Plants Used In Cancer Treatment

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Plants Used In Cancer Treatment

• Part - I

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Cancer

• Cancer is a diverse group of diseases
  characterized by uncontrolled growth of abnormal
  cells
• Cells divide more frequently than normal cells
  and do so in a disorderly fashion, producing
  tumors and other imbalances in cell numbers .
• Forms of cancer attack all parts of the body and
  victims of all ages
• In US alone over half a million people die from
  cancer each year - 2nd leading cause of death
• Cancer costs billions of dollars in medical
  expenses just in the United States

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Major locations of cancer

• Cancers of the prostate, breast, lung, and colon
  account for 56 of all cases in the U.S.
• These are the leading causes of cancer deaths for
  all racial and ethnic groups
• Lung cancer accounts for only 13 of all cases
  but causes 29 of all cancer deaths, making it
  the leading cause of cancer deaths

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Major types of cancers

• Over 200 types of cancer are known grouped into
  major categories
• Carcinomas
• Sarcomas
• Melanomas
• Teratomas
• Leukemias and Lymphomas

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Carcinomas

• Develop from epithelial cells, such as the inside
  of the cheek or the lining of the intestine
• Can occur in many regions of body - glands,
  ducts, mucus membranes
• esophagus, stomach, colon, intestines

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Sarcomas

• Develop in connective and supporting tissues
  (e.g., muscle, cartilage, bone, fatty tissues)
• Often very malignant increasing rapidly in size
  and invading neighboring tissues

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Melanomas

• Type of skin cancer often occurring on legs,
  neck, and head
• Often spreads rapidly
• Frequently seen as a black mole (containing
  melanin)

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Other Types

• Teratomas arise from embryonic cells that may be
  present in ovary, testicles, and other areas
• Leukemias and lymphomas cancer of blood and lymph
  forming tissues (i.e. bone marrow, spleen,
  thymus) which involve cell divisions in body
  fluids characterized by excess of white blood
  cells

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Cancer Therapy

• Search for cancer cures is relentless
• Plants have figured prominently in folk remedies
  for cancer
• Over 3000 plant species had been used
• Ancient records from Egypt (Ebers Papyrus), from
  India, from Greece, and Rome all contain
  direction for plant use to treat various cancers

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Modern Search for drugs

• Beginning in 1955 National Cancer Institute (one
  of the NIH institute) began intensive screening
  process to find anti-cancer compounds
• Initially screening was just on synthetic
  chemicals - over 400,000 compounds tested
• Expanded to microbial products and then plant
  extracts - initially very few plants

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Search expands to plants

• In the late 1950's National Cancer Institute and
  USDA began major search for plants with
  anti-cancer properties
• Thousands of plants were scientifically screened,
  and several have become standard chemotherapy for
  different forms of cancers
• In early 1980s program was discontinued because
  few new compounds developed
• Problem may have been screening assay because
  only using mouse leukemia cell line

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New screening renewed interest in plants and
other natural products

• Starting in 1985 new screening assays were
  developed by NCI using diverse panel of human
  tumor cell lines
• 60 human cell lines from nine cancer types
  (leukemia, lung, colon, CNS, melanoma, ovarian,
  renal, prostate, and breast)
• Preliminary screening with 3 cell lines and
  positive extracts tested on all 60

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Search continues today

• Search is not over since only a small percentage
  of plants have been screened
• Major push on plants from tropical and
  subtropical regions of world through major
  research institutes
• Missouri Botanical Garden
• New York Botanical Gardem
• University of Chicago
• Also big push on fungi, cyanobacteria, and marine
  organisms
• Especially interested in treatments for solid
  tumors

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Current Plant Based Therapies

• Periwinkle
• Mayapple
• Yew
• Camptotheca
• Lapachol

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Periwinkle - vinca alkaloids

• Catharanthus roseus is known as the common or
  Madagascar periwinkle,
• Formerly classified as Vinca rosea
• Perennial evergreen herb in Apocynaceae
• Originally native to island of Madagascar
• Widely cultivated for hundreds of years and now
  found growing wild in most warm regions of world,
  including the Southern US

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Madagascar Periwinkle

• The plants grow one or two feet high,
• Glossy, dark green leaves (1-2 in. long)
• Flowers all summer
• Flower colors from white to pink to purple

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Traditional uses of periwinkle

• Used to treat a wide assortment of diseases
• In Europe, folk remedy for diabetes for centuries
• In India, juice from the leaves to treat wasp
  stings.
• In Hawaii, boiled to make a poultice to stop
  bleeding.
• In China, an astringent, diuretic and cough
  remedy.
• In Central and South America, homemade cold
  remedy to ease lung congestion and inflammation
  and sore throats
• Throughout the Caribbean, an flower extract to
  treat eye irritation and infections

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Interest in Periwinkle

• Researchers noticed the plant in the 1950's when
  they learned of a tea Jamaicans were drinking to
  treat diabetes
• Two groups began independently working on
  periwinkle
• Univ of Western Ontario - Beer and Noble
  -interested in plant as a possible oral insulin
  - they isolated alkalod - vinblastin
• Eli Lilly Pharmaceuticals - Svoboda -

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Lilly Pharmaceuticals

• Svoboda injected a crude extract of the whole
  periwinkle plant into mice that were infected
  with P-1534 leukemia
• 60-80 of the mice experienced prolonged life
• Lilly produced vinblastin as the drug Velban
• Also synthesized another alkaloid, vincristine
  (VCR), as the drug Oncovin
• First human tests in 1960 - 49 yr old man dying
  of Hodgkins disease - within one week man was
  walking - 4 mos tumor gone

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More alkaloids in periwinkle

• Overall 70 alkaloids have been identified in
  periwinkle
• Some have anticancer properties
• Some lower blood sugar levels
• Some act as hemostatics (arrest bleeding)
• Periwinkles also contain the alkaloids reserpine
  and serpentine, which are powerful tranquilizer

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Use today

• Vincristine and vinblastine major
  chemotherapeutic agents
• Vincristine has been especially effective for
  treating acute childhood leukemia, often with 99
  remission rates
• Vinblastine has been especially effective for
  treating Hodgkin's disease - which had been
  considered a fatal up to that point

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More success

• Vincristine is also a major cure of Wilms' tumor
  (80) and Burkitt's lymphoma (50), when used in
  combination with other drugs
• Both alkaloids also used for other types of
  cancers
• Periwinkle gave researchers hope that some types
  of cancers can be overcome by simple chemotherapy

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Mode of action of vinca alkaloids

• Vinblastine, vincristine, and two sem-synthetic
  derivatives (vindesine and vinorelbine) all have
  the same mode of action
• Inhibit mitosis in metaphase
• Bind to tubulin monomers, thus preventing the
  cell from making the spindles it needs to
  separate the chromosomes
• Some evidence that they also inhibit cells
  ability to synthesize both DNA and RNA

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Potent Drugs

• They are all administered intravenously once a
  week these solutions are
• All fatal if they're administered any other way,
  and can cause a lot of tissue irritation if they
  leak out of the vein.
• Compounds are very similar in structure and have
  the same basic action, they have distinctly
  different effects on the body.

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Vinblastine

• Marketed as Velban
• Half-life in the bloodstream of 24 hours
• Vinblastine is mainly useful for treating
  Hodgkin's disease, lymphocytic lymphoma,
  histiocytic lymphoma, advanced testicular cancer,
  advanced breast cancer, Kaposi's sarcoma
• It also seems to fight cancer by interfering with
  glutamic acid metabolism

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Side effects of vinblastine

• Side effects include hair loss, nausea, lowered
  blood cell counts, headache, stomach pain,
  numbness, constipation and mouth sores
• Bone marrow damage is the typical dose-limiting
  factor
• Cause severe birth defects in lab animals so not
  used on pregnant patients

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Vincristine

• Marketed as Oncovin
• Serum half-life of about 85 hours.
• Used mainly to treat acute leukemia,
  rhabdomyosarcoma, neuroblastoma, Hodgkin's
  disease and other lymphomas.
• Neurotoxicity is the dose limiting factor (it can
  cause damage to the peripheral nervous system)

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Side effects of vincristine

• Same as those found with vinblastine
• Nervous system problems such as sensory
  impairment
• Breathing problems or lung spasms shortly after
  the drug is administered
• Secondary cancers if they receive the drug along
  with other anticancer drugs that are known to be
  carcinogens
• Severe birth defects in animal tests

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Vindesine -semi synthetic

• Marketed as Eldisine and Fildesin
• Serum half-life of about 24 hours
• Mainly to treat melanoma and lung cancers
  (carcinomas) and, with other drugs, to treat
  uterine cancers
• Toxicity and side effects are similar to those of
  vinblastine

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Vinorelbine - semi-synthetic

• Still in clinical trials - will be marketed as
  navelbine if approved
• Clinical trials as a treatment for ovarian cancer
• Seems to have a wider range of antitumor activity
  than the other vinca alkaloids
• In preclinical trials, it showed promise in
  treating epithelial ovarian cancers and, in
  combination with other drugs, non-small-cell lung
  cancers
• Side effects include diarrhea, nausea, hair loss,
  leukopenia