapacho

• Tabebuia impetiginosa is tree in the family
  Bignoniaceae (catalpa family)
• Native to rainforests throughout Central and
  South America -- especially Paraguay, Argentina
  and Brazil
• Bark of this tree and closely related species are
  used in Central and South American folk medicine
  to make a tea that is used to treat a wide range
  of maladies, from arthritis to ulcers to diabetes
  to cancer

19
Lapacho

• Tabebuia is a large genus with over 100 species
  throughout rain forests and highlands in South
  America
• Not all have medicinal uses but several do
• Not all have been studied either for secondary
  products
• Lapacho available as an herbal tea / dietary
  supplement

20
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

21
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

22
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

23
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

24
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
• Also contrary to the studies done in South
  America using lapacho tea

25
Current investigations

• Number of on-going pre-clinical studies using
  beta-lapachone
• Most are still in animal testing phase
• Results look promising
• Mode of action seems to be inhibition of DNA
  topomerase - I but may be different action than
  camptothecins

26
Other on-going studies

• Since beta-lapachone in humans has been limited
  due to its toxicity, derivatives made
• 3-allyl-beta-lapachone has been found to have
  lower toxicity in cell culture tests and may
  prove to be more useful
• Great deal of interest in anti-viral effects of
  beta-lapachone

27
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

28
Other plants

• Many other plants that have anti-cancer
  properties
• Also fungi and bacteria
• Some are used in chemotherapy
• Others in clinical trials
• Others not developed
• Many others not investigated yet